Alarming Drop in Early Stage Colorectal Cancer Diagnoses After COVID-19 Outbreak: A Real-World Analysis from the Italian COVID-DELAY Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has triggered the disruption of health care on a global scale. With Italy tangled up in the pandemic response, oncology care has been largely diverted and cancer screenings suspended. Our multicenter Italian study aimed to evaluate whether COVID-19 has impacted access to diagnosis, staging, and treatment for patients newly diagnosed with colorectal cancer (CRC), compared with pre-pandemic time. METHODS: All consecutive new CRC patients referred to 8 Italian oncology institutions between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset, radiological and cytohistological diagnosis, treatment start and first radiological evaluation were analyzed and compared with the same months of 2019. RESULTS: A reduction (29%) in newly diagnosed CRC cases was seen when compared with 2019 (360 vs 506). New CRC patients in 2020 were less likely to be diagnosed with early stage (stages I-II-III) CRC (63% vs 78%, P < .01). Gender and sidedness were similar regardless of the year. The percentage of tumors with any mutation among BRAF, NRAS, and KRAS genes were significantly different between the 2 years (61% in 2020 vs 50% in 2019, P = .04). Timing of access to cancer diagnosis, staging, and treatment for patients with CRC has not been negatively affected by the pandemic. Significantly shorter temporal intervals were observed between symptom onset and first oncological appointment (69 vs 79 days, P = .01) and between histological diagnosis and first oncological appointment (34 vs 42 days, P < .01) during 2020 compared with 2019. Fewer CRC cases were discussed in multidisciplinary meetings during 2020 (38% vs 50%, P = .01). CONCLUSIONS: Our data highlight a significant drop in CRC diagnosis after COVID-19, especially for early stage disease. The study also reveals a remarkable setback in the multidisciplinary management of patients with CRC. Despite this, Italian oncologists were able to ensure diagnostic-therapeutic pathways proper operation after March 2020.

Glycolytic competence in gastric adenocarcinomas negatively impacts survival outcomes of patients treated with salvage paclitaxel-ramucirumab.

INTRODUCTION: For energy production, cancer cells maintain a high rate of glycolysis instead of oxidative phosphorylation converting glucose into lactic acid. This metabolic shift is useful to survive in unfavorable microenvironments. We investigated whether a positive glycolytic profile (PGP) in gastric adenocarcinomas may be associated with unfavorable outcomes under an anticancer systemic therapy, including the anti-angiogenic ramucirumab. MATERIALS AND METHODS: Normal mucosa (NM) and primary tumor (PT) of 40 metastatic gastric adenocarcinomas patients who received second-line paclitaxel-ramucirumab (PR) were analyzed for mRNA expression of the following genes: HK-1, HK-2, PKM-2, LDH-A, and GLUT-1. Patients were categorized with PGP when at least a doubling of mRNA expression (PT vs. NM) in all glycolytic core enzymes (HK-1 or HK-2, PKM-2, LDH-A) was observed. PGP was also related to TP53 mutational status. RESULTS: Mean LDH-A, HK-2, PKM-2 mRNA expression levels were significantly higher in PT compared with NM. 18 patients were classified as PGP, which was associated with significantly worse progression-free and overall survival times. No significant association was observed between PGP and clinical-pathologic features, including TP53 positive mutational status, in 28 samples. CONCLUSIONS: Glycolytic proficiency may negatively affect survival outcomes of metastatic gastric cancer patients treated with PR systemic therapy. TP53 mutational status alone does not seem to explain such a metabolic shift.

A phase II study of modified FOLFOX as first-line chemotherapy for metastatic gastric cancer in elderly patients with associated diseases.

BACKGROUND: Elderly patients are generally underrepresented in the study populations of combination chemotherapy trials. This study evaluates the efficacy and safety of a modified FOLFOX regimen in elderly patients with metastatic gastric cancer and presenting associated disease(s). METHODS: A total of 43 patients aged ≥70 years received oxaliplatin 85 mg/m(2) together with 6S-leucovorin 200 mg/m(2) on day 1, followed by a 46-h infusion of 5-fluorouracil 2,400 mg/m(2), every 2 weeks. Assessment of response was performed every four cycles according to RECIST criteria. RESULTS: Median patient age was 74 years (range, 70-83 years). Overall response rate was 34.9% [95% confidence interval (CI), 20.6-49.1, with 3 complete responses and 12 partial responses. Grade 3 neutropenia occurred in 4 patients (9.3%), fatigue in 3 patients (7.0%), and vomiting in 2 patients (4.6%). Grade 2 and 3 peripheral neuropathy was observed in 5 patients (11.6%) and 1 patient (2.3%), respectively. No treatment-related death was observed. Median progression-free and overall survival were 6.8 and 10.5 months, respectively. CONCLUSIONS: This modified FOLFOX regimen is an active and well-tolerated treatment for elderly patients with metastatic gastric cancer and also represents a good therapeutic option in patients with associated disease(s).

