Undetected Micrometastases Research Articles

MILACC study: Did undetected micrometastases impact recurrence in the LACC trial? (1116)

MILACC study: Did undetected micrometastases impact recurrence in the LACC trial? (1116)

Neoadjuvant polychemotherapy in the complex treatment of gastric cancer

Objective. To analyze and systematize data on the use of neoadjuvant chemotherapy in the complex treatment of stomach cancer.Materials and methods. The original publications containing information on the use of neoadjuvant chemotherapy in the complex treatment of gastric cancer deposited in the resources of PubMed and the information portal eLIBRARY.RU have been studied.Results. The most important aspects concerning the use of neoadjuvant polychemotherapy in the complex treatment of gastric cancer have been outlined.Conclusion. According to the available literature data, the use of neoadjuvant chemotherapy can serve as an important factor in preventing the progression of the tumor process due to the impact on undetected micrometastases, but many aspects are not covered sufficiently in scientific publications. Therefore, the study of neoadjuvant chemotherapy in the complex treatment of gastric cancer, including D2 lymphodissection, is currently very relevant.

Up-regulation of pro-angiogenic molecules and events does not relate with an angiogenic switch in metastatic osteosarcoma cells but to cell survival features.

Osteosarcoma (OS) is the most frequent malignant bone tumor, affecting predominantly children. Metastases represent a major clinical challenge and an estimated 80% would present undetectable micrometastases at diagnosis. The identification of metastatic traits and molecules would impact in micrometastasis management. We demonstrated that OS LM7 metastatic cells secretome was able to induce microvascular endothelium cell rearrangements, an angiogenic-related trait. A proteomic analysis indicated a gain in angiogenic-related pathways in these cells, as compared to their parental-non-metastatic OS SAOS2 cells counterpart. Further, factors with proangiogenic functions like VEGF and PDGF were upregulated in LM7 cells. However, no differential angiogenic response was induced by LM7 cells in vivo. Regulation of the Fas-FasL axis is key for OS cells to colonize the lungs in this model. Analysis of the proteomic data with emphasis in apoptosis pathways and related processes revealed that the percentage of genes associated with those, presented similar levels in SAOS2 and LM7 cells. Further, the balance of expression levels of proteins with pro- and antiapoptotic functions in both cell types was subtle. Interestingly and of relevance to the model, Fas associated Factor 1 (FAF1), which participates in Fas signaling, was present in LM7 cells and was not detected in SAOS2 cells. The subtle differences in apoptosis-related events and molecules, together with the reported cell-survival functions of the identified angiogenic factors and the increased survival features that we observed in LM7 cells, suggest that the gain in angiogenesis-related pathways in metastatic OS cells would relate to a prosurvival switch rather to an angiogenic switch as an advantage feature to colonize the lungs. OS metastatic cells also displayed higher adhesion towards microvascular endothelium cells suggesting an advantage for tissue colonization. A gain in angiogenesis pathways and molecules does not result in major angiogenic potential. Together, our results suggest that metastatic OS cells would elicit signaling associated to a prosurvival phenotype, allowing homing into the hostile site for metastasis. During the gain of metastatic traits process, cell populations displaying higher adhesive ability to microvascular endothelium, negative regulation of the Fas-FasL axis in the lung parenchyma and a prosurvival switch, would be selected. This opens a new scenario where antiangiogenic treatments would affect cell survival rather than angiogenesis, and provides a molecular panel of expression that may help in distinguishing OS cells with different metastatic potential.

Precision medicine for adjuvant chemotherapy of resected colorectal cancer.

Colorectal cancer (CRC) is the most common cancer and the second leading cause of cancer death in Japan. Surgical resection is the only curative option for localized disease. However, undetectable micrometastases remaining after curative surgery may cause disease recurrence. Adjuvant chemotherapy aims to eradicate these micrometastases to improve the cure rate. Unfortunately, few reliable prognostic and predictive markers are available that identify patients at high risk for CRC during early‐stage disease. However, promising biomarkers may become available in the near future. Such biomarkers provide information for stratifying a patient's risk and for selecting the optimal treatment. Here, we provide an overview of current relevant prognostic and predictive biomarkers applicable to adjuvant treatment of early‐stage CRC and focus on the future of this field.

