BACKGROUND:Retrospective data suggest an association between bevacizumab efficacy and the incidence of arterial hypertension (AHT). Additionally, epigenetic mechanisms have been related to AHT. METHODS:This prospective observational study conducted by GEICAM Spanish Breast Cancer Research Group included metastatic breast (MBC) or colorectal (mCRC) cancer patients treated with bevacizumab-containing chemotherapy as first-line treatment. Blood pressure (BP) levels were measured (conventional and 24-h Holter monitoring) at baseline and up to cycle 3. Primary endpoint assessed BP levels increase as predictive factor for progression-free survival (PFS). Germline DNA methylation profile was explored in pre-treatment blood samples; principal component analysis was used to define an epigenetic predictive score for increased BP levels. RESULTS:From Oct-2012 to Jul-2016, 143 (78 MBC and 65 mCRC) patients were included. The incidence of AHT according to guidelines was neither predictive of PFS nor of best overall tumor response (BOR). No statistically significant association was observed with systolic BP nor diastolic BP increment for PFS or BOR. Grade 3 and 4 adverse events were observed in 37 and 5% of patients, respectively. We identified 27 sites which baseline methylation status was significantly associated to BP levels increase secondary to bevacizumab-containing chemotherapy. CONCLUSIONS:Neither the frequency of AHT nor the increase of BP levels were predictive of efficacy in MBC and mCRC patients treated with bevacizumab-containing chemotherapy. CLINICAL TRIAL REGISTRY:ClinicalTrials.gov Identifier: NCT01733628.

Background Hereditary leiomyomatosis and renal cell cancer syndrome is a rare autosomal dominant hereditary syndrome. Previously, we published the largest cohort of FH mutation carriers in Spain and observed a highly recurrent missense heterozygous variant, FH (NM_000143.4):c.1118A > G p.(Asn373Ser), in 104 individuals from 31 apparently unrelated families. Here, we aimed to establish its founder effect and characterize the associated clinical phenotype. Results Haplotype analysis confirmed that families shared a common haplotype (32/38 markers) spanning 0.61–0.82 Mb, indicating this recurrent variant was inherited from a founder ancestor. Cutaneous and uterine leiomyomatosis were diagnosed in 64.6% (64/99) and 98% (50/51) of patients, respectively, and renal cell cancer was present in 10.4% (10/96). The pathogenic FH _c.1118A > G variant is a Spanish founder mutation that originated 12–26 generations ago. We estimate that the variant may have appeared between 1370 and 1720. Individuals carrying this founder mutation had similar frequency of renal cell cancer and a higher frequency of renal cysts and leiomyomas than those in other cohorts of this syndrome. Conclusions In the Spanish province of Alicante there is a high prevalence of HLRCC because of the founder mutation FH c.1118A > G; p.(Asn373Ser). The characterization of founder mutations provides accurate and specific information regarding their penetrance and expressivity. In individuals with suspected HLRCC from the province of Alicante, genetic testing by direct analysis of the founder FH c.1118A > G; p.(Asn373Ser) mutation may be a faster and more efficient diagnostic tool compared with complete gene sequencing.

Hereditary breast and ovarian cancer syndrome (HBOC) is a clinical entity characterized by an increased risk of developing breast and ovarian cancer. The genetic diagnosis is based on the identification of heterozygous germinal variants in HBOC susceptibility genes. However, it has recently been described that constitutional mosaic variants can contribute to the aetiology of HBOC. In constitutional mosaicism, individuals have at least two genotypically distinct populations of cells that arise from an early post-zygote event. The mutational event occurs early enough in development to affect several tissues. It is detected in germinal genetic studies as low variant allele frequency (VAF) variants (<30%) that are generally overlooked during the prioritization process. Constitutional mosaic variants can affect both somatic and germinal cells, and thus can be passed to the offspring and have important consequences for genetic counselling. In this work, we report the c.9648+1G>A mosaic variant in the BRCA2 gene and propose a diagnostic algorithm to deal with potential mosaic findings identified by Next Generation Sequencing (NGS).

