Browsing by Author "Del Bel Belluz, L."

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Assessing tumor molecular profiling to guide treatments for patients with advanced female genital tract malignancy
(Impact Journals, 2017) Carter, P.; Alifrangis, C.; Cereser, B.; Chandrasinghe, P.; Del Bel Belluz, L.; Fotopoulou, C.; Frilling, A.; Herzog, T.; Moderau, N.; Tabassum, N.; Krell, J.; Stebbing, J.
Tumor molecular profiling has enabled selection of targeted therapies in a host of solid tumors. Here we used a retrospective clinical cohort, to evaluate the benefit of tailoring treatments for female genital tract malignancy, using tumor molecular profiles. Clinical outcome data for 112 patients was retrospectively separated into two groups. These either followed a matched treatment plan that incorporated at least one drug recommended according to their tumor profile and none that were expected to have no benefit (64 patients), or was unmatched with suggested treatments and received at least one drug that was anticipated to lack benefit for that tumor (48 patients). In the group of patients whose drugs matched those recommended by molecular profiling of their tumor, their overall survival was 593 days on average, compared to 449 days for patients that did not; removing drugs predicted to have no benefit from treatment regimens received after profiling increased survival by 144 days on average (P = 0.0265). In the matched treatment group, 30% of patients had died by the last time of monitoring, whereas this was 40% in the unmatched group (P = 0.2778). The IHC biomarker for the progesterone receptor was demonstrated to be prognostic for survival.
The benefit of tumor molecular profiling on predicting treatments for colorectal adenocarcinomas
(Impact Journals, 2018) Carter, P.; Alifrangis, C.; Chandrasinghe, P.; Cereser, B.; Del Bel Belluz, L.; Leo, C.A.; Moderau, N.; Tabassum, N.; Warusavitarne, J.; Krell, J.; Stebbing, J.
Correction: Does molecular profiling of tumors using the Caris molecular intelligence platform improve outcomes for cancer patients?
(Impact Journals LLC, 2018) Carter, P.; Alifrangis, C.; Cereser, B.; Chandrasinghe, P.; Del Bel Belluz, L.; Herzog, T.; Levitan, J.; Moderau, N.; Schwartzberg, L.; Tabassum, N.; Wen, J.; Krell, J.; Stebbing, J.
This corrects the article DOI: 10.18632/oncotarget.24258.]. Erratum for Does molecular profiling of tumors using the Caris molecular intelligence platform improve outcomes for cancer patients? [Oncotarget. 2018 ;9(10):9456-9467]
Correction: The benefit of tumor molecular profiling on predicting treatments for colorectal adenocarcinomas
(Impact Journals LLC, 2018) Carter, P.; Alifrangis, C.; Chandrasinghe, P.; Cereser, B.; Del Bel Belluz, L.; Leo, C.A.; Moderau, N.; Tabassum, N.; Warusavitarne, J.; Krell, J.; Stebbing, J.
This corrects the article DOI: 10.18632/oncotarget.24257. Erratum for The benefit of tumor molecular profiling on predicting treatments for colorectal adenocarcinomas [Oncotarget. 2018 ;9(13):11371-11376]
Does molecular profiling of tumors using the Caris molecular intelligence platform improve outcomes for cancer patients?
(Impact Journals, 2018) Carter, P.; Alifrangis, C.; Cereser, B.; Chandrasinghe, P.; Del Bel Belluz, L.; Herzog, T.; Levitan, J.; Moderau, N.; Schwartzberg, L.; Tabassum, N.; Wen, J.; Krell, J.; Stebbing, J.
We evaluated the effect of tailoring treatments based on predictions informed by tumor molecular profiles across a range of cancers, using data from Caris Life Sciences. These included breast carcinoma, colorectal adenocarcinoma, female genital tract malignancy, lung non-small cell lung cancer, neuroendocrine tumors, ovarian surface epithelial carcinomas, and urinary tract cancers.Molecular profiles using mostly immunohistochemistry (IHC) and DNA sequencing for tumors from 841 patients had been previously used to recommend treatments; some physicians followed the suggestions completely while some did not. This information was assessed to find out if the outcome was better for the patients where their received drugs matched recommendations.The IHC biomarker for the progesterone receptor and for the androgen receptor were found to be most prognostic for survival overall. The IHC biomarkers for P-glycoprotein (PGP), tyrosine-protein kinase Met (cMET) and the DNA excision repair protein ERCC1 were also shown to be significant predictors of outcome. Patients whose treatments matched those predicted to be of benefit survived for an average of 512 days, compared to 468 days for those that did not (P = 0.0684). In the matched treatment group, 34% of patients were deceased at the completion of monitoring, whereas this was 47% in the unmatched group (P = 0.0001).