Implications of immune-mediated metastatic growth on metastatic dormancy, blow-up, early detection, and treatment.

Metastatic seeding of distant organs can occur in the very early stages of primary tumor development. Once seeded, these micrometastases may enter a dormant phase that can last decades. Curiously, the surgical removal of the primary tumor can stimulate the accelerated growth of distant metastases, a phenomenon known as metastatic blow-up. Recent clinical evidence has shown that the immune response can have strong tumor promoting effects. In this work, we investigate if the pro-tumor effects of the immune response can have a significant contribution to metastatic dormancy and metastatic blow-up. We develop an ordinary differential equation model of the immune-mediated theory of metastasis. We include both anti- and pro-tumor immune effects, in addition to the experimentally observed phenomenon of tumor-induced immune cell phenotypic plasticity. Using geometric singular perturbation analysis, we derive a rather simple model that captures the main processes and, at the same time, can be fully analyzed. Literature-derived parameter estimates are obtained, and model robustness is demonstrated through a time dependent sensitivity analysis. We determine conditions under which the parameterized model can successfully explain both metastatic dormancy and blow-up. The results confirm the significant active role of the immune system in the metastatic process. Numerical simulations suggest a novel measure to predict the occurrence of future metastatic blow-up in addition to new potential avenues for treatment of clinically undetectable micrometastases.

Hepatic micrometastases are associated with poor prognosis in patients with liver metastases from neuroendocrine tumors of the digestive tract

Pathologic examination of hepatic metastasectomies from patients with metastatic small intestinal or pancreatic neuroendocrine tumor frequently reveals micrometastases undetectable by radiologic or macroscopic gross examination. This finding raises the possibility that undetectable micrometastases remain in these patients after metastasectomy. Here we examined liver resections for micrometastases and assessed their impact on prognosis. Hepatic metastasectomies from 65 patients with neuroendocrine tumor of the small intestine (N = 43) or pancreas (N = 22) were reviewed for the presence of micrometastases, which were defined as microscopic tumor foci ≤1 mm in greatest dimension. Medical records were also reviewed for patient demographics, clinical history, and follow-up data. Micrometastasis was identified in 36 (55%) of 65 hepatic resection specimens. More hepatic micrometastases were seen in small intestinal cases than in pancreatic cases (29/43, 67%, versus 7/22, 32%; P < .01). They were typically present within portal tracts, sometimes with extension into the periportal region or sinusoidal spaces away from the portal tracts. Patients without hepatic micrometastases had fewer macrometastases or more R0 hepatic resections than those with micrometastases. The presence of hepatic micrometastases was associated with poor overall survival both before (hazard ratio [HR] 3.43; 95% CI 1.14-10.30; P = .03) and after accounting for confounding variables in stratified Cox regression (HR 4.82; 95% CI 1.0621.79; P = .04). In conclusion, hepatic micrometastases are common in patients with metastatic small intestinal or pancreatic neuroendocrine tumor and are independently associated with poor prognosis. These data suggest that surgical resection of hepatic metastases is likely not curative in these patients.

Significance of SYT8 For the Detection, Prediction, and Treatment of Peritoneal Metastasis From Gastric Cancer.

To develop novel diagnostic and therapeutic targets specific for peritoneal metastasis of gastric cancer (GC). Advanced GC frequently recurs because of undetected micrometastases even after curative resection. Peritoneal metastasis has been the most frequent recurrent pattern after gastrectomy and is incurable. We conducted a recurrence pattern-specific transcriptome analysis in an independent cohort of 16 patients with stage III GC who underwent curative gastrectomy and adjuvant S-1 for screening candidate molecules specific for peritoneal metastasis of GC. Next, another 340 patients were allocated to discovery and validation sets (1:2) to evaluate the diagnostic and predictive value of the candidate molecule. The results of quantitative reverse-transcription PCR and immunohistochemical analysis were correlated with clinical characteristics and survival. The effects of siRNA-mediated knockdown on phenotype and fluorouracil sensitivity of GC cells were evaluated in vitro, and the therapeutic effects of siRNAs were evaluated using a mouse xenograft model. Synaptotagmin VIII (SYT8) was identified as a candidate biomarker specific to peritoneal metastasis. In the discovery set, the optimal cut-off of SYT8 expression was established as 0.005. Expression levels of SYT8 mRNA in GC tissues were elevated in the validation set comprising patients with peritoneal recurrence or metastasis. SYT8 levels above the cut-off value were significantly and specifically associated with peritoneal metastasis, and served as an independent prognostic marker for peritoneal recurrence-free survival of patients with stage II/III GC. The survival difference between patients with SYT8 levels above and below the cut-off was associated with patients who received adjuvant chemotherapy. Inhibition of SYT8 expression by GC cells correlated with decreased invasion, migration, and fluorouracil resistance. Intraperitoneal administration of SYT8-siRNA inhibited the growth of peritoneal nodules and prolonged survival of mice engrafted with GC cells. SYT8 represents a promising target for the detection, prediction, and treatment of peritoneal metastasis of GC.

