Background

Diet is an important risk factor of colorectal cancer (CRC) and affects cancer risk through its effects on colonic microbial metabolism. Few population-based studies have examined the relationship between diet-derived metabolites and the risk of CRC in the context of Asian diet, microbiota composition and anatomical subsite.

Methods

We conducted a nested case-control study of 350 incident CRC (211 colon and 139 rectal) cases and 350 matched controls within the Singapore Chinese Health Study, a prospective cohort of 63,257 men and women. Liquid and gas chromatography-mass spectrometries were used to quantify 61 plasma metabolites, including amino acids, carnitine, acylcarnitines, short chain fatty acids, bile acids, monosaccharides and organic compounds. Conditional logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI).

Results

Compared to controls, colon cancer cases had statistically significant higher mean levels of glutamine, arginine, tauroursodeoxycholic acid (TUDCA), taurodeoxycholic acid (TDCA), glycodeoxycholic acid (GDCA), and lower mean levels of leucine and valine. Rectal cancer cases had statistically significant higher mean levels of mannose, glucose and isobutyric acid than controls. 9 metabolites [arginine, glutamine, mannose, deoxycholic acid (DCA), GDCA, taurochenodeoxycholic acid (TCDCA), TDCA, TUDCA and betaine] were associated with an increased risk of colon cancer (all p < 0.05). Valine was inversely associated with colon cancer (OR_{3rd vs 1st tertile} 0.45; 95% CI, 0.25-0.81). 7 metabolites (glucose, mannose, propionic acid, DCA, GDCA, TDCA and glycolate) were associated with an increased risk of rectal cancer (all p < 0.05). Only glucose significantly improved the risk prediction of rectal cancer. No metabolites led to an improvement in the predictive model for colon cancer.

Conclusions

Dysregulation of secondary bile acids, monosaccharides, amino acids and short chain fatty acids may play a role in CRC development. Further studies are required to validate our findings.

Legal entity responsible for the study

The authors.

Funding

National Medical Research Council.

Disclosure

All authors have declared no conflicts of interest.

Background

Precision medicine is associated with favorable outcomes in selected patients. We initiated IMPACT 2, a randomized study to compare PFS in patients with metastatic cancer treated on the basis of tumor genomic profiling results vs. those whose treatment was not selected based on genomic analysis. Herein, we assessed the association between patient characteristics and overall survival (OS).

Methods

Patients with advanced, metastatic cancer underwent tumor biopsy and genomic profiling (Foundation One). Variants were filtered to eliminate germline mutations (annotation, ANNOVAR) and artifacts. Patients were presented at tumor board and were randomized if they met criteria for clinical trials. OS was measured from enrollment on study until last follow-up or death from any cause.

Results

From 5/2014 to 4/2017, 320 of 391 enrolled patients completed tumor profiling. Baseline characteristics (n = 320) were as follows: men, 47%; median age, 63 yrs (range, 25-83); performance status 1, 88%; median no. of prior therapies, 3 (range, 0-14); liver metastases, 40%; albumin < 3.5 g/L, 12%; LDH > 618 IU/L, 29%; platelet count > or < the normal limits, 15%. Most common tumor types were head and neck, 19%; gastrointestinal, 16%; and lung, 11%. Most frequently mutated genes: TP53, 42%; KRAS,16%; PIK3CA,12%; and CDKN2A, 11%. Of 320 patients, 69 (22%) were randomized; of the remaining 251 patients, 153 (61%) received other treatment (investigational or standard). Results of multivariate analyses for OS are displayed below.Table:

449PD

Conclusions

In patients with metastatic cancer, age < 60 yrs, absence of liver metastases, normal albumin and LDH levels, and absence of KRAS or TP53 mutations were independent factors predicting longer OS. We demonstrated the feasibility of molecular profiling using newly obtained tumor biopsies and treating patients prospectively. The study is ongoing. Outcomes for randomized patients are awaited upon completion of the study.

Clinical trial identification

www.clinicaltrials.gov NCT02152254, First posted June 2, 2014.

Legal entity responsible for the study

The authors.

Funding

Foundation Medicine.

