Search

Purpose The human epidermal growth factor receptor 2 (HER2) is an established therapeutic target for various kinds of solid tumors. HER2 amplification occurs in approximately 1% to 6% of colorectal cancer. In this study, we aimed to assess the efficacy and safety of trastuzumab in combination with chemotherapy in HER2-positive metastatic colorectal cancer (mCRC). Materials and Methods An open-label, phase II trial (Clinicaltrials.gov: NCT03185988) was designed to evaluate the antitumor activity of trastuzumab and chemotherapy in HER2-positive digestive cancers excluding gastric cancer in 2017. Patients from this trial with HER2-positive, KRAS/BRAF wild-type, unresectable mCRC were analyzed in this manuscript. Eligible patients were treated with trastuzumab (8 mg/kg loading dose and then 6 mg/kg every 3 weeks) and irinotecan (120 mg/m2 days 1 and 8 every 3 weeks). The primary endpoint was the objective response rate. Results Twenty-one HER2-positive mCRC patients were enrolled in this study. Seven patients (33.3%) achieved an objective response, and 11 patients (52.4%) had stable disease as their best response. The median progression-free survival (PFS) was 4.3 months (95% confidence interval, 2.7 to 5.9). Four of the 21 patients (19.0%) had grade 3 adverse events, including leukopenia, neutropenia, urinary tract infection, and diarrhea. No treatment-related death was reported. Exploratory analyses revealed that high tumor tissue HER2 copy number was associated with better therapeutic response and PFS. Alterations in the mitogen-activated protein kinase pathway, HER2 gene, phosphoinositide 3-kinase/AKT pathway, and cell cycle control genes were potential drivers of trastuzumab resistance in mCRC. Conclusion Trastuzumab combined with chemotherapy is a potentially effective and well-tolerated therapeutic regimen in mCRC with a high HER2 copy number. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitors (ICIs) have dramatically improved survival in advanced gastrointestinal (GI) cancer patients, but also resulted in immune-related adverse events (irAEs). This study aimed to evaluate serological biomarkers of irAEs and treatment response in GI cancer patients. Patients and methods: Metastatic GI cancer patients were enrolled between August 1, 2015, and July 31, 2017. Serum samples were collected at baseline, and a panel of 59 serum biomarkers was tested. The occurrence of irAEs was analyzed, and serological biomarker expression was correlated with irAE incidence and prognosis. Results: Fifty-one patients were enrolled, of whom 47.1% (24/51) were diagnosed with irAEs, including 4 patients (7.8%) with grade 3-5 irAEs. The most common irAE was thyroiditis (9/51, 17.6%), followed by colitis (7/51, 13.7%). The expression of CD28 (P = 0.042), IL-4 (P = 0.033), IL-15 (P = 0.024) and PD-L1 (P = 0.018) was significantly elevated in patients with grade 3-5 irAEs. For organ-specific irAEs, IL-6 levels were higher in patients with thyroiditis and colitis, while IL-22 and SCF levels were higher in patients with colitis. Increased IL-1α, IL-21, LIF, and PIGF-1 levels were significantly associated with myositis incidence, while the serum levels of six cytokines (BTLA, GM-CSF, IL-4, PD-1, PD-L1 and TIM-3) were higher in patients with rash. Prognostic analysis showed that patients with irAEs had better tumor response (P = 0.029), improved PFS (median survival: undefined vs. 2.1 months, P = 0.002), and extended OS (median survival: undefined vs. 4.3 months, P = 0.003). The prognostic value of irAEs was only significant in patients who received anti-PD-1 inhibitors, but not in those who received anti-PD-L1 inhibitors. Besides, elevated BTLA (median OS: not reached vs. 7 months; P = 0.0168) and PD-1 (median OS: not reached vs. 7 months; P = 0.0223) concentrations were associated with longer OS. Conclusions: Serological proteins are promising markers for predicting immune-related toxicity and prognosis in GI cancer patients. Organ-specific irAEs have various cytokine profiles. Although further validation is needed before clinical application, this study provided a direction for identifying patients at risk for irAEs, and guiding patient selection for ICI therapy. [ABSTRACT FROM AUTHOR]