Abstract P5-07-10: Circulating microRNAs as early predictors of relapse in operable breast cancer

Abstract Background: Metastasis remains a major threat for patients (pts) with operable breast cancer (BC). Recurrence could arise from a state of tumour dormancy during which there is growth restriction of undetectable micrometastases. The expression of dormancy and metastasis related miRNAs was evaluated in the plasma of pts with operable BC obtained before adjuvant therapy in order to discover novel biomarkers for the prediction of relapse. Methods: Plasma miR-21, miR-23b, miR-190, miR-200b and miR-200c expression was assessed by qRT-PCR in 133 pts with early BC (non-relapsed, n=84; relapsed, n=49). Expression was classified as high or low according to the median values and was associated with pts' clinicopathological characteristics and clinical outcome. Results: No correlation was observed between the expression of miRNAs and the clinicopathological characteristics of pts. After a median f-up of 90.5 mo, median Disease Free Interval (DFI) was significantly lower in pts with high compared to low miR-21 [105 mo vs not reached (NR); p=0.001], miR-200c (105.2 mo vs NR; p=0.007), or both miR-21 and miR-200c expression (81.37 mo vs NR; p=0.001). miR-21-high was also associated with decreased median Overall Survival (OS; p=0.041). In multivariate analysis the number of infiltrated axillary lymph nodes (N3 vs N0-N2, HR: 2.86; p= 0.004) and miR-21 expression (high vs low, HR: 2.824; p=0.001) were independent negative prognostic factors for DFI, whereas negative hormone receptor status (HR: 3.062; p=0.024) and miR-21 high (HR: 3.545; p=0.029) independently predicted for worse OS. Moreover, miR-21 expression was higher in pts presenting early relapse (defined as relapse at ≤ 3 yrs) compared to those without relapse at 5 yrs (p=0.032). Furthermore, higher miR-21 (p=0.038), miR-23b (p=0.039), miR-200b (p=0.027) and miR-200c (p&amp;lt;0.001) levels were observed in pts with late relapse (at ≥ 5 yrs) compared to those without relapse. Conclusions: Differential expression levels of metastasis and/or dormancy related circulating miRNAs are encountered before adjuvant therapy in pts with operable BC presenting subsequent relapse compared to non-relapsed pts. In addition, circulating miRNAs could predict for early or late recurrence years before clinical detection of metastases. These results merit prospective validation in an independent pt cohort. Citation Format: Agelaki S, Papadaki C, Stratigos M, Spiliotaki M, Markakis G, Mastrostamatis G, Mavroudis D, Ioannis S. Circulating microRNAs as early predictors of relapse in operable breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-07-10.

Stochastic and Deterministic Models for the Metastatic Emission Process: Formalisms and Crosslinks.

Although the detection of metastases radically changes prognosis of and treatment decisions for a cancer patient, clinically undetectable micrometastases hamper a consistent classification into localized or metastatic disease. This chapter discusses mathematical modeling efforts that could help to estimate the metastatic risk in such a situation. We focus on two approaches: (1) a stochastic framework describing metastatic emission events at random times, formalized via Poisson processes, and (2) a deterministic framework describing the micrometastatic state through a size-structured density function in a partial differential equation model. Three aspects are addressed in this chapter. First, a motivation for the Poisson process framework is presented and modeling hypotheses and mechanisms are introduced. Second, we extend the Poisson model to account for secondary metastatic emission. Third, we highlight an inherent crosslink between the stochastic and deterministic frameworks and discuss its implications. For increased accessibility the chapter is split into an informal presentation of the results using a minimum of mathematical formalism and a rigorous mathematical treatment for more theoretically interested readers.