Disclosure

A.M. Tsimberidou: Research grant / Funding (institution): IMMATICS; Research grant / Funding (institution): Tempus; Research grant / Funding (institution): Parker Institute for Cancer Immunotherapy; Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Baxalta; Research grant / Funding (institution): Foundation Medicine; Research grant / Funding (institution): Boston Biomedical; Research grant / Funding (institution): Placon Therapeutics; Research grant / Funding (institution): Karus Therapeutics; Research grant / Funding (institution): Tvardi; Research grant / Funding (institution): OBI Pharma; Advisory / Consultancy: Roche, Europe; Advisory / Consultancy: Covance; Advisory / Consultancy: Genentech. D.S. Hong: Research grant / Funding (self): Adaptimmune; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): Bayer; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Daichi-Sanko; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Infinity; Research grant / Funding (institution): Kite; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): LOXO; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Medimmune; Research grant / Funding (institution): Molecular Template; Research grant / Funding (institution): Novartis. All other authors have declared no conflicts of interest.

Background

Circulating DNA (cfDNA) has emerged as a potential biomarker in cancer, and is the subject of extensive studies in translational and clinical research. Our group has been interested in its implication and clinical significance in the field of oncology for many years, and is now focused on evaluating its potential for early cancer detection.

Methods

We recently developed a screening test (MNR: Multi Normalized Ratio), based on various cfDNA parameters determined by a specific q-PCR based method, targeting both nuclear and mitochondrial sequences.

Results

When applied to the supernatant of cell culture, the MNR had a discriminative potential of 100% between normal and cancer cell lines. An extensive evaluation of this test was carried out in plasma samples of 289 healthy subjects and 987 cancer patients (CRC, breast, liver, pancreatic, ovarian) of all stages. Preliminary results revealed a high potential with an AUC of 0.81 (0.78-0.84, 95% CI), a 70% sensitivity (Se) and 77% specificity (Sp). In breast cancer (N = 169), an AUC of 0.82 (0.78-0.86, 95% CI) with 72% Se and 80% Sp were observed. In all stages CRC patients (N = 795), the results showed an AUC of 0.80 (0.78-0.84, 95%, CI), 75% Se and 70% Sp; for CRC stages 0/I/II (N = 426), an AUC of 0.79 (0.75-0.82, 95% CI), 70% Se and 72% Sp; and for CRC stage IV (N = 186), a 0.86 AUC (0.82-0.89, 95% CI) with 75% Se and 80% Sp. When combining the MNR to a total cfDNA concentration threshold value (AUC = 0.81 (0.79-0.83, 95% CI), 72% Se and 76% Sp for all stage cancers (N = 987)), in a test cohort of 173 stages 0/I/II CRC patients and 132 healthy individuals, we increased the sensitivity and specificity to 74% and 95% respectively. Furthermore we recently discovered that cfDNA fragmentation, as determined by Whole Genome Sequencing using either double or single strand library, is also a parameter enabling discrimination between healthy and cancer individuals.

Conclusions

The implementation of a multi-parametric test combining total cfDNA quantification, MNR and fragmentation biomarkers, with help of a decision tree in machine learning, is currently on-going. Our data suggest that our strategy in targeting cfDNA structural features might be powerful for early cancer detection, and appears as an alternative or a synergistic combination to the detection of mutations.

Legal entity responsible for the study

Alain R. Thierry - INSERM (Institut national de la santé et de la recherche médicale).

Funding

MSDAvenir - Mitest / Alain R. Thierry is supported by INSERM (Institut national de la santé et de la recherche médicale).

Disclosure

All authors have declared no conflicts of interest.

Background

The clinical utility of non-invasive liquid biopsy and ability to accurately detect EGFR mutations in circulating-tumor DNA of patients with NSCLC has been well demonstrated. This expands the pool of patients eligible for molecular testing. The cobas^® EGFR Mutation Test v2 (cobas test) is a real-time PCR test for qualitative and semi-quantitative detection of 42 EGFR mutations in DNA from tissue and circulating free DNA (cfDNA) from K2 EDTA plasma. Blood collected in K2 EDTA requires plasma be separated within 8 hours, which can be a barrier to molecular testing and thus impact treatment decisions. The Roche Cell-Free DNA Collection Tube (Roche cfDNA) stabilizes blood up to 8 days, allowing greater flexibility in transportation and time to plasma separation. Here the suitability of plasma from Roche cfDNA tubes for use with the cobas test is demonstrated.