Molecular profiling of advanced breast cancer tumors is beneficial in assisting clinical treatment plans
(Impact Journals, 2018) Carter, P.; Alifrangis, C.; Cereser, B.; Chandrasinghe, P.; Del Bel Belluz, L.; Moderau, N.; Poyia, F.; Schwatzberg, L.S.; Tabassum, N.; Wen, J.; Krell, J.; Stebbing, J.
We used data obtained by Caris Life Sciences, to evaluate the benefits of tailoring treatments for a breast carcinoma cohort by using tumor molecular profiles to inform decisions. Data for 92 breast cancer patients from the commercial Caris Molecular Intelligence database was retrospectively divided into two groups, so that the first always followed treatment recommendations, whereas in the second group all patients received at least one drug after profiling that was predicted to lack benefit. The biomarker and drug associations were based on tests including fluorescent in situ hybridization and DNA sequencing, although immunohistochemistry was the main test used. Patients whose drugs matched those recommended according to their tumor profile had an average overall survival of 667 days, compared to 510 days for patients that did not (P=0.0316). In the matched treatment group, 26% of patients were deceased by the last time of monitoring, whereas this was 41% in the unmatched group (P=0.1257). We therefore confirm the ability of tumor molecular profiling to improve survival of breast cancer patients. Immunohistochemistry biomarkers for the androgen, estrogen and progesterone receptors were found to be prognostic for survival.
SMAD7 shows a biphasic expression pattern during progression of ulcerative colitis-associated colorectal cancer
(Oxford University Press, 2019) Chandrasinghe, P.; Cereser, B.; Moorghen, M.; Spaggiari, P.; Maroli, A.; Del Bel Belluz, L.; Hart, A.; Spinelli, A.; Stebbing, J.; Warusavitarne, J.
BACKGROUND: Ulcerative colitis (UC) is an idiopathic inflammation of the intestine with an increased risk of developing colitis-associated cancer (CAC). Currently, clinical trials are underway aiming to inhibit SMAD7 to ameliorate inflammation. While the direct effect of depleting SMAD7, an inhibitory molecule in the transforming growth factor-β1 (TGFβ1) pathway, may be therapeutic in UC, its indirect effect on CAC development is largely unknown. TGFβ1 is known to enhance late stages of sporadic colorectal cancers (CRC), where SMAD7 is also elevated. Therefore, we hypothesise that removing inhibition of this pathway by depleting SMAD7 may also be detrimental for CAC. We therefore evaluated the expression of SMAD7 in the colonic epithelium during the inflammation associated neoplastic process to determine a possible role of SMAD7 in CAC. METHODS: The expression of SMAD7 protein and mRNA in colonic epithelia was assessed by immunohistochemistry (IHC) and in situ hybridisation (ISH),, respectively, in a cohort of 53 archival colon samples (17 CAC, 12 dysplastic, 12 inflammed, 12 non-neoplastic/non-inflammed) from patients who have undergone colectomies for UC and CAC. The expression within the epithelial cells was evaluated by both digital quantification and validated by blind scoring by a pathologist. Significant differences were tested with one-way ANOVA and Mann–Whitney U test. RESULTS: Cytoplasmic expression of SMAD7 protein is significantly higher in the inflammed epithelium compared with non-inflamed epithelium (p < 0.0001). Interestingly, a significant decrease of the same was detected in dysplasia (p = 0.01), although this group is characterised by a higher variability. SMAD7 levels are elevated in cancer compared with dysplasia, suggesting a biphasic expression (p = 0.009), which could be in part due to the different genetic composition. SMAD7 mRNA expression was not significantly different across different stages of CAC (p = 0.49). We hypothesise that the lack of correlation between mRNA and protein levels could be attributed to yet unknown post-transcriptional or post-translational regulations. CONCLUSIONS:In our cohort of UC affected colon tissues, SMAD7 demonstrated a biphasic expression pattern along the different stages of CAC with peaks during active inflammation and cancer. The increase in SMAD7 expression during neoplastic transformation, comparable to sporadic CRC, may be a protective response of the epithelium to inhibit the effect of TGFβ1. Although inhibiting SMAD7 as a therapy for UC may remit inflammation, we hypothesise it may exacerbate CAC due to further enhancement in TGFβ1 signalling. We envisage further mechanistic studies in vitro, in particular in organoids, could help in understanding the TGFβ superfamily pathway in CAC.