Ecuador's geography is very irregular, each region is at a different altitude, rising from sea level to more than 2800 m above sea level. In this sense, the altitude variable becomes important in the behavior of an internal combustion engine. In this work, the behavior of an internal combustion engine with indirect electronic injection is studied at different heights above sea level to facilitate diagnostic tasks. This behavior is determined through the signals emitted by the absolute pressure sensors of the intake manifold and the throttle position, obtained in 11 places with a difference of approximately 500 m in altitude up to 4500 m above sea level. Analysis of these signals indicates the MAP sensor voltage variations are approximately 0.38 V per 1000 m and the engine vacuum decreases approximately 7.7 kPa per 1000 m of the head. Furthermore, the correction ratio made by the electronic control unit ECU on the pulse width and the ignition advance with the height has been determined. These results generated by this research work are important to understand the behavior of engines at altitude and facilitate automotive diagnosis. (c) 2022 Elsevier Ltd. All rights reserved. Selection and peer-review under responsibility of the scientific committee of the Advances in Mechanical Engineering Trends.

The immune system plays a central role in the pathogenesis of cancer, inhibiting as well as promoting effects on tumor development. Tumor-infiltrating lymphocytes (TIL) and PD-L1 expression have been described as factors with prognostic influence in the early stages of breast cancer. However, its relationship to other classical prognostic factors of estimated importance is unknown.

Introduction: Retrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy. Patients and methods: Survival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling. Results: Of 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15-1.48; p < 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13-1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00-1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05-1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21-1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13-1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08-1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS. Conclusion: Considering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function. (C) 2021 Elsevier Ltd, BASO - The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

E-cadherin, encoded by CDH1, is an essential molecule for epithelial homeostasis, whose loss or aberrant expression results in disturbed cell–cell adhesion, increased cell invasion and metastasis. Carriers of CDH1 germline mutations have a high risk of developing diffuse gastric cancer and lobular breast cancer, associated with the cancer syndrome Hereditary Diffuse Gastric Cancer (HDGC). The ubiquitous availability of cancer panels has led to the identification of an increasing amount of “incidental” CDH1 genetic variants that pose a serious clinical challenge. This has sparked intensive research aiming at an accurate classification of the variants and consequent validation of their clinical relevance. The present study addressed the significance of a novel CDH1 variant, G212E, identified in an unusually large pedigree displaying strong aggregation of diffuse gastric cancer. We undertook a comprehensive pipeline encompassing family data, in silico predictions, in vitro assays and in vivo strategies, which validated the deleterious phenotype induced by this genetic alteration. In particular, we demonstrated that the G212E variant affects the stability and localization, as well as the adhesive and anti-invasive functions of E-cadherin, triggering epithelial disruption and disorganization. Our findings illustrate the clinical implication of a complementary approach for effective variant categorization and patient management.

Purpose Germline pathogenic variants are estimated to affect 3–5% of renal cell carcinoma (RCC) patients. However, higher mutational prevalence in non–clear cell RCC (non-ccRCC) and advanced disease has been suggested. Methods To clarify the prevalence of pathogenic germline variants in metastatic RCC, we sequenced 29 cancer susceptibility genes in 294 unselected metastatic RCC cases plus 21 patients with clinical hereditary features. In 145 tumors, genes frequently mutated in RCC were sequenced and methylation was assessed in selected cases. Results Germline variants in RCC predisposition genes ( FH , VHL ) were detected in 1.4% of the unselected metastatic patients, with higher frequency in non-ccRCC versus ccRCC (6.4% and 0.4%; P = 0.0025) and in younger patients ( P = 0.036). Among the 315 studied patients, 14% of non–type 1 papillary cases (4 of 28), all metastatic <1 year after diagnosis, carried a FH germline variant with loss of heterozygosity and tumor genome hypermethylation. Variants in other cancer-associated genes (e.g., MUTYH, BRCA2, CHEK2 ) occurred in 5.1% of the unselected series, with unclear significance for RCC. Conclusion Our findings confirm a high prevalence of pathogenic germline variants in RCC predisposition genes in metastatic non-ccRCC, and highlight that metastatic patients with papillary type 2 or unconventional histologies compatible with FH would benefit from genetic screening.

