Silent theatre 2 – Sunday 3 November

3:50 pm-4:15 pm

Room: Hall 4


Programme session type(s): Silent theatre

Cachexia-related biomarkers predict shortened survival and treatment-related adverse outcomes in a population receiving palliative chemotherapy for lung cancer
Speaker: Joanna Bowden
Affiliation: NHS Fife, Kirkcaldy, UK, University of Edinburgh, Edinburgh, UK, University of St Andrews, St Andrews, UK

Abstract:

Optimal patient selection for palliative chemotherapy for lung cancer poses significant challenges. Several factors are associated with adverse outcomes in lung cancer, including poor performance status (measured by Eastern Cooperative Oncology Group, ECOG PS), low body mass index (BMI), weight loss and systemic inflammation. We sought to identify predictive variables for a range of adverse outcomes in a population receiving palliative chemotherapy for lung cancer.

Method

A retrospective cohort study of patients who received first-line palliative chemotherapy for lung cancer during 2013-2015 in South East Scotland was undertaken. Demographic and clinical data was extracted from electronic health records. Body composition analysis was conducted using diagnostic computed tomography scans to evaluate muscularity (skeletal muscle index, SMI) and muscle density (muscle attenuation, MA). Established thresholds for variables were utilised where available. Where not available, optimal stratification was used to derive discriminatory thresholds for overall survival (OS). Outcome measures included OS and treatment-related adverse events. Only OS is reported here.

Time to event data were analysed using Kaplan-Meier methods and Cox Proportional Hazards regression.

Results

397 patients were included; 259 with non-small cell lung cancer (NSCLC) and 138 small cell lung cancer (SCLC). 295 (80%) had an ECOG PS of 0/1 at diagnosis. Mean BMI was 25.9 (SD=5.3)

Median OS was 215 days (95%CI 191, 239). 191 patients (48%) received fewer than 4 cycles of chemotherapy; their median survival was 112 days (95%CI 97-127), p<0.001.

Independent predictors of reduced OS were baseline NLR ≥4, Albumin <35, SMI and MA. ECOG PS was not a significant predictor of OS. 4 composite models based on independent predictors were explored.

Conclusion

It is possible to identify patients at significant risk of reduced OS and other adverse outcomes at diagnosis. Our predictive models require further validation and could improve patient selection for palliative chemotherapy for lung cancer in the future.

Modulation of tumor microenvironment by targeting cancer associated fibroblasts in dendritic cell based immunotherapy
Speaker: Sheefa Mirza
Affiliation: University of Witwatersrand

Abstract:

Cancer associated fibroblasts (CAFs), main component of TME, have an important role in generating immunosuppresive TME by modulating recruitment and functions of tumor-associated immune cells by secreting various growth hormones, miRNAs and cytokines. Curcumin is known to modulate numerous target proteins including transcription factors, receptors, kinases, cytokines, enzymes and growth factors. Thus, aim of the study was to evaluate the effect of miRNAs and cytokines released by lung cancer patients’ derived CAFs and to assess immunomodulatory potential of curcumin on DC maturation by targeting these CAFs through modulating their TME.


Method

CAFs were cultured and characterized using CAF-specific markers. rGM-CSF and rIL-4 were used to generate immature DCs (imDCs).Further, imDCs were cultured in conditioned media derived from CAFs (CAFs-CM) as well as NFs (Normal Fibroblasts) to evaluate the effect of CAFs on DC maturation. mDCs were characterized by qRT-PCR using CD80, CD83, CD86 and CTLA4. Moreover, miR-221, miR-222, miR-155, miR-142-3p and miR-146a were assessed to evaluate their epigenetic regulation on DC maturation. Cytokine profiling of CAFs-CM as well as CAFs-CM treated with curcumin was conducted.

Results

α-SMA+Vimentin+ cells were considered as CAFs. Significant upregulation of CD80, CD83 and CD86 was observed when cultured in NFs-CM while a remarkable downregulation of these markers was found when cultured in CAFs-CM. CTLA-4 was down regulated in NFs-CM as compared to CAFs-CM, suggesting the role of CAFs in generation of regulatory DCs. Amongst all miRNAs, miR-146a was shown to be up regulated dramatically in CAF-DCs (DCs cultured in CAFs-CM) as well as in CAFs-CM, suggesting the immunosuppressive role of miR-146a. Further, an increased expression of miR-146a was positively correlated with increased expression of anti-inflammatory cytokines like IL-6, IL-10, TGF-β and decreased expression of TNF-α (pro-inflammatory) in CM derived from CAF-DCs. Moreover, curcumin had the potential to convert regulatory DCs facilitated by CAFs into mDCs, which were characterized by high expression of co-stimulatory molecules, low expression of CTLA4, lower levels of immune suppressive cytokines production, lower levels of miR-146a.

Conclusion

These findings provide insight into understanding the immunomodulatory role of curcumin in targeting CAFs and modulating the tumor microenvironment, thus enhancing antitumor immune response in DC based therapy.

Serum hormones and prostate cancer incidence and mortality in UK Biobank
Speaker: Ruth Travis
Affiliation: University of Oxford

Abstract:

Modifiable risk factors for prostate cancer are not well established. Insulin-like growth factor-I (IGF-I) and testosterone have been implicated in prostate cancer development and progression, but these associations are not fully understood. We investigated the associations of circulating concentrations of IGF-I, free (biologically active testosterone) and total testosterone, and sex hormone binding globulin (SHBG) with prostate cancer incidence and mortality in a large British cohort.

Method

We studied up to 200,452 male UK Biobank participants who were free from cancer and not receiving hormone therapy at recruitment, and had hormone measurements on baseline blood samples. Free testosterone was calculated from measured total testosterone and binding protein concentrations. Follow-up for cancer incidence and vital status was via data linkage to national registries. Cox proportional hazards models yielded multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for prostate cancer incidence and mortality by serum hormone concentrations. HRs were corrected for regression dilution using repeat hormone measurements from a subsample of up to 7794 men.

Results

After a mean follow-up of 6.9 years, 5412 men were diagnosed with prostate cancer and 296 had died from the disease. Higher circulating IGF-I was associated with an elevated risk of prostate cancer diagnosis (HR per 1 SD increase = 1.11, 95%CI 1.07-1.15) and prostate cancer mortality (1.17, 1.01-1.36). Higher free testosterone was associated with an elevated risk of incident prostate cancer (1.14, 1.08-1.20), whereas higher SHBG was associated with a lower risk (0.93, 0.90-0.96), but neither was associated with prostate cancer mortality. Total testosterone concentration was not associated with prostate cancer incidence or mortality.

Conclusion

The findings from this large prospective cohort study of circulating hormone concentrations support the hypothesised roles of IGF-I and free testosterone in prostate cancer development. Future research will examine associations by tumour characteristics.