Impact of Signet-Ring Cell Histology in the Management of Patients with Non-Metastatic Gastric Cancer: Results from a Retrospective Multicenter Analysis Comparing FLOT Perioperative Chemotherapy vs. Surgery Followed by Adjuvant Chemotherapy.

BACKGROUND: FLOT perioperative chemotherapy represents the standard of care in non-metastatic gastric cancer patients. Signet-ring cell positivity is associated with a worse prognosis in patients with gastric cancer treated with chemotherapy. Comparison between FLOT perioperative chemotherapy vs. surgery followed by adjuvant chemotherapy based on signet-ring cell positivity is lacking. The aim of the analysis was to compare perioperative FLOT with adjuvant chemotherapy in gastric cancer patients stratified by signet-ring cell positivity. METHODS: We conducted a retrospective multicenter analysis based on disease-free survival (DFS) and overall survival (OS) in patients with gastric cancer who received perioperative chemotherapy with a FLOT regimen and compared their survival with a historical cohort of patients treated with adjuvant chemotherapy, matched by cT and cN stage and by tumor histological features. RESULTS: Seventy-six patients were enrolled and 24 (32%) were signet-ring cell positive. At a median follow-up time of 39 months, the median DFS was 26.3 months and the median OS was 37.3 months. Signet-ring cell positivity was associated with a shorter OS (median OS: 20.4 vs. 46.9 months, HR: 3.30, 95%CI: 1.56-6.99, p = 0.0018) and DFS (mDFS: 15.2 vs. 38.6 months, HR: 3.18, 95%CI: 1.55-6.54, p = 0.0016). This was confirmed by multivariate analysis for DFS (Exp(B): 2.55) and OS (Exp(B): 2.68). After propensity score matching, statistically significant shorter DFS (HR: 3.30, 95%CI: 1.50-7.35, p = 0.003) and OS (HR: 5.25, 95%CI: 2.18-12-68, p = 0.0002) were observed for patients with signet-ring cell positivity who received perioperative treatment vs. those who received surgery followed by adjuvant chemotherapy. CONCLUSIONS: Signet-ring positivity was associated with shorter DFS and OS in patients who received perioperative treatment with FLOT compared with surgery followed by adjuvant therapy. These data suggest that for patients with signet-ring cell histology, FLOT perioperative treatment might not always be the best choice of treatment, and further research should be focused on this group of patients.

The role of HER-3 expression in the prediction of clinical outcome for advanced colorectal cancer patients receiving irinotecan and cetuximab.

Preclinical data suggested that, in the presence of human epidermal growth factor receptor (HER)-3-altered activation, colorectal cancer cells may escape anti-epidermal growth factor receptor (EGFR)-mediated cell death. HER-3 overexpression may then represent a key factor for resistance to anti-EGFR antibodies in colorectal cancer. The aim of our analysis was to investigate a possible correlation between HER-3 expression and clinical outcome in wild-type K-RAS advanced colorectal cancer patients receiving cetuximab and irinotecan. We retrospectively analyzed immunoreactivity for HER-3 in wild-type K-RAS advanced colorectal cancer patients receiving irinotecan and cetuximab. Eighty-four advanced wild-type K-RAS colorectal cancer patients were available for HER-3 analysis. Forty patients (48%) had a HER-3(-) colorectal tumor, whereas the remaining 44 cases (52%) were deemed HER-3(+). In patients with HER-3(-) and HER-3(+) tumors, we observed a partial response in 17 (42%) and eight (18%) patients respectively; progressive disease occurred in 11 (35%) and 26 (53%) patients with HER-3(-) and HER-3(+) tumors, respectively (p = .003). The median progression-free survival time was 6.3 months in patients with HER-3(-) tumors and 2.8 months for those who had HER-3-overexpressing tumors (p < .0001). The median overall survival time was 13.6 months in patients showing HER-3(-) tumors and 10.5 months for those who had HER-3-expressing tumors (p = .01). HER-3 proved to be a predictive factor for clinical outcome in wild-type K-RAS colorectal cancer patients treated with cetuximab. Combined HER-3 and K-RAS analysis may represent an effective strategy for better selection of responding colorectal cancer patients.