Methods

Test performance with Roche cfDNA plasma was verified with NSCLC patient specimens or surrogate samples (sheared cell line DNA in healthy donor plasma). Correlation was tested using paired draws in K2 EDTA and Roche cfDNA tubes for 51 NSCLC patients and 20 healthy donor surrogate samples. Limit of detection (LoD) and linearity established with K2 EDTA plasma were verified with Roche cfDNA plasma. Reproducibility was assessed using surrogate samples at two levels with multiple operators, Roche cfDNA tube lots, instruments, days and sites. Blood storage conditions were established at an external laboratory with 6 NSCLC patient specimens.

Results

Compared to K2 EDTA plasma, Roche cfDNA plasma had a PPA, NPA and OPA of 100.0% with the cobas test. LoD for EGFR mutation detection in Roche cfDNA plasma was verified as ≤ 100 cp/mL. Linearity for EGFR mutations in Roche cfDNA plasma was verified. The reproducibility study had a call agreement of ≥ 98.6%. Blood in Roche cfDNA tubes was stable for up to 8 days at 18-25ºC with one excursion of up to 24 hours at 15-30ºC prior to separation.

Conclusions

Use of the Roche cfDNA tube with the cobas^® EGFR Mutation Test v2 provides the flexibility to store blood for up to 8 days prior to separation, with equivalent performance to K2 EDTA plasma, and facilitates use of liquid biopsy for NSCLC patients needing molecular testing.

Legal entity responsible for the study

Roche Molecular Systems Inc.

Funding

AstraZeneca PLC.

Disclosure

T.E. May: Full / Part-time employment: Roche Molecular Solutions. S.A. Scudder: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche Molecular Solutions. S.J. Joshi: Full / Part-time employment: Roche Molecular Solutions. M. Kohlmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca, PLC. N. Shrestha: Full / Part-time employment: Roche Molecular Solutions. N. Lee: Full / Part-time employment: Roche Molecular Solutions. J. Lai: Full / Part-time employment: Roche Molecular Systems Inc. M. Tsourounis: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca PLC. A. Kohlmann: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca PLC. P. O’Donnell: Full / Part-time employment, Spouse / Financial dependant: Roche Molecular Systems. H. Halait: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche Molecular Systems. All other authors have declared no conflicts of interest.

Background

Weight loss prior to cancer treatment carry a negative impact on clinical outcomes. However, few studies have addressed whether weight assessment over time is plagued by high dropout rates and whether weight change carries a prognostic association in the same manner as it does at baseline.

Methods

A pooled analysis of individual patient data was undertaken among non-small cell lung cancer patients who participated in prospective cancer treatment trials from the Alliance for Clinical Trials in Oncology from 1998-2008. This study examined 1) rates of missing weight data over time and 2) the prognostic association of weight beyond baseline assessment.

Results

822 chemotherapy-treated patients were examined. 659 (80%) were still on treatment at the beginning of cycle 2. Weight was available for 656 (80%) patients. However, by cycles 3 and 4, weight was available for only 448 (55%) and 384 (47%) patients, respectively. From baseline to immediately prior to cycle 2, 224 patients (34% of 656) lost more than 2% baseline weight, and 226 (34%) lost between 0 and 2%. With respect to prognostic associations, the median survival time from the beginning of cycle 2 was 6.9, 10.9, and 13.0 months for patients with weight loss of 2% or more, loss of < 2%, and those with weight gain, respectively. In multivariate analyses, after adjustment for age, gender, performance score, type of treatment, and body mass index, weight loss of 2% or more was associated with poor survival compared to weight loss of < 2% (hazard ratio (HR) = 1.57; 95% CI [1.27 to 1.95]; P <.001). Although weight gain was not associated with improved overall survival, it was associated with better progression-free survival outcomes (HR = 0.81; 95% CI [0.66 to 0.99]; P=.04).

Conclusions

Weight is a clinically useful endpoint and should be integrated into cancer cachexia trials because of its ease of frequent measurement and sustained prognostic association.

Legal entity responsible for the study

The authors.

Funding

Fred C and Katherine B Andersen Foundation and the United States National Cancer Institute.

Disclosure

All authors have declared no conflicts of interest.