BackgroundAssociation between rectal or colon cancer risk and serine hydroxymethyltransferase 1 (SHMT1) C1420T or methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms was assessed. The serum total homocysteine (HCY), marker of folate metabolism was also investigated.MethodsThe SHMT1 and MTHFR genotypes were determined by real-time PCR and PCR-RFLP, respectively in 476 patients with rectal, 479 patients with colon cancer and in 461 and 478, respective controls matched for age and sex. Homocysteine levels were determined by HPLC kit. The association between polymorphisms and cancer risk was evaluated by logistic regression analysis adjusted for age, sex and body mass index. The population stratification bias was also estimated.ResultsThere was no association of genotypes or diplotypes with colon cancer. The rectal cancer risk was significantly lower for SHMT1 TT (OR = 0.57, 95% confidence interval (CI) 0.36-0.89) and higher for MTHFR CT genotypes (OR = 1.4, 95%CI 1.06-1.84). A gene-dosage effect was observed for SHMT1 with progressively decreasing risk with increasing number of T allele (p = 0.014). The stratified analysis according to age and sex revealed that the association is mainly present in the younger (< 60 years) or male subgroup. As expected from genotype analysis, the SHMT1 T allele/MTHFR CC diplotype was associated with reduced rectal cancer risk (OR 0.56, 95%CI 0.42-0.77 vs all other diplotypes together). The above results are unlikely to suffer from population stratification bias. In controls HCY was influenced by SHMT1 polymorphism, while in patients it was affected only by Dukes' stage. In patients with Dukes' stage C or D HCY can be considered as a tumor marker only in case of SHMT1 1420CC genotypes.ConclusionsA protective effect of SHMT1 1420T allele or SHMT1 1420 T allele/MTHFR 677 CC diplotype against rectal but not colon cancer risk was demonstrated. The presence of SHMT1 1420 T allele significantly increases the HCY levels in controls but not in patients. Homocysteine could be considered as a tumor marker in SHMT1 1420 wild-type (CC) CRC patients in Dukes' stage C and D. Further studies need to clarify why SHMT1 and MTHFR polymorphisms are associated only with rectal and not colon cancer risk.

The antiproliferative effect of 5-fluorouracil (5-FU) in the presence of low dose non-steroidal anti-inflammatory drugs (NSAIDs) on high cyclooxygenase-2 (COX-2)-expressing HCA-7 and low COX-2-expressing HT-29 colon carcinoma cell lines was investigated. Pharmacogenetic parameters were studied to characterize the 5-FU sensitivity of the two cell lines. Thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms were determined by PCR analysis. Cell proliferation was measured by SRB assay, cell cycle distribution and apoptosis by FACS analysis. Cyclooxygenase expression was detected by Western blot and also by fluorescence microscopy. Prostaglandin E(2) (PGE(2)) levels were investigated with ELISA kit. The HT-29 cell line was found to be homozygous for TS 2R and 1494ins6 and T homozygous for MTHFR 677 polymorphisms predicting high 5-FU sensitivity (IC(50): 10 microM). TS 3R homozygosity, TS 1496del6 and MTHFR 677CT heterozygosity may explain the modest 5-FU sensitivity (IC(50): 1.1 mM) of the HCA-7 cell line. Indomethacin and NS-398 (10 microM and 1.77 microM, respectively) reduced the PGE(2) level in HCA-7 cells (>90%). Low concentrations of NSAIDs without antiproliferative potency increased the S-phase arrest and enhanced the cytotoxic action of 5-FU only in HCA-7 cells after 48-hours treatment. The presented data suggested that the enhancement of 5-FU cytotoxicity by indomethacin or NS-398 applied in low dose is related to the potency of NSAIDs to modulate the cell-cycle distribution and the apoptosis; however, it seems that this effect might be dependent on cell phenotype, namely on the COX-2 expression.