Treatment for non-small-cell lung cancer and circulating tumor cells.

Surgery is the main curative therapy for patients with localized non-small-cell lung cancer while radiotherapy (RT), alone or with concurrent platinum-based chemotherapy, remains the primary curative modality for locoregionally advanced non-small-cell lung cancer. The risk of distant metastasis is high after curative-intent treatment, largely attributable to the presence of undetected micrometastases, but which could also be related to treatment-related increases in circulating tumor cells (CTCs). CTC mobilization by RT or systemic therapies might either reflect efficient tumor destruction with improved prognosis, or might promote metastasis and thus represent a potential therapeutic target. RT may induce prometastatic biological alterations in CTC at the cellular level, which are detectable by ‘liquid biopsies’, though their rarity represents a major challenge. Improved methods of isolation and ex vivo propagation will be essential for the future of CTC research.

Abstract 1964: Identification of a novel molecule target for the detection, prediction, and treatment of peritoneal metastasis of gastric cancer

Abstract Background: Advanced gastric cancer (GC) frequently recurs because of undetected micrometastases even when disease is localized and patients undergo curative resection. Moreover, peritoneal metastasis is fatal. We aimed to develop novel diagnostic and therapeutic targets specific for peritoneal metastasis of GC to improve management. Methods: We conducted a metastatic pathway-specific transcriptome analysis to identify candidate biomarkers comprising 340 patients allocated to discovery and validation sets (1:2) to evaluate the diagnostic and predictive value. The mRNA and protein levels in primary GC tissues were compared with patients’ clinical characteristics and survival. The effects of siRNA-mediated knockdown on phenotype and fluorouracil sensitivity of GC cells were evaluated in vitro, and the therapeutic effects of siRNAs were evaluated using a mouse xenograft model. Results: Synaptotagmin VIII (SYT8) was identified as a candidate biomarker specific to peritoneal metastasis. SYT8 levels were elevated in the validation set comprising patients with peritoneal recurrence or metastasis. High SYT8 levels were significantly and specifically associated with peritoneal metastasis, and served as an independent prognostic marker for peritoneal recurrence-free survival of patients with stage II/III GC. The survival difference between high and low SYT8 levels was associated with patients who received adjuvant chemotherapy. Inhibition of SYT8 expression by GC cells correlated with decreased invasion, migration, and fluorouracil resistance. Intraperitoneal administration of SYT8-siRNA inhibited the growth of peritoneal nodules and prolonged survival of mice engrafted with GC cells. Conclusions: SYT8 expression represents a promising diagnostic and predictive biomarker for peritoneal metastasis of GC. Citation Format: Mitsuro Kanda, Haruyoshi Tanaka, Dai Shimizu, Daisuke Kobayashi, Chie Tanaka, Hideki Takami, Masamichi Hayashi, Naoki Iwata, Yukiko Niwa, Suguru Yamada, Tsutomu Fujii, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera. Identification of a novel molecule target for the detection, prediction, and treatment of peritoneal metastasis of gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1964. doi:10.1158/1538-7445.AM2017-1964

Circulating microRNAs (miRNAs) as predictors of relapse in early breast cancer (BC).