Retrospective Cohort Study of Caveolin-1 Expression as Prognostic Factor in Unresectable Locally Advanced or Metastatic Pancreatic Cancer Patients.

Caveolin-1 (Cav-1) plays a key role in various neoplastic diseases and is upregulated in different cancers, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, Cav-1 is critical for the uptake of albumin as well as nab-paclitaxel in PDAC cells. Here, we investigated the prognostic impact of Cav-1 expression in a cohort of 39 metastatic PDAC patients treated with different first-line chemotherapy regimens. We also assessed the predictive value of Cav-1 in patients treated with gemcitabine and nab-paclitaxel. Cav-1 expression was evaluated by immunohistochemistry staining in neoplastic and stromal cells, using metastatic sites or primary tumor tissue specimens. Higher levels of Cav-1 expression were associated with significantly worse overall survival (OS) and progression-free survival (PFS). No differences in OS were found between patients treated with gemcitabine + nab-paclitaxel vs. other chemotherapy options. Multivariate analysis for OS and PFS confirmed the independent prognostic role of Cav-1 expression. Our study evidenced a negative prognostic role of Cav-1 in patients affected by metastatic/locally advanced unresectable PDAC. Moreover, Cav-1 expression seems not to predict different response rates to different types of first-line treatment. Future prospective trials will be necessary to confirm the prognostic role of Cav-1 and explore Cav-1 specific inhibitors as a therapeutic option for advanced PDAC patients.

An observational retrospective analysis of the main metastatic site and corresponding locoregional treatment as a prognostic factor in metastatic gastric cancer.

Despite novel drugs, the prognosis for patients with metastatic gastric cancer remains poor. In rare instances, locoregional therapies are used in addition to standard chemotherapy in patients with oligometastatic involvement. This type of approach has not been supported by solid published evidence. The aim of the present retrospective study was to assess the prognostic impact of factors such as metastatic site, tumour histology and locoregional treatment in patients with metastatic gastric cancer. A total of 184 patients with metastatic gastric or gastroesophageal junction adenocarcinoma who received at least one line of palliative therapy with doublet or triplet chemotherapy were enrolled in the current analysis. Median overall survival (OS) was 8.32 months (95% CI, 7.02-9.41) and median progression-free survival (PFS) was 4.16 months (95% CI, 3.24-5.08). Lung metastases vs. other sites of metastatic involvement [hazard ratio (HR), 0.27; P=0.0133] and intestinal histology (HR, 0.48; P=0.08) were significantly associated with an improved OS. Improved PFS was also observed (HR, 0.49; P=0.10 and HR, 0.72; P=0.08 for lung metastases and intestinal histology, respectively). Second line chemotherapy and locoregional treatment of metastases (surgery or radiotherapy) were associated with improved OS (HR, 0.52; P<0.0001 and HR, 0.35; P<0.0001, respectively). Multivariate analysis confirmed an independent prognostic role for OS only for locoregional treatment, second line treatment and intestinal histology. The present results suggested that the presence of lung metastases alone was not a relevant prognostic factor and was influenced by the availability of further lines of treatment or by locoregional treatments. Locoregional treatments in patients with oligometastatic disease should be offered as they allow prolonged survival in patients with otherwise relatively short life expectancy.

Predictive ability of a drug-based score in patients with advanced non-small-cell lung cancer receiving first-line immunotherapy.