The impact of thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), and serine hydroxymethyltransferase 1 (SHMT1) gene polymorphisms and that of dihydropyrimidine dehydrogenase (DPD) enzyme activity, serum total homocysteine level, and estimated serum creatinine clearance on first-line 5-fluorouracil, leucovorin, irinotecan, and bevacizumab (FOLFIRI+bevacizumab) regimen efficacy in metastatic colorectal cancer patients was investigated. DNA was extracted from peripheral blood mononuclear cells. Genotyping was performed for TYMS 5'UTR variable number tandem repeat, TYMS 3'UTR ins/del, MTHFR C677T, and SHMT1 C1420T polymorphisms. The DPD activity of peripheral blood mononuclear cells was also determined. The univariate and multivariate analyses demonstrated that the SHMT1 1420T allele was associated with better response (P=0.025) and longer progression-free survival (PFS) (P=0.00004) and overall survival (OS) (P=0.034). Grade ≥2 hypertension was also an independent prognostic factor of longer progression-free survival and OS. Bevacizumab-related hypertension might be a predictive marker of treatment efficacy (P=0.0002 for OS) in the case of wild (CC) SHMT1 1420 genotypes only.

Background: The combination of venetoclax (Ven), a selective oral B-cell lymphoma-2 inhibitor, and obinutuzumab (Obi), a type II anti-CD20 monoclonal antibody, is approved as a 12-cycle fixed duration treatment for adult patients (pts) with previously untreated chronic lymphocytic leukemia (CLL). In the CLL14 study, pts with CLL and coexisting conditions treated with Ven-Obi achieved high rates of undetectable minimal residual disease (uMRD), translating into a 4-year progression free survival (PFS) of 74%. Despite these favorable results, disease relapse may occur after cessation of the fixed duration therapy, particularly for those with higher risk genetics, such as TP53 aberrancy and unmutated IgHV. A key unanswered question in the field is, for pts who initially had a clinical response after first-line (1L) Ven-Obi treatment, how much clinical benefit would they receive from retreatment with Ven-Obi after developing progressive disease (PD)? Retreatment with Ven-Obi would provide a line of treatment in addition to other regimens such as BTK inhibitors. In patients with relapsed/refractory (R/R) CLL, one of the current standard therapies is the combination of Ven and rituximab (R). Updated results from the phase 3 MURANO trial of 24-cycle fixed duration Ven-R demonstrated that patients with disease progression after treatment completion and clinical response had a best overall response rate (ORR) of 72.2% upon Ven-R retreatment. The results of the MURANO study and the favorable safety profile of Ven-Obi suggest that retreatment with Ven-Obi after initial therapy with Ven-Obi may be effective in pts with relapsed CLL. The present study is the first prospective clinical trial to evaluate the efficacy and safety of retreatment with Ven-Obi at the time of PD in pts who had initially responded to 1L Ven-Obi for at least 12 months (mo) after completing therapy. Study Design and Methods: Pts are eligible for this multicenter, open-label, non-randomized, phase 2 study (NCT04895436) if they have a diagnosis of CLL according to iwCLL criteria, were treated with Ven-Obi fixed duration therapy, and achieved a best response of either complete remission (CR), CR with incomplete marrow recovery (CRi), nodular partial remission (nPR), or partial remission (PR). Pts must also have had at least 12 mo of remission between the last dose of Ven and PD. Pts will be divided into two cohorts: PD more than 2 years after completing 1L treatment (Co-1), and pts with PD between 1-2 years post 1L therapy (Co-2). Pts receive Obi (100 mg intravenously [IV] on Day [D] 1 and additional 900mg on either D1 or D2, then 1000mg on D8 and D15 of Cycle [C] 1 and subsequently on D1C2-6). Ven is administered orally once daily (QD) beginning on C1D22, including a 5-week ramp-up period (weekly dose increases from 20, 50, 100, 200, to 400mg QD), followed by 400mg QD thereafter on 28-day cycles, for a total of 12 or 24 cycles in Co-1 and Co-2, respectively. Pts in Co-2 with detectable MRD (≥10 -4) after 15 months of therapy may continue Ven monotherapy beyond mo 24 at the investigator's discretion. The primary objective is to