HLRCC is an autosomal dominant condition due to fumarate hydratase gene (FH) germline pathogenic variants. It is characterized by predisposition to skin and uterine leiomyomas, renal cysts (RCy) and renal cell cancer (RCC). So far, no phenotype/genotype correlations have been described. We aimed to characterize the genetic, clinical, epidemiological and pathological features of RCy and RCC in the largest Spanish series of FH variants carriers. We performed a multicentre, observational, retrospective study of a cohort of 197 patients, 74 index, with genetic diagnosis of HLRCC. We analysed FH pathogenic variants, presence of RCy and RCC, diagnosis age, histology, stage, treatment, survival and known risk factors for RCC as arterial hypertension, tobacco exposure and obesity using the software R v3.6.0. The study was approved by the Hospital General Universitario de Elche Ethics Committee. We identified 27 FH pathogenic variants: 13 missense, 5 frameshift, 4 large deletions, 3 splice site, 2 nonsense. Of 153 patients with radiological records 57 presented RCy (37.3%), which were more frequent in missense variants carriers (p = 0.017). Tobacco exposure (p= 0.076), and obesity (p = 0.058) show a trend to RCy. There were 19 cases of RCC (10.9%) among 175 patients with confirmed clinical information, 11 males/8 females, 7 with RCy. The median age at diagnosis was 37 years, range 10-67. One patient presented 2 synchronous bilateral RCC. Histological patterns were 14 papillary (10 type 2), 4 clear cells, 2 unclassified carcinoma. No significant differences were found by type of variant or risk factors. Six were stage I, 2 stage II, 3 stage III, 4 stage IV, and 4 not available. The median overall survival (mOS) in stages III-IV was 2.9 years [CI 95% 2.4-3.4]. In stages I-II the mOS is not reached. Six patients with metastatic disease received anti-angiogenic treatments with mOS 34.9 months [CI 95%: 29.0-40.9]. RCy were more frequent in missense mutations carriers. The RCC frequency (10.9%) was lower than in other published cohorts. Being papillary type-2 the most frequent histology, other histological patterns do not exclude HLRCC. Anti-angiogenic treatment offered similar results of overall survival than in sporadic RCC.

1580 Background: HLRCC is a hereditary condition with autosomal dominant inheritance due to germline mutations in the fumarate-hydratase gene ( FH). It is characterized by skin leiomyomas (SLM) in 48-84% of individuals, uterine leiomyomas (ULM) in 30-72%, renal cysts (RCy) and renal cell cancer (RCC) in 15-34%. We aimed to describe the genetics, the clinical features and the potential genotype-phenotype associations in the largest cohort of FH mutation carriers from Spain. Methods: We performed a multicenter, observational, retrospective study of individuals with genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records. We analyzed genetic variants and looked for genotype-phenotype associations. Statistical analyses were performed by IBM-SPSS Statistics-v.22. Results: We included 197 individuals (113 women, 84 men), 74 index cases and 123 relatives. Twenty-seven different variants were detected, 26 pathogenic (12 missense, 5 frameshift, 4 large-deletions, 3 splice-site and 2 nonsense) and 1 variant of unknown significance (missense). Of 182 patients with full skin examination, 64.8% presented SLM (median age 36 years; range 8-85). ULM were diagnosed in 90.3% of 103 women with gynecologic exam (median age 30 years; range 17- 55). Hysterectomy was performed in 62.9% (median age 34 years; range 21-54). Of 153 patients with radiological records, 37.3 % presented RCy. Nineteen patients (10.9%) presented RCC, 11 males and 8 females (median age 37 years; range 10-67). The histological diagnoses were: 14 papillary, of which 10 were type 2; 3 clear cell carcinoma and 2 unclassified carcinoma. Six tumors had stage I, 2 stage II, 3 stage III, 4 stage IV, and 4 not available. The median overall survival among patients at stages 3-4 was 2.9 years [1.3-4.5]. Patients with missense pathogenic variants showed higher risk of developing SLM (p = 0.043) and ULM (p = 0.002) than those with loss of function variants. Conclusions: In our cohort, the frequency of RCC (10.9%) is lower than that published in cohorts of similar sample size. The most frequent histology was the papillary type-2; however, other histological patterns do not exclude HLRCC. Individuals with missense pathogenic variants show higher incidence of SLM and ULM.