BACKGROUND: We previously demonstrated the cumulative poor prognostic role of concomitant medications on the clinical outcome of patients with advanced cancer treated with immune checkpoint inhibitors, creating and validating a drug-based prognostic score to be calculated before immunotherapy initiation in patients with advanced solid tumours. This 'drug score' was calculated assigning score 1 for each between proton-pump inhibitor and antibiotic administration until a month before cancer therapy initiation and score 2 in case of corticosteroid intake. The good risk group included patients with score 0, intermediate risk with score 1-2 and poor risk with score 3-4. METHODS: Aiming at validating the prognostic and putative predictive ability depending on the anticancer therapy, we performed the present comparative analysis in two cohorts of advanced non-small-cell lung cancer (NSCLC), respectively, receiving first-line pembrolizumab or chemotherapy through a random case-control matching and through a pooled multivariable analysis including the interaction between the computed score and the therapeutic modality (pembrolizumab vs chemotherapy). RESULTS: Nine hundred fifty and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. After the case-control random matching, 589 patients from the pembrolizumab cohort and 589 from the chemotherapy cohort were paired, with no statistically significant differences between the characteristics of the matched subjects. Among the pembrolizumab-treated group, good, intermediate and poor risk evaluable patients achieved an objective response rate (ORR) of 50.0%, 37.7% and 23.4%, respectively, (p < 0.0001), whereas among the chemotherapy-treated group, patients achieved an ORR of 37.0%, 40.0% and 32.4%, respectively (p = 0.4346). The median progression-free survival (PFS) of good, intermediate and poor risk groups was 13.9 months, 6.3 months and 2.8 months, respectively, within the pembrolizumab cohort (p < 0.0001), and 6.2 months, 6.2 months and 4.3 months, respectively, within the chemotherapy cohort (p = 0.0280). Among the pembrolizumab-treated patients, the median overall survival (OS) for good, intermediate and poor risk patients was 31.4 months, 14.5 months and 5.8 months, respectively, (p < 0.0001), whereas among the chemotherapy-treated patients, it was 18.3 months, 16.8 months and 10.6 months, respectively (p = 0.0003). A similar trend was reported considering the two entire populations. At the pooled analysis, the interaction term between the score and the therapeutic modality was statistically significant with respect to ORR (p = 0.0052), PFS (p = 0.0003) and OS (p < 0.0001), confirming the significantly different effect of the score within the two cohorts. CONCLUSION: Our 'drug score' showed a predictive ability with respect to ORR in the immunotherapy cohort only, suggesting it might be a useful tool for identifying patients unlikely to benefit from first-line single-agent pembrolizumab. In addition, the prognostic stratification in terms of PFS and OS was significantly more pronounced among the pembrolizumab-treated patients.

Insulin-like growth factor 1 expression correlates with clinical outcome in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan.

Seventy to 40% of K-RAS wild type colorectal tumors does not seem to benefit from treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies. Recent data suggested that in presence of IGF-1 system, altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. The interaction between IGF-1 expression and K-RAS mutational analysis was tested to verify the ability of IGF-1 to identify a subgroup of patients more likely to benefit from EGFR-targeted antibodies treatment. IGF-1 expression and K-RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab. One hundred twelve patients were analyzed. IGF-1 was negative in 30 patients (27%) and overexpressed in the remaining 82 cases (73%). In IGF-1 negative and IGF-1 positive tumors, we observed progressive disease in 9 (30%) and 55 (67%) patients, respectively (p = 0.001). Median progression-free survival was 7.5 mo in patients showing IGF-1 negative tumors and 3 mo for IGF-1 expressing tumors (p = 0.002). Among K-RAS wild type patients, IGF-1 negative and positive tumors showed a partial response to cetuximab-irinotecan in 13 (65%) and 11 (22%) cases, respectively (p = 0.002). Median progression-free survival in IGF-1 negative tumors was 10 mo and 3.2 mo in IGF-1 positive colorectal cancers (p = 0.02). IGF-1 proved to be a possible predictive factor for resistance to anti-EGFR monoclonal antibodies in K-RAS wild type colorectal cancer. Combined IGF-1 and K-RAS analysis may represent an effective strategy for a better selection of responding colorectal cancer patients.

TP53 Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy.