e23030 Background: Disease relapse is usually a lethal development following treatment of early BC. Recurrence could arise from a state of tumour dormancy during which there is growth restriction of undetectable micrometastases. The expression of dormancy and metastasis related miRNAs was evaluated in the plasma of patients (pts) with early BC obtained before adjuvant therapy in order to discover novel biomarkers for the prediction of relapse. Methods: PlasmamiR-21, miR-23b, miR-190, miR-200b and miR-200c expression was assessed by qRT-PCR in 133 pts with early BC (non-relapsed, n = 84; relapsed, n = 49). Expression was classified as high or low according to the median values. Results: No correlation was observed between the expression of miRNAs and the clinicopathological characteristics of pts. After a median follow-up of 94 mo, median Disease Free Interval (DFI) was significantly lower in pts with high compared to low miR-21 [105.03 mo vs not reached (NR); p= 0.001], miR-200c (105.2 mo vs NR; p= 0.007), or both miR-21 and miR-200c expression (81.37 mo vs NR; p= 0.001). miR-21-high was also associated with decreased median Overall Survival (OS; p= 0.041). In multivariate analysis the number of infiltrated axillary lymph nodes (N3 vs N0-N2, HR: 2.86; p= 0.004) and miR-21 expression (high vs low, HR: 2.824; p= 0.001) were independent negative prognostic factors for DFI, whereas negative hormone receptor status (HR: 3.062; p= 0.024) and miR-21 high (HR: 3.545; p= 0.029) independently predicted for worse OS. Moreover, miR-21 expression was higher in pts with early relapse (defined as relapse at ≤ 3 yrs) compared to non-relapsed at 5 yrs ( p= 0.032). In addition, higher miR-21 ( p= 0.038), miR-23b ( p= 0.039), miR-200b ( p= 0.027) and miR-200c ( p&lt; 0.001) levels were observed in pts with late relapse (at ≥ 5 yrs) compared to those without relapse. Conclusions: Differential expression levels of metastasis and/or dormancy related circulating miRNAs are detectable before adjuvant therapy in pts with early BC presenting subsequent relapse compared to non-relapsed pts. Circulating miRNAs can predict for early or late recurrence years before clinical detection of metastases. These results merit prospective validation in an independent patient cohort.

Does the mobilization of circulating tumour cells during cancer therapy cause metastasis?

Despite progressive improvements in the management of patients with locoregionally confined, advanced-stage solid tumours, distant metastasis remains a very common - and usually fatal - mode of failure after attempted curative treatment. Surgery and radiotherapy are the primary curative modalities for these patients, often combined with each other and/or with chemotherapy. Distant metastasis occurring after treatment can arise from previously undetected micrometastases or, alternatively, from persistent locoregional disease. Another possibility is that treatment itself might sometimes cause or promote metastasis. Surgical interventions in patients with cancer, including biopsies, are commonly associated with increased concentrations of circulating tumour cells (CTCs). High CTC numbers are associated with an unfavourable prognosis in many cancers. Radiotherapy and systemic antitumour therapies might also mobilize CTCs. We review the preclinical and clinical data concerning cancer treatments, CTC mobilization and other factors that might promote metastasis. Contemporary treatment regimens represent the best available curative options for patients who might otherwise die from locally confined, advanced-stage cancers; however, if such treatments can promote metastasis, this process must be understood and addressed therapeutically to improve patient survival.

Identifying Reproducible Molecular Biomarkers for Gastric Cancer Metastasis with the Aid of Recurrence Information.

To precisely diagnose metastasis state is important for tailoring treatments for gastric cancer patients. However, the routinely employed radiological and pathologic tests for tumour metastasis have considerable high false negative rates, which may retard the identification of reproducible metastasis-related molecular biomarkers for gastric cancer. In this research, using three datasets, we firstly shwed that differentially expressed genes (DEGs) between metastatic tissue samples and non-metastatic tissue samples could hardly be reproducibly detected with a proper statistical control when the metastatic and non-metastatic samples were defined by TNM stage alone. Then, assuming that undetectable micrometastases are the prime cause for recurrence of early stage patients with curative resection, we reclassified all the “non-metastatic” samples as metastatic samples whenever the patients experienced tumour recurrence during follow-up after tumour resection. In this way, we were able to find distinct and reproducible DEGs between the reclassified metastatic and non-metastatic tissue samples and concordantly significant DNA methylation alterations distinguishing metastatic tissues and non-metastatic tissues of gastric cancer. Our analyses suggested that the follow-up recurrence information for patients should be employed in the research of tumour metastasis in order to decrease the confounding effects of false non-metastatic samples with undetected micrometastases.

Cathepsin L in tumor angiogenesis and its therapeutic intervention by the small molecule inhibitor KGP94.