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants (p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.

Multimodality treatment has been the standard of care for LARC for the past decades, but the optimal sequencing strategy is a matter of debate. The addition of induction or consolidation chemotherapy (CT) to standard neoadjuvant CRT may increase tumour downstaging and anticipate systemic treatment of micrometastatic disease. However, several randomized clinical trials (RCT) have evaluated the role of TNT vs. CRT with inconsistent results, with the small size of most studies possibly leading to an underestimation of the effect of the TNT strategy. We therefore performed a systematic review and MA of RCTs in this setting to synthesize available data and help decision-making. A systematic search was performed through MEDLINE, EMBASE, ESMO and ASCO meeting abstracts up to May 2020 to identify RCTs for neoadjuvant treatment comparing standard neoadjuvant radiotherapy vs. TNT (induction or consolidation CT + RT) followed by surgery. Studies were reviewed by two authors and discrepancies were resolved by consensus or by a third author. Data including pathological complete response (pCR) rate, disease-free survival (DFS), overall survival (OS) and adverse effects (AEs) were extracted. The primary endpoint was the pCR rate. A MA with fixed and random effect models comparing the different regimens with direct comparisons was conducted. Eight RCTs including 2175 patients with stage II-III LARC were identified. Overall, the pooled analysis demonstrated that TNT significantly improved pCR rate (OR= 0.52, 95% CI 0.38-0.71, p < 0.001) and 3 year-DFS (HR=0.73, 95% CI 0.62-0.87, p=0.01). No difference was found in 3 year-OS among treatment strategies (HR=0.89, 95% CI 0.71-1.10). When Short Course RT and CRT trials were analysed separately, a statistically significant benefit in pCR ( HR=0.51,p=0.003; HR 0.7, P=0.02 respectively) and 3 y-DFS rates (HR= 0.75, p=0.003;HR=0.82, P=0.03) was maintained, favouring the TNT strategy. Grade 3-4 AEs were not significantly different in both strategies (OR=1.1; P=0.33). No significant heterogeneity was found among RCTs. The results of direct MA suggest that TNT vs. CRT improves pCR and 3-y DFS rates for patients with LARC. TNT may become a new standard of care in LARC, although longer follow-up is needed to properly assess its impact on OS.

Background: The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients presentwith advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%-10%. The genetic basis is unknown in the majority of families although around 10%-13% of families carry germlinemutations in known genes associated with hereditary cancer and pancreatitis syndromes. Methods: Panel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome. Findings: Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting themultigene phenotype of FPC. Interpretation: The genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development. Funding: This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013-2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund "A way to achieve Europe" (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Tematica de investigacion cooperativa en cancer: RTICC (RD12/0036/0073) and La Asociacion Espanola contra el Cancer: AECC (Grupos Coordinados Estables 2016). (c) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Purpose Several clinical guidelines recommend genetic screening ofDPYD, including coverage of the variants c.1905 + 1G>A(DPYD*2A), c.1679T>G(DPYD*13), c.2846A>T, and c.1129-5923C>G, before initiating treatment with fluoropyrimidines. However, this screening is often inadequate at predicting the occurrence of severe fluoropyrimidine-induced toxicity in patients. Methods Using a complementary approach combining wholeDPYDexome sequencing and insilicoand structural analysis, as well as phenotyping of DPD by measuring uracilemia (U), dihydrouracilemia (UH2), and the UH2/U ratio in plasma, we were able to characterize and interpretDPYDvariants in 28 patients with severe fluoropyrimidine-induced toxicity after negative screening. Results Twenty-five out of 28 patients (90%) had at least 1 variant in theDPYDcoding sequence, and 42% of the variants (6/14) were classified as potentially deleterious by at least 2 of the following algorithms: SIFT, Poly-Phen-2, and DPYD varifier. We identified two very rare deleterious mutations, namely, c.2087G>A (p.R696H) and c.2324T>G (p.L775W). We were able to demonstrate partial DPD deficiency, as measured by the UH2/U ratio in a patient carrying the variant p.L775W for the first time. Conclusion Whole exon sequencing ofDPYDin patients with suspicion of partial DPD deficiency can help to identify rare or new variants that lead to enzyme inactivation. Combining different techniques can yield abundant information without increasing workload and cost burden, thus making it a useful approach for implementation in patient care.