Loss of p53 promotes vascular endothelial growth factor (VEGF)-A up-regulation and the angiogenic potential of cancer cells. We investigated TP53 somatic mutations in 110 primary gastric adenocarcinomas of two retrospective metastatic series including 48 patients treated with second-line Ramucirumab/Paclitaxel and 62 patients who received first-line chemotherapy with Cisplatin or Oxaliplatin plus 5-Fluorouracil. Missense mutations were classified by tumor protein p53 (TP53) mutant-specific residual transcriptional activity scores (TP53RTAS) and used to stratify patients into two groups: transcriptionally TP53Active and TP53Inactive. The primary endpoint was overall survival (OS). An additional analysis was addressed to measure VEGF/VEGF receptor 2 (VEGFR2) expression levels in relation to the TP53RTAS. In the Ramucirumab/Paclitaxel group, 29/48 (60.4%) patients had TP53 mutations. Ten patients with TP53Inactive mutations showed better OS than carriers of other TP53 mutations. This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval = 0.17-0.85, p = 0.02). In the chemotherapy group, 41/62 (66%) patients had TP53 mutations, and the 11 carriers of TP53Inactive mutations showed the worst OS (Hazard Ratio = 2.64, 95% confidence interval = 1.17-5.95, p = 0.02). VEGF-A mRNA expression levels were significantly increased in TP53Inactive cases. Further studies are warranted to explore the effect of TP53Inactive mutations in different anti-cancer regimens. This information would lead to new tailored therapy strategies for this lethal disease.

Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice.

BACKGROUND: Concomitant medications, such as steroids, proton pump inhibitors (PPI) and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors. METHODS: We conducted a multicenter observational retrospective study aimed at evaluating the impact of concomitant medications on clinical outcomes, by weighing their associations with baseline clinical characteristics (including performance status, burden of disease and body mass index) and the underlying causes for their prescription. This analysis included consecutive stage IV patients with cancer, who underwent treatment with single agent antiprogrammed death-1/programmed death ligand-1 (PD-1/PD-L1) with standard doses and schedules at the medical oncology departments of 20 Italian institutions. Each medication taken at the immunotherapy initiation was screened and collected into key categories as follows: corticosteroids, antibiotics, gastric acid suppressants (including proton pump inhibitors - PPIs), statins and other lipid-lowering agents, aspirin, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/Angiotensin II receptor blockers, calcium antagonists, ß-blockers, metformin and other oral antidiabetics, opioids. RESULTS: From June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and ß-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), p<0.0001), prophylactic systemic antibiotics (HR 1.85 (95% CI 1.23 to 2.78), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.09 to 1.53), p=0.0021), PPIs (HR 1.26 (95% CI 1.07 to 1.48), p=0.0050), anticoagulants (HR 1.43 (95% CI: 1.16 to 1.77), p=0.0007) and opioids (HR 1.71 (95% CI 1.28 to 2.28), p=0.0002) were confirmed to have a significantly higher risk of disease progression. Patients receiving cancer-related steroids (HR 2.16 (95% CI 1.76 to 2.65), p<0.0001), prophylactic systemic antibiotics (HR 1.93 (95% CI 1.25 to 2.98), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.06 to 1.57), p=0.0091), PPI (HR 1.26 (95% CI 1.04 to 1.52), p=0.0172), anticoagulants (HR 1.45 (95% CI 1.14 to 1.84), p=0.0024) and opioids (HR 1.53 (95% CI 1.11 to 2.11), p=0.0098) were confirmed to have a significantly higher risk of death. CONCLUSION: We confirmed the association between baseline steroids administered for cancer-related indication, systemic antibiotics, PPIs and worse clinical outcomes with PD-1/PD-L1 checkpoint inhibitors, which can be assumed to have immune-modulating detrimental effects.

Prognostic role of thymidylate synthase polymorphisms in gastric cancer patients treated with surgery and adjuvant chemotherapy.

PURPOSE: To investigate the prognostic role of thymidylate synthase (TS) polymorphisms in gastric cancer patients treated with radical surgery and fluorouracil-based adjuvant chemotherapy. EXPERIMENTAL DESIGN: Ninety gastric cancer cases were identified among 187 patients previously enrolled in prospective case-control studies for disease susceptibility. Patients were genotyped for a G/C nucleotide change within a triple 28 bp variable number of tandem repeat sequence in the TS 5'-untranslated region (5'-UTR) and a 6 bp deletion in the TS 3'-untranslated region (3'-UTR). According to available functional data, patients with 5'-UTR 2R/2R, 2R/3C, 3C/3C genotypes were classified as low TS producers (5'-UTRlow) and patients with 5'-UTR 3G/3G, 3G/3C, 2R/3G genotypes as high TS producers (5'UTRhigh). Patients with 3'-UTR del6/del6 and del6/ins6 genotypes were classified as low TS producers (3'-UTRlow) and patients with 3'-UTR ins6/ins6 genotype as high TS producers (3'-UTRhigh). The prognostic analysis was based on 5'-UTR/3'-UTR combined genotypes. RESULTS: Ten patients (11%) were 5'-UTRhigh/3'-UTRhigh, 36 patients were 5'-UTRhigh/3'-UTRlow, 19 patients were 5'-UTRlow/3'-UTRhigh, and 25 patients were 5'-UTRlow/3'-UTRlow. 5'-UTRlow/3'-UTRlow patients showed the best outcome and the threshold of statistical significance was achieved in the comparison of disease-free survival and overall survival with 5'-UTRhigh/3'-UTRlow patients and 5'-UTRhigh/3'-UTRhigh patients. The presence of at least one high TS expression genotype showed independent adverse prognostic role in multivariate analysis. CONCLUSIONS: The prognostic role of TS polymorphisms in gastric cancer deserves further investigation because the adverse effect of high TS expression genotypes may be a relevant information to improve adjuvant chemotherapeutic strategies.