A significant proportion of breast cancer patients harbor clinically undetectable micrometastases at the time of diagnosis. If left untreated, these micro-metastases may lead to disease relapse and possibly death. Hence, there is significant interest in the development of novel anti-metastatic agents that could also curb the growth of pre-established micrometastases. Like primary tumor, the growth of metastases also is driven by angiogenesis. Although the role of cysteine protease Cathepsin L (CTSL) in metastasis associated tumor cell functions such as migration and invasion is well recognized, its role in tumor angiogenesis remains less explored. The present study examines the contribution of CTSL to breast cancer angiogenesis and evaluates the anti-angiogenic efficacy of CTSL inhibitor KGP94. CTSL semi-quantitative RT-PCR analysis on breast tissue panels revealed significant upregulation of CTSL in breast cancer patients which strongly correlated with increased relapse and metastatic incidence and poor overall survival. Preclinically, CTSL ablation using shRNA or KGP94 treatment led to a significant reduction in MDA-MB-231 tumor cell induced angiogenesisin vivo. In-vitro assessments demonstrated a significant decrease in various angiogenic properties such as endothelial cell sprouting, migration, invasion, tube formation and proliferation in the presence of KGP94. Microarray analyses revealed a significant upregulation of cell cycle related genes by CTSL. Western blot analyses further confirmed upregulation of members of the cyclin family by CTSL. Collectively, these data indicate that CTSL is an important contributor to tumor angiogenesis and that the CTSL inhibition may have therapeutic utility in the treatment of breast cancer patients.

Potential of activatable FAP-targeting immunoliposomes in intraoperative imaging of spontaneous metastases

Despite intensive research and medical advances met, metastatic disease remains the most common cause of death in cancer patients. This results from late diagnosis, poor therapeutic response and undetected micrometastases and tumor margins during surgery. One approach to overcome these challenges involves fluorescence imaging, which exploits the properties of fluorescent probes for diagnostic detection of molecular structures at the onset of transformation and for intraoperative detection of metastases and tumor margins in real time. Considering these benefits, many contrast agents suitable for fluorescence imaging have been reported. However, most reports only demonstrate the detection of primary tumors and not the detection of metastases or their application in models of image-guided surgery.In this work, we demonstrate the influence of fibroblast activation protein (FAP) on the metastatic potential of fibrosarcoma cells and elucidate the efficacy of activatable FAP-targeting immunoliposomes (FAP-IL) for image-guided detection of the spontaneous metastases in mice models. Furthermore, we characterized the biodistribution and cellular localization of the liposomal fluorescent components in mice organs and traced their excretion over time in urine and feces. Taken together, activatable FAP-IL enhances intraoperative imaging of metastases. Their high accumulation in metastases, subsequent localization in the bile canaliculi and liver kupffer cells and suitable excretion in feces substantiates their potency as contrast agents for intraoperative imaging.

Intravital imaging of the effects of 5-fluorouracil on the murine liver microenvironment using 2-photon laser scanning microscopy.

5-fluorouracil (5FU) is often used in the treatment of colorectal cancer. 5FU improves the median overall and disease-free survival rates and reduces recurrence rates in patients who have undergone curative surgical resection. However, in the adjuvant setting, whether 5FU eradicates clinically undetectable micrometastases in target organs such as the liver, or whether 5-FU inhibits the adhesion of circulating tumor cells has not yet been established. In the present study, 5FU was administered following the inoculation of red fluorescent protein-expressing HT29 cells into green fluorescent protein (GFP)-transgenic nude mice to examine its inhibitory effect. 2-photon laser scanning microscopy was performed at selected time points for time-series imaging of liver metastasis of GFP-transgenic mice. The cell number in vessels was quantified to evaluate the response of the tumor microenvironment to chemotherapy. HT29 cells were visualized in hepatic sinusoids at the single-cell level. A total of 2 hours after the injection (early stage), time-series imaging revealed that the number of caught tumor cells gradually reduced over time. In the 5FU treatment group, no significant difference was observed in the cell number in the early stage. One week after the injection (late stage), a difference in morphology was observed. The results of the present study indicated that 5FU eradicated clinically undetectable micrometastases in liver tissues by acting as a cytotoxic agent opposed to preventing adhesion. The present study indicated that time-series intravital 2-photon laser scanning microscopic imaging of metastatic tumor xenografts may facilitate the screening and evaluation of novel chemotherapeutic agents with less interindividual variability.

Adjuvant and neoadjuvant therapy of tumors of the gastrointestinal tract.

