Predictive Biomarkers Of Toxicity Research Articles

ABCC1, ABCG2 and FOXP3: Predictive Biomarkers of Toxicity from Methotrexate Treatment in Patients Diagnosed with Moderate-to-Severe Psoriasis.

Methotrexate (MTX) is one of the most extensively used drugs in the treatment of moderate-to-severe psoriasis (PS). However, it frequently must be suspended owing to the toxicity in certain patients. To evaluate the influence of ABCC1, ABCG2, and FOXP3 in the development of MTX toxicity in PS. Retrospective cohort study with 101 patients. Five single-nucleotide polymorphisms (SNPs) were genotyped using real-time polymerase chain reaction with TaqMan probes. Patients carrying ABCC1 rs2238476-AG genotype (AG vs. GG: OR = 8.04; 95% CI = 1.48-46.78; p = 0.015); FOXP3 rs376154-GT and GG genotypes (GT vs. TT/GG: OR = 3.86; 95% CI = 1.17-13.92; p = 0.031) and ABCG2 rs13120400-T allele (T vs. CC: OR = 8.33; 95% CI = 1.24-164.79; p = 0.059) showed a higher risk of developing more than one adverse effect. The toxicity analysis by subtypes showed that the ABCC1 rs2238476-AG genotype (AG vs. GG: OR = 8.10; 95% CI = 1.69-46.63; p = 0.011) and FOXP3 rs376154-GT genotype (OR = 4.11; 95% CI = 1.22-15.30; p = 0.027) were associated with the appearance of asthenia. No association of the other ABCC1 polymorphisms (rs35592 and rs246240) with MTX toxicity was found. ABCC1, ABCG2, and FOXP3 polymorphisms can be considered to be risk biomarkers of toxicities in PS patients treated with MTX.

Germline variants disrupting microRNAs predict long-term genitourinary toxicity after prostate cancer radiation

Background and purposeThe purpose of this study was to determine whether single nucleotide polymorphisms disrupting microRNA targets (mirSNPs) can serve as predictive biomarkers for toxicity after radiotherapy for prostate cancer and whether these may be differentially predictive depending on radiation fractionation. Materials and methodsWe identified 201 men treated with two forms of definitive radiotherapy for prostate cancer at two institutions: 108 men received conventionally-fractionated radiotherapy (CF-RT) and 93 received stereotactic body radiotherapy (SBRT). Germline DNA was evaluated for the presence of functional mirSNPs. Random forest, boosted trees and elastic net models were developed to predict late grade ≥2 GU toxicity by the RTOG scale. ResultsThe crude incidence of late grade ≥2 GU toxicity was 16% after CF-RT and 15% after SBRT. An elastic net model based on 22 mirSNPs differentiated CF-RT patients at high risk (71.5%) versus low risk (7.5%) for toxicity, with an area under the curve (AUC) values of 0.76–0.81. An elastic net model based on 32 mirSNPs differentiated SBRT patients at high risk (64.7%) versus low risk (3.9%) for toxicity, with an area under the curve (AUC) values of 0.81–0.87. These models were specific to treatment type delivered. Prospective studies are warranted to further validate these results. ConclusionPredictive models using germline mirSNPs have high accuracy for predicting late grade ≥2 GU toxicity after either CF-RT or SBRT, and are unique for each treatment, suggesting that germline predictors of late radiation sensitivity are fractionation-dependent. Prospective studies are warranted to further validate these results.

Treatment-related toxicity and improved outcomes with immune checkpoint inhibitors in patients with hepatocellular carcinoma.

4085 Background: The development of treatment-related adverse events (trAE) correlates favorably with clinical outcomes in multiple studies of patients receiving immune checkpoint inhibitors (ICI), however, this relationship is undefined in patients with hepatocellular carcinoma (HCC). This retrospective multi-center study aimed to examine whether trAEs are prognostic in HCC. Methods: We established an international consortium of 10 tertiary-care referral centers located in Europe (n = 67), United States (US, n = 248) and Asia (n = 42) to test whether the development of clinically significant trAE (i.e. graded >2, trAE2) predicted for improved overall (OS), progression-free survival (PFS), and overall response rates (ORR) following ICI, and subsequently validated this association in a separate cohort of 406 HCC patients receiving ICI therapy as part of international clinical trials submitted to the US Food and Drug Administration (FDA) in support of marketing applications. Results: In a multi-institutional cohort of 357 patients, 274 (77%) with Barcelona Clinic Liver Cancer (BCLC) stage C HCC mostly treated with ICI monotherapy (n = 304, 85%), trAE were reported in 146 patients (41%). Development of trAE2 were associated with longer OS (23.3 versus 12.2 months) and PFS (8.6 months versus 3.7 months). After adjusting for viral aetiology, gender, presence of cirrhosis, Child-Pugh class, BCLC stage, AFP levels, ECOG-PS, ICI regimen (mono/combination therapy) and receipt of corticosteroid therapy, trAE2 were confirmed predictors of improved OS (HR 0.55; 95%CI:0.34-0.88) and PFS (HR 0.51; 95%CI: 0.35-0.74). TrAE2 were associated with higher ORR (27% versus 16%) from ICI. The association between trAE2 and patients’ OS (HR 0.49; 95%CI:0.34-0.70) and PFS (HR 0.43; 95%CI:0.32-0.59) was also observed in the FDA dataset. After a 6-weeks landmark selection, trAE2 were confirmed to be associated with improved PFS (HR 0.59; 95%CI:0.39-0.87); the additional analysis adjusted for tumour response and duration of treatment within the FDA cohort further confirmed the association with longer PFS (HR 0.67; 95%CI: 0.47-0.94). Conclusions: Development of trAE2 may correlate with response and survival in patients with HCC receiving ICI, a clinical setting where the lack of biomarkers still represents an unmet need. Prospective studies aimed at understanding the underlying immunologic foundations of such relationship are warranted to identify predictive biomarkers of toxicity and response.