Host genetic variants in the IGF binding protein-3 impact on survival of patients with advanced gastric cancer treated with palliative chemotherapy.

AIM: IGF binding protein-3 (IGFBP-3) displays growth inhibitory/proapoptotic action and counteracts the IGF-1 tumor-promoting effects by downregulating its bioavailability. We investigated whether IGFBP-3 SNPs determining high IGFBP-3 circulating levels are associated with improved survival of patients with advanced gastric cancer treated with palliative chemotherapy. MATERIALS & METHODS: A total of 185 patients undergoing combination chemotherapy for relapsed/metastatic disease were considered eligible for the present clinical investigation. Four functional IGFBP-3 SNPs (rs3110697, rs2854746, rs2864744 and rs2960436) were studied for association with overall survival (OS). RESULTS: In the multivariate model including SNPs and clinicopathologic features, the rs285744 A allele and the rs2960436 A allele showed favorable association with survival. The hazard ratios for rs285744 C/A and A/A genotypes were 0.38 (95% CI: 0.18-0.66) and 0.20 (95% CI: 0.09-0.39), respectively. The hazard ratios for rs2960436 G/A and A/A genotypes were 0.41 (95% CI: 0.25-0.68) and 0.35 (95% CI: 0.16-0.58), respectively. Bonferroni-corrected p-values for the rs285744 A/A genotype and the rs2960436 A/A genotype were 0.012 and 0.024, respectively. There was linkage disequilibrium between the four variants and there were four common haplotypes (>5% estimated frequency). The most common haplotype (GCAA) included all alleles causing IGFBP-3 upregulation and their carriers demonstrated the best outcome in the log-rank comparison of survival curves. CONCLUSION: Genetic regulation of the IGFBP-3 impacts on survival of patients with advanced gastric cancer. This finding deserves additional studies because of its prognostic and therapeutic implications.

Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer.

PURPOSE: Regulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy. PATIENTS AND METHODS: Patients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)(n) dinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response. RESULTS: In 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (chi(2) test = 12.7; P = .001) and treatment response (chi(2) test = 9.45; P = .008) than EGFR intron-1 L/L carriers. CONCLUSION: Although additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.

Polymorphisms in genes involved in DNA repair and metabolism of xenobiotics in individual susceptibility to sporadic diffuse gastric cancer.

BACKGROUND: Gastric cancer is the second highest cause of cancer mortality in the world, despite declining rates of incidence in many industrialized countries. We carried out a case-control study to evaluate whether polymorphisms of DNA repair and glutathione S-transferase (GST) genes modulate the risk of developing diffuse gastric cancer. METHODS: ERCC1 118 T/C, XRCC1 399 G/A, XPD 312 G/A, XPD 751 A/C, XRCC3 241 C/T, MS 919 A/G, GSTP1 105 A/G, GSTM1-null/positive and GSTT1-null/positive genotypes were obtained for a series of 126 Helicobacter pylori-negative diffuse gastric cancer patients and 144 Helicobacter pylori-negative controls sampled from the population of Marche, an area with high gastric cancer risk in central Italy. RESULTS: GSTP1 105 A/G and GSTP1 105 G/G genotypes were identified as protective factors, with odds ratio (OR) of 0.4 (95% CI 0.17-0.81, p=0.01) and OR=0.58 (95% CI 0.33-1, p=0.05), respectively. GSTT1-null genotype was identified as a protective factor, with OR=0.48 (95% CI 0.22-0.99, p=0.04). There was no significant difference between cases and controls for XPD 751 A/C, ERCC1 118 T/C, XRCC3 241 C/T, XRCC1 399 G/A, XPD 312 G/A, GSTM1-null/positive and MS 919 A/G polymorphisms. CONCLUSIONS: This study suggests that GSTP1 105A/G and GSTT1-null/positive genotypes might be associated with a reduced risk for sporadic diffuse gastric cancer. Clin Chem Lab Med 2007;45:822-8.