3549 Background: The outcome for mCRC has changed since the introduction of new chemotherapy schedules and targeted therapies, however new predictive biomarkers are needed. bCTCs and BRAF / PIK3CA mutations have been studied as a potential predictive biomarkers. The primary endpoint was progression-free survival (PFS) in pts WT KRAS and <3 bCTCs, according to BRAF/ PIK3CA status. Methods: This is an open, multicentric, randomized phase II trial and included wildtype KRAS mCRC pts (RAS after approval of protocol amendment), younger than ≤70 with <3 bCTCs, ECOG 0-1 and available tissue for molecular analyses. Pts were stratified per number of metastatic organs involved (1 vs >1) and mutation status of BRAF and/or PIK3CA (WT vs MUT) and randomized to group A (FOLFIRI+Bev) or group B (FOLFIRI+Cet). Results: 240 pts (196 WT and 44 MUT: 6 BRAF, 12 PIK3CA and 6 BRAF + PIK3CA) were included. General characteristics per mutation status (WT vs MUT): Mean age (59 vs 61 years), gender (Male/Female 68/32 vs 70/30%), ECOG 0/1 (57/43 vs 66/34%), primary tumor unresected (48 vs 64%), RAS MUT in 12 pts (11 and 1 pts, respectively), previous chemotherapy (12 vs 9%). Overall response rate (ORR) was 52 and 41% in the WT and MUT groups, respectively. PFS and overall survival (OS) are presented in the table. Conclusions: In the low risk mCRC pts according to bCTCs, BRAF and/or PIK3CA MUT have a negative impact in OS and a trend to worse PFS in the ITT population. The impact of treatment is under evaluation and will be provided during the meeting. Clinical trial information: 2012-000840-90. [Table: see text]

痣样基底细胞癌综合征 (NBCCS) 又称 Gorlin 综合征,每 56,000 人中只有一人发病。此类综合征通常为父母遗传,并且男女发病率相同(常染色体显性遗传)。NBCCS 患者可能表现出的典型特征有多手指或脚趾、肋骨不规则、面部形状不规则以及大头症。有时伴肿瘤生长,特别是颌骨囊肿以及皮肤基底细胞瘤 (BCC),该综合征由此得名。NBCCS 是因位于第 9 号染色体长臂的 PTCH1 基因变异(突变)导致的。PTCH1 在 Hedgehog (HH)/GLI 细胞信号通路中的一系列化学过程中起到抑制作用。在 NBCCS 中,突变使 PTCH1 失去活性,导致发出过多的 Hedgehog 信号。这种失控可能导致骨骼和肿瘤异常。在发病家族中,患者具有相同的基因突变,异常情况却大相径庭。来自西班牙的研究组研究了 22 个无亲属关系的西班牙 NBCCS 患者,旨在了解临床特定异常与特异性基因突变之间是否存在任何关联。BCC 非常常见,见于 96% 的患者中,且 43% 的患者年龄在 50 岁以上;77% 出现颌骨囊肿。之前在 NBCCS 中未发现两种异常:双子宫以及良性神经瘤。研究组发现了 19 种之前尚未报道过的 PTCH1 突变。但是,他们未找到任何能将突变类型和临床异常联系起来的模式。因此可假定,除 PTCH1 突变之外的其他因素导致临床特征。