assess the efficacy of Ven-Obi in Co-1 as measured by ORR, defined as a proportion of pts achieving a best response of PR/nPR or CR/CRi at the end of combination therapy (EOCT) assessment (EOCT + 3 mo). Key secondary objectives are CR/CRi at EOCT, CR/CRi rate at end of therapy (EOT), ORR at EOT, time to response (TTR), duration of response (DOR), PFS, overall survival (OS), time to next treatment (TTNT), and uMRD (10 -4)rate at EOCT and EOT. Safety endpoints include the type, frequency, and severity of treatment-emergent adverse events (AEs), and serious AEs. Prespecified exploratory biomarker endpoints include MRD kinetics up to 12 mo post-treatment, and correlations of baseline characteristics of IgHV, TP53 mutation, and del (17p) status with outcomes. Point and interval estimates will be used to characterize the efficacy of Ven-Obi retreatment; exact binomial (Clopper-Pearson) 95% confidence intervals will be provided alongside the corresponding point estimates for the response rates of interest (ORR, CR rate, and uMRD rate), while Kaplan-Meier methodology will be used to summarize the time-to-event endpoints (DOR, PFS, OS, and TTNT). Finally, descriptive statistical summaries will be reported for several patient-reported outcome (PRO) measures, including the EORTC QLQ-CLL-17, EQ-5D-5L, and FACIT-F. Figure 1 Figure 1. Disclosures Davids: Takeda: Consultancy; Novartis: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Merck: Consultancy; MEI Pharma: Consultancy; Adaptive Biotechnologies: Consultancy; Pharmacyclics: Consultancy, Research Funding; Research to Practice: Consultancy; Ascentage Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Surface Oncology: Research Funding; Astra-Zeneca: Consultancy, Research Funding; Eli Lilly and Company: Consultancy; Genentech: Consultancy, Research Funding; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; BeiGene: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Fischer: Abbvie: Honoraria; Roche: Honoraria, Other: Travel Grants. Porro Lurà: F. Hoffmann - La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Sinai: AbbVie Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Sail: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Pesko: AbbVie: Current Employment, Current equity holder in publicly-traded company. Pai: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Komlosi: AbbVie: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hallek: Roche: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau. Brown: Beigene: Consultancy; Janssen: Consultancy; Pfizer: Consultancy; Eli Lilly and Company: Consultancy; Nextcea: Consultancy; Genentech/Roche: Consultancy; Bristol-Myers Squib/Juno/Celegene: Consultancy; Novartis: Consultancy; Morphosys AG: Consultancy; MEI Pharma: Consultancy; Acerta/Astra-Zeneca: Consultancy; Abbvie: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; TG Therapeutics: Research Funding; Sun: Research Funding; SecuraBio: Research Funding; Loxo/Lilly: Research Funding; Gilead: Research Funding; Rigel: Consultancy; Catapult: Consultancy. Al-Sawaf: AbbVie: Honoraria, Research Funding; Adaptive: Honoraria; AstraZeneca: Honoraria; Beigene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with Obinutuzumab, a type II anti-CD20 monoclonal antibody, for first-line therapy for chronic lymphocytic leukemia.

Venetoclax, a potent B-cell lymphoma-2 (BCL-2) inhibitor, has demonstrated clinical efficacy in chronic lymphocytic leukemia (CLL). VENICE II is an open-label, single-arm, phase 3b study (NCT02980731) evaluating the impact of venetoclax monotherapy (400 mg once daily) for 2 years on health-related quality of life (HRQoL) of patients with relapsed/refractory CLL. The primary endpoint was mean change in the global health status (GHS)/quality of life (QoL) subscale of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) from baseline to Week 48. Overall, 210 patients received !1 dose of venetoclax; median treatment duration was 67.4 weeks. The primary endpoint was met with mean improvement of þ9.3 points (n ¼ 156, 95% confidence interval 6.1-12.5; p¼.004) in GHS/QoL. At Week 48, clinically meaningful improvements were observed for role functioning, fatigue, and insomnia domains of EORTC QLQ-C30, suggesting venetoclax monotherapy has a positive impact on HRQoL. No new safety signals were reported.