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy.

PURPOSE: The objective is to investigate whether polymorphisms with putative influence on fluorouracil/oxaliplatin activity are associated with clinical outcomes of patients with advanced colorectal cancer treated with first-line oxaliplatin, folinic acid, and fluorouracil palliative chemotherapy. MATERIALS AND METHODS: Consecutive patients were prospectively enrolled onto medical oncology units in Central Italy. Patients were required to have cytologically/histologically confirmed metastatic disease with at least one measurable lesion. Peripheral blood samples were used for genotyping 12 polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase, xeroderma pigmentosum group D (XPD), excision repair cross complementing group 1 (ERCC1), x-ray cross complementing group 1, x-ray cross complementing protein 3, glutathione S-transferases (GSTs) genes. The primary end point of the study was to investigate the association between genotypes and progression-free survival (PFS). RESULTS: In 166 patients, ERCC1-118 T/T, XPD-751 A/C, and XPD-751 C/C genotypes were independently associated with adverse PFS. The presence of two risk genotypes (ERCC1-118 T/T combined with either XPD-751 A/C or XPD-751 C/C) occurred in 50 patients (31%). This profiling showed an independent role for unfavorable PFS with a hazard ratio of 2.84% and 95% CI of 1.47 to 5.45 (P = .002). Neurotoxicity was significantly associated with GSTP1-105 A/G. Carriers of the GSTP1-105 G/G genotype were more prone to suffer from grade 3 neurotoxicity than carriers of GSTP1-105 A/G and GSTP1-105 A/A genotypes. CONCLUSION: A pharmacogenetic approach may be an innovative strategy for optimizing palliative chemotherapy in patients with advanced colorectal cancer. These findings deserve confirmation in additional prospective studies.

Uridine diphosphate glucuronosyl transferase 1A1 promoter polymorphism predicts the risk of gastrointestinal toxicity and fatigue induced by irinotecan-based chemotherapy.

BACKGROUND: In the current Phase II study, the authors evaluated the association between genomic polymorphic variants in uridine diphosphate glucuronosyl transferase (UGT1A1), methylenetetrahydrofolate reductase (MTHFR), and thymidylate synthase (TS) genes, and the incidence of the adverse effects of irinotecan and raltitrexed in previously heavily treated patients with metastatic colorectal carcinoma. METHODS: Fifty-six patients received irinotecan (at a dose of 80 mg/m(2) on Days 1, 8, 15, and 22 every 5 wks), combined with raltitrexed (at a dose of 3 mg/m(2) every 3 wks). Genotyping for the MTHFR C677T polymorphism, the TATA box region in the UGT1A1 promoter, and tandem repeats in the TS promoter was performed on genomic DNA extracted from blood. Nineteen variables related to patient, disease, and treatment characteristics, together with genotypes, were analyzed using a binary logistic regression model with stepwise selection to evaluate their correlation with adverse reactions. RESULTS: Toxicities (determined according to the National Cancer Institute Common Toxicity Criteria) were evaluated in 169 cycles. Grade 3/4 neutropenia was reported to occur in 2% of cycles, Grade 2-4 nausea was reported to occur in 19% of cycles, Grade 2-4 emesis was reported to occur in 9% of cycles, Grade 2-4 diarrhea was reported to occur in 20% of cycles, Grade 2/3 fatigue was reported to occur in 11% of cycles, and Grade 3/4 hepatic toxicity was reported to occur in 7% of cycles. Homozygosis for six TA repeats in the promoter region of the UGT1A1 gene was found to be the main predictive factor for diarrhea (P < 0.00005), emesis (P = 0.0001), and fatigue (P = 0.007). Homozygosis for two tandem repeats in the TS promoter was found to be predictive of a reduced incidence of fatigue (P = 0.044). MTHFR C677T polymorphism was not found to be associated with any adverse reaction. CONCLUSIONS: In the current study, UGT1A1 promoter polymorphism was found to be predictive of the risk of diarrhea, emesis, and fatigue caused by chemotherapy with irinotecan and raltitrexed. Screening for UGT1A1 promoter polymorphism may be clinically useful for identifying patients at a higher risk of developing a severe or potentially life-threatening toxicity after irinotecan-based chemotherapy.

