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Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer.

ABSTRACT: We explored plasma and urinary concentrations of two members of the vascular endothelial growth factor (VEGF) family and their receptors as potential response and toxicity biomarkers of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The concentrations of VEGF, placental growth factor (PlGF), soluble VEGF receptor 1 (sVEGFR-1), and sVEGFR-2 were measured in plasma and urine at baseline and during treatment. Pretreatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment as well as for acute toxicity in patients with locally advanced rectal cancer treated prospectively in 2002-2008 with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery in a phase I/II trial. Of all biomarkers, pretreatment plasma sVEGFR-1-an endogenous blocker of VEGF and PlGF, and a factor linked with "vascular normalization"-was associated with both primary tumor regression and the development of adverse events after neoadjuvant bevacizumab and chemoradiation. Based on the findings in this exploratory study, we propose that plasma sVEGFR-1 should be further studied as a potential biomarker to stratify patients in future studies of bevacizumab and/or cytotoxics in the neoadjuvant setting.

SUBMITTER: Duda DG

PROVIDER: S-EPMC3061828 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Complete pathological response to bevacizumab and chemoradiation in advanced rectal cancer.

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Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer

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2023-05-31 | GSE233517 | GEO

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Nomogram to predict ypN status after chemoradiation in patients with locally advanced rectal cancer.

Project description:BACKGROUND: Pelvic lymph node (LN) status after preoperative chemoradiotherapy (CRT) is an important indicator of oncologic outcome in patients with locally advanced rectal cancer. The purpose of this study was to develop a nomogram to predict LN status after preoperative CRT in locally advanced rectal cancer patients. METHODS: The nomogram was developed in a training cohort (n=891) using logistic regression analyses and validated in a validation cohort (n=258) from a prospectively registered tumour registry at Asan Medical Center. The model was internally and externally validated for discrimination and calibration using bootstrap resampling. Model performance was evaluated by the concordance index (c-index) and calibration curve. RESULTS: Pretreatment ypT stage, patient age, preCRT tumour differentiation, cN stage, lymphovascular invasion, and perineural invasion were reliable predictors of LN metastasis after preoperative CRT. The nomogram developed using these parameters had c-indices of 0.81 (training) and 0.77 (validation). The calibration plot suggested good agreement between actual and nomogram-predicted LN status after preoperative CRT. CONCLUSIONS: This nomogram improves prediction of LN status after preoperative CRT in patients with locally advanced rectal cancer. It will be useful for counselling patients as well as for the design and stratification of patients in clinical trials.

| S-EPMC4102937 | biostudies-other

Discriminating cancer-related and cancer-unrelated chemoradiation-response genes for locally advanced rectal cancers.

Project description:For patients with locally advanced rectal cancer (LARC) treated with preoperation chemoradiation (pCRT), identifying differentially expressed (DE) genes between non-responders and responders is a common approach for investigating mechanisms of chemoradiation resistance. However, some of such DE genes might be irrelevant to cancer itself but simply reflect the pharmacokinetic differences of the normal tissues. In this study, we adopted the RankComp algorithm to identify DE genes for each of LARC sample compared with its own normal state. Then, we identified genes with significantly different deregulation frequencies between the non-responders and responders, defined as cancer-related pCRT-response genes. Pathway enrichment and protein-protein interaction analyses showed that these genes specifically and intensively interacted with currently known effective genes of pCRT, involving in DNA replication, cell cycle and DNA repair. In contrast, after excluding the cancer-related pCRT-response genes, the other DE genes between non-responders and responders were enriched in many pathways of drug and protein metabolisms and transports, and interacted with both the known effective genes and pharmacokinetic genes. Hence, these two types of DE genes should be distinguished for investigating mechanisms of pCRT response in LARCs.

| S-EPMC5109405 | biostudies-literature

Phase I Trial of Trametinib with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer.

Project description:PurposeThe RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and KRAS, NRAS, and BRAF mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC).Patients and methodsPatients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m2/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples.ResultsPatients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses.ConclusionsThe combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a RAS/RAF-mutant selected population.

| S-EPMC7334091 | biostudies-literature

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