Tumors of the gastrointestinal tract (GIT) - is an extremely heterogeneous group of tumors and characterized by a variety of morphological, genetic characteristics and different approaches to treatment. Most of the tumors can be removed surgically, but as the results of follow-up show, even in case of radical surgical treatment at least half of patients die because of distant metastases. It means that at the time of radical surgery a large number of patients have undetectable micrometastases and therefore the disease is systemic. Adjuvant therapy is a drug therapy after radical surgery, aimed to eradicate distant micrometastases in order to increase overall and disease-free survival. There is no doubt that strong attention of oncologists to the adjuvant treatment of gastrointestinal tumors is dictated by a will to achieve increase in progression-free survival after radical surgery. This period of life of a cancer patient can be equated to a period of temporary recovery when the patient for a considerable length of time does not need any special treatment, leads an active lifestyle and may even go back to work. From the point of view of the public healthcare adjuvant chemotherapy (CT) is the most important. For today research and the searching of optimal regimes of adjuvant chemotherapy of gastrointestinal tumors continue. The basic principle of adjuvant therapy regimen selection - is proved high efficiency in the treatment of metastatic disease. At the same time neoadjuvant regimens are studied. The aim of neoadjuvant chemotherapy is to reduce tumor size, to provide partial destruction of tumor cells (ideally - to achieve complete morphological regression), that allows to performs the operation of smaller volume than the operation that would be performed without neoadjuvant chemotherapy. Currently, principles based on randomized clinical trials with a high level of evidence are established for the selection a regimen of adjuvant and neoadjuvant chemotherapy of gastrointestinal tumors.

Immunotherapy of Metastatic Colorectal Cancer: Prevailing Challenges and New Perspectives.

Patients with recurring or metastatic colorectal cancer (mCRC) have strikingly low long-term survival, while conventional treatments such as chemotherapeutic intervention and radiation therapy marginally improve longevity. Although, many factors involving immunosurveillance and immunosuppression were recently validated as important for patient prognosis and care, a multitude of experimental immunotherapies designed to combat unresectable mCRC have, in few cases, successfully mobilized antitumor immune cells against malignancies, nor conclusively or consistently granted protection, complete remission, and/or stable disease from immunotherapy - of which benefit less than 10% of those receiving therapy. After decades of progress, however, new insights into the mechanisms of immunosuppression, tolerance, and mutation profiling established novel therapies that circumvent these immunological barriers. This review underlines the most exciting methods to date that manipulate immune cells to curb mCRC, including adoptive cell therapy, dendritic cell vaccines, and checkpoint inhibitor antibodies - of which hint at effective and enduring protection against disease progression and undetected micrometastases.

Abstract 4176: Identifying analytes associated with poor prognosis in CRC

Abstract Cancer patients with undetectable micrometastases at the time of diagnosis are in danger of subsequent metastatic growth that worsens their outcome. Therefore, identification of these patients with latent metastases could reduce morbidity and mortality by helping physicians to choose whether to treat with an adjuvant therapy. In colorectal carcinoma (CRC), 20-30% of stage II patients will have a recurrence at a distant site after removal of the primary tumor. In order for cancer cells to metastasize, they must switch to an “invasive phenotype”. To identify molecular changes in cancer that drive invasion, our laboratory previously built a molecular network model of invasive subcellular structures termed invadopodia. Centrality and random walk analyses identified candidate signaling hubs that may control invadopodia formation or activity. To identify which of these hubs control invasion in specific cancers, we are mining reverse phase protein array (RPPA) data from publicly available human tumor datasets. In this study, we focused on analysis of RPPA data from TCGA in CRC patients, segregated by poor prognosis and good prognosis. We tested three different definitions of poor prognosis: recurrence, survival, and TNM status at diagnosis. We found several promising analytes that were significantly associated with each poor prognosis definition, and recurrence provided the best separation of good vs. poor prognosis. Interestingly, many of the analytes significantly associated with survival are involved in apoptosis. Additionally, we refined the analysis by using a subset of patients (stage I-II), which resulted in even better separation of good vs. poor prognosis. We identified several analytes that are already significantly associated with the invadopodia network (src kinase and PI 3-kinase). We also identified some potential new invadopodia regulators, such as Cox2. This method has potential both to improve CRC survival by identifying patients that need adjuvant therapy as well as identify novel drivers of invadopodia. Citation Format: Christi Lynn French, Alissa Weaver. Identifying analytes associated with poor prognosis in CRC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4176. doi:10.1158/1538-7445.AM2014-4176