Pharmacogenetic profiling and clinical outcome of patients with advanced gastric cancer treated with palliative chemotherapy.

PURPOSE: To investigate whether polymorphisms with putative influence on fluorouracil/cisplatin activity are associated with clinical outcomes of patients with advanced gastric cancer (AGC). PATIENTS AND METHODS: Peripheral blood samples from 175 prospectively enrolled AGC patients treated with fluorouracil/cisplatin palliative chemotherapy were used for genotyping 13 polymorphisms in nine genes (TS, MTHFR, XPD, ERCC1, XRCC1, XRCC3, GSTPI, GSTTI, GSTMI). Genotypes were correlated to response and survival. RESULTS: The overall response rate was 41%, the median progression-free survival (PFS) was 24 weeks (range, 4 to 50 weeks), and the median overall survival (OS) was 39 weeks (range, 8 to 72+ weeks). Chemoresistance and poor survival were significantly associated with TS 5'-UTR 3G-genotype (2R/3G, 3C/3G, 3G/3G) and GSTP1 105 A/A homozygous genotype. Sixty-one patients (35%) did not show any of these risk genotypes (group 0), 57 patients (32.5%) showed one of the two risk genotypes (group 1), and 57 patients (32.5%) showed both risk genotypes (group 2). Median PFS and OS in group 0 patients were 32 weeks (range, 8 to 50 weeks) and 49 weeks (range, 18 to 72+ weeks), respectively. Group 1 and group 2 patients showed significantly worse PFS (median, 26 weeks [range, 6 to 44 weeks] and 14 weeks [range, 4 to 38 weeks], respectively) and worse OS (median, 39 weeks [range, 10 to 58 weeks] and 28 weeks [range, 8 to 56 weeks]), respectively, than group 0 patients. This adverse effect was retained in multivariate analysis. CONCLUSION: Specific polymorphisms may influence clinical outcomes of AGC patients. Selecting palliative chemotherapy on the basis of pretreatment genotyping may represent an innovative strategy that warrants prospective studies.

Methylenetetrahydrofolate reductase 677C/T gene polymorphism, gastric cancer susceptibility and genomic DNA hypomethylation in an at-risk Italian population.

We performed a case-control study to examine the relationship between MTHFR C677T gene polymorphism (MTHFR677C/T) and gastric cancer susceptibility in at-risk populations in central Italy. To explore genomic DNA hypomethylation as a potential etiologic mechanism, this phenomenon was evaluated in carriers of the MTHFR677T/T genotype and carriers of the wild-type MTHFR677C/C genotype. Lymphocyte genomic DNA from 162 gastric cancer patients and 164 controls was used for MTHFR677C/T genotyping. Unconditional regression analysis with ORs and 95% CIs was used to investigate the association of the polymorphism with disease. Genomic DNA methylation status by an established enzymatic assay that measures the DNA accepting capacity of methyl groups (inversely related to endogenous methylation) was assessed in a random sample of 40 carriers of the wild-type MTHFR677C/C genotype and 40 carriers of the MTHFR677T/T genotype. The global allelic distribution was in Hardy-Weinberg equilibrium. The MTHFR677T allele was significantly associated with gastric cancer risk with an OR of 2.49 (95% CI 1.48-4.20) in heterozygous MTHFR677C/T carriers and an OR of 2.85 (95% CI 1.52-5.35) in homozygous MTHFR677T/T carriers. This risk association was retained in subgroup analyses by tumor histotype and location. Genomic DNA hypomethylation status in MTHFR677T/T carriers was significantly higher than in subjects with wild-type MTHF677C/C genotype (p = 0.012). In the studied population, MTHFR677T played the role of a moderate-penetrance gastric cancer susceptibility allele. Possession of the MTHFR677T/T genotype was significantly associated with genomic DNA hypomethylation. These findings deserve further investigation in the context of novel strategies for gastric cancer prevention.