Immunotherapy: enhancing the efficacy of this promising therapeutic in multiple cancers.

Cancer treatments often reach a refractory period leading to treatment failure and patients developing disease recurrence. This can be due to tumour cells escaping the immune response and creating an immunosuppressive microenvironment enhancing cancer progression. Immunotherapy has become a promising tool for cancer treatment as it restores the anti-tumour response of the patient's immune system. Immune checkpoint inhibitors are the most widely studied immunotherapies worldwide and are now approved for multiple cancers. However, chimeric antigen receptor (CAR)-T cell therapy has also shown promise by targeting T lymphocytes that are genetically modified ex vivo to express CARs and this is now approved to treat some haematological cancers. Although immunotherapy has shown successful treatment outcomes in multiple cancers, some patients do not respond to this treatment. Therefore, approaches to enhance the efficacy of immunotherapies are likely to be the key to improve their effectiveness. Therefore, combination therapies of checkpoint inhibitors +/- chemotherapy are at the forefront of current research. Furthermore, biomarkers that predict treatment response are now beginning to emerge. Additionally, utilising nanoparticles as a newly targeted drug delivery system to enhance CAR-T cell therapy may enhance the efficacy of the cells when re-infused within the patient. Even if efficacy is enhanced, severe immune-related adverse events (irAEs) occur that are life-threatening and could lead to therapy being stopped. Therefore, predictive biomarkers for toxicity are also needed to improve both the patient's quality of life and treatment outcomes. This review will look at the current immunotherapies in clinical trials and discuss how to enhance their efficacy.

Abstract A052: Predictive wild-type RAS/BRAF and pharmacogenetic biomarkers drive selection of metastatic colorectal cancer patients fit for intensive first-line FIr-C/FOx-C schedule adding cetuximab to triplet chemotherapy

Abstract Background: Intensive-first line bevacizumab (BEV) addition to triplet chemotherapy significantly increased clinical outcome in metastatic colorectal cancer (MCRC) patients. Cetuximab (CET) addition to doublet chemotherapy significantly increased clinical outcome in RAS wild-type MCRC. This phase II study investigated safety and activity of FIr-C/FOx-C schedule of weekly CET added to triplet chemotherapy in first line RAS wild-type MCRC. Methods: The phase II study was planned according to Simon two-step design: delta 15% (p0 70%, p1 85%), power 80%, α 5%, β 20%; projected objective responses (ORR), I step 14/19 patients. FIr-C/FOx-C schedule: 5-fluorouracil (5-FU) 12h-timed-flat-infusion 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; associated to weekly alternating irinotecan (CPT-11) 160 mg/m2, days 1,15 or oxaliplatin (OXP) 80 mg/m2, days 8, 22; CET 400 mg/m2 loading dose, then 250 mg/m2 days 1,8,15,22; every 4 weeks. Toxicity and limiting toxicity syndromes (LTS) were evaluated and compared using chi-square test; activity and efficacy using log-rank test. 5-FU degradation rate (5-FUDR) and single nucleotide polymorphisms (SNP) of 4 genes (DYPD, CYP3A4, ABCB1, UGT1A1) involved in metabolism of 5-FU and CPT-11 were evaluated in individual patients showing LTS and at the recommended doses as predictive biomarkers of toxicity. Results: Twenty-nine consecutive patients <75 years with primary/intermediate Cumulative Illness Rating Scale (CIRS) were enrolled. From April 2014, only KRAS/NRAS wild-type patients were eligible: median age 59; young-elderly (yE) 7 (24%); liver-limited metastases (L-L) 7, 24%. Due to limiting gastrointestinal toxicity, recommended doses of CPT-11 and 5-FU were 120 and 750 mg/m2, respectively. Activity data met the primary endpoint: 14 OR out of 18 evaluable patients as treated (76%). Preliminary phase II data confirm 17 OR out of 23 evaluable patients intent-to-treat (74%). Liver metastasectomies were performed in 14%, 57% L-L. At median follow-up 18 months, median progression-free survival (PFS) was 12 months, median overall survival (OS) 23 months. OS was significantly worse in yE compared to non-elderly patients (p = 0.045). At the recommended doses, received DI was >80% for each drug and cumulative G3-4 toxicities in 13 patients were: diarrhea 23%, asthenia 15%, vomiting 8%, hypertransaminasemy 8%. LTS, consisting of the LT, associated or not to G2 or other LT, were observed overall in 19 patients (65.5%), 83% in yE. LTS were prevalently multiple than single site (59% versus 7%, chi square 7.703, p = 0.006). Reduced FUDR, CYP3A4 and UGT1A1 SNPs, also frequently associated, were particularly observed in patients showing gastrointestinal LTS, while not in patients without LTS. Conclusion: Intensive first-line FIr-C/FOx-C regimen at the modified recommended doses is tolerable and highly effective in RAS wild-type MCRC patients, with significantly increased LTS multiple sites, justifying careful selection of fit patients using a panel of 5 predictive biomarkers of 5-FU and CPT11 toxicity. Citation Format: Gemma Bruera, Silvia Massacese, Antonella Dal Mas, Corrado Ficorella, Eugenio Ciacco, Giuseppe Calvisi, Maurizio Simmaco, Enrico Ricevuto. Predictive wild-type RAS/BRAF and pharmacogenetic biomarkers drive selection of metastatic colorectal cancer patients fit for intensive first-line FIr-C/FOx-C schedule adding cetuximab to triplet chemotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A052.