Objective: Immune checkpoint inhibitors (ICIs) have achieved remarkable results in cancer treatments. However, there is no effective predictive biomarker for gastrointestinal (GI) cancer. Methods: We conducted integrative analyses of the genomic and survival data of ICI-treated GI cancer patients from the Memorial Sloan Kettering Cancer Center cohort (MSK-GI, n = 227), the Janjigian cohort (n = 40), and the Peking University Cancer Hospital & Institute cohort (PUCH, n = 80) to determine the possible associations between DNA damage response and repair (DDR) gene mutations and clinical outcomes. Data from The Cancer Genome Atlas database were analyzed to determine the possible correlations between DDR gene mutations and the tumor microenvironment. Results: In the MSK cohort, the presence of ≥ 2 DDR gene mutations was correlated with prolonged overall survival (OS). The Janjigian and PUCH cohorts further confirmed that subgroups with ≥ 2 DDR gene mutations displayed a prolonged OS and a higher durable clinical benefit. Furthermore, the DDR gene mutation load could be considered as an independent prognostic factor, and exhibited a potential predictive value for survival in GI cancer patients treated with ICIs. Mechanistically, we showed that the presence of ≥ 2 DDR gene mutations was correlated with higher levels of tumor mutation burden, neoantigen, and T cell infiltration. Conclusions: The DDR gene mutation status was correlated with favorable clinical outcomes in GI cancer patients receiving ICIs, which could serve as a potential biomarker to guide patient selection for immunotherapy. [ABSTRACT FROM AUTHOR]

Plant height (PH), a crucial trait related to yield potential in crop plants, is known to be typically quantitatively inherited. However, its full expression can be inhibited by a limited water supply. In this study, the genetic basis of the developmental behaviour of PH was assessed in a 150-line wheat (Triticum aestivum L.) doubled haploid population (Hanxuan 10×Lumai 14) grown in 10 environments (year×site×water regime combinations) by unconditional and conditional quantitative trait locus (QTL) analyses in a mixed linear model. Genes that were expressed selectively during ontogeny were identified. No single QTL was continually active in all periods of PH growth, and QTLs with additive effects (A-QTLs) expressed in the period S1|S0 (the period from the original point to the jointing stage) formed a foundation for PH development. Additive main effects (a effects), which were mostly expressed in S1|S0, were more important than epistatic main effects (aa effects) or QTL×environment interaction (QE) effects, suggesting that S1|S0 was the most significant development period affecting PH growth. A few QTLs, such as QPh.cgb-6B.7, showed high adaptability for water-limited environments. Many QTLs, including four A-QTLs (QPh.cgb-2D.1, QPh.cgb-4B.1, QPh.cgb-4D.1, and QPh.cgb-5A.7) coincident with previously identified reduced height (Rht) genes (Rht8, Rht1, Rht2, and Rht9), interacted with more than one other QTL, indicating that the genetic architecture underlying PH development is a network of genes with additive and epistatic effects. Therefore, based on multilocus combinations in S1|S0, superior genotypes were predicted for guiding improvements in breeding for PH. [ABSTRACT FROM PUBLISHER]

A recombinant inbred line (RIL) population with 305 lines derived from a cross of Hanxuan 10 × Lumai 14 was used to identify the dynamic quantitative trait loci (QTL) for plant height (PH) in wheat ( Triticum aestivum L.). Plant heights of RILs were measured at five stages in three environments. Total of seven genomic regions covering PH QTL clusters on different chromosomes identified from a DH population derived from the same cross as the RIL were used as the candidate QTLs and extensively analyzed. Five additive QTLs and eight pairs of epistatic QTLs significantly affecting plant height development were detected by unconditional QTL mapping method. Six additive QTLs and four pairs of epistatic QTLs were identified using conditional mapping approach. Among them, three additive QTLs ( QPh.cgb- 1B.3, QPh.cgb- 4D.1, QPh.cgb- 5B.2) and three pairs of epistatic QTLs ( QPh.cgb- 1B.1– QPh.cgb- 1B.3, QPh.cgb- 2A.1– QPh.cgb- 2D.1, QPh.cgb- 2D.1– QPh.cgb- 5B.2) were common QTLs detected by both methods. Three QTLs ( QPh.cgb- 4D.1, QPh.cgb- 5B.3, QPh.cgb- 5B.4) were expressed under both drought and well-water conditions. The present data are useful for wheat genetic manipulations through molecular marker-assisted selection (MAS), and provides new insights into understanding the genetic mechanism and regulation network underlying the development of plant height in crops. Our result in this study indicated that combining unconditional and conditional mapping methods could make it possible to reveal not only the stable/conserved QTLs for the developmental traits such as plant height but also the dynamic expression feature of the QTLs. [ABSTRACT FROM AUTHOR]