Germline changes in the CDH1 tumor suppressor gene predispose to diffuse gastric cancer and lobular breast cancer. In carriers of deleterious germline CDH1 variants, prophylactic gastrectomy is recommended. In case of germline missense variants, it is mandatory to assess the functional impact on E-cadherin, the protein encoded by CDH1, and to predict their clinical significance. Herein, we have identified a recurrent germline missense variant, c.1679C>G, segregating with gastric cancer in three unrelated Spanish families. Through genetic, transcriptional, in silico and in vitro studies, we demonstrate the deleterious effect of the c.1679C>G variant and its association with hereditary diffuse gastric cancer, providing relevant data to relatives and allowing an accurate genetic counseling.

INTRODUCTION:The aim of this study was to evaluate the efficacy and safety of maintenance therapy with axitinib versus placebo following induction therapy in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS:In this double-blinded, phase II trial, patients with mCRC who had not progressed after 6 to 8 months of first-line chemotherapy were randomized to receive axitinib (5 mg twice a day) (arm A) or placebo (arm B). RESULTS:Forty-nine patients were included: 25 in arm A and 24 in arm B. The median follow-up was 26.07 months (95% confidence interval [CI], 18.44-31.73 months). Progression-free survival (PFS) rate at 6 months was 40.00% (95% CI, 21.28%-58.12%) in the axitinib arm versus 8.33% (95% CI, 1.44%-23.30%) in the placebo arm (P = .0141). The median PFS was statistically significantly longer in the axitinib group than in the placebo group (4.96 vs. 3.16 months; hazard ratio, 0.46; 95% CI, 0.25-0.86; P = .0116). Median overall survival was also longer in the axitinib arm but did not reach statistical significance (27.61 vs. 19.99 months; hazard ratio, 0.68; 95% CI, 0.31-1.48; P = .3279). Grade 3 to 4 treatment-related toxicities were experienced by 7 patients (28%) in cohort A and 1 patient (4%) in cohort B (P = .0488). The most frequent grade 3 to 4 treatment-related toxicities were hypertension, diarrhea, and asthenia. There were no toxic deaths. The study was prematurely closed because of slow recruitment. CONCLUSIONS:In our study, maintenance treatment with axitinib monotherapy showed a significant increase in PFS and a good safety profile. Axitinib should be further explored as a possible option for first-line chemotherapy maintenance treatment in patients with mCRC.

Preventing severe irinotecan-induced adverse reactions would allow us to offer better treatment and improve patients' quality of life. Transporters, metabolizing enzymes, and genes involved in the folate pathway have been associated with irinotecan-induced toxicity. We analyzed 12 polymorphisms in UGT1A1, ABCB1, ABCG2, ABCC4, ABCC5, and MTHFR in 158 patients with metastatic colorectal cancer treated with irinotecan and studied the association with grade >2 adverse reactions (CTCAE). Among the most frequent ADRs, the SNPs rs1128503, rs2032582, and rs1045642 in ABCB1 and rs1801133 in MTHFR were associated with hematological toxicity and overall toxicity. The SNP rs11568678 in ABCC4 was also associated with overall toxicity. After correction of P values using a false discovery rate, only ABCB1 variants remained statistically significant. Haplotype analysis in ABCB1 showed an 11.3-fold and 4.6-fold increased risk of hematological toxicity (95% CI, 1.459-88.622) and overall toxicity (95% CI, 2.283-9.386), respectively. Consequently, genotyping of the three SNPs in ABCB1 can predict overall toxicity and hematological toxicity with a diagnostic odds ratio of 4.40 and 9.94, respectively. Genotyping of ABCB1 variants can help to prevent severe adverse reactions to irinotecan-based treatments in colorectal cancer.