Beyond traditional therapies: clinical significance of complex molecular profiling in patients with advanced solid tumours-results from a Turkish multi-centre study.

OBJECTIVE: The objective of this multi-centre, real-world study was to examine the potential influence of comprehensive molecular profiling on the development of treatment decisions or adjustments for patients with advanced solid malignancies. We then evaluated the impact of these informed choices on patient treatment outcomes. METHODS: The study encompassed 234 adult patients (mean age: 52.7 ± 14.3 years, 54.7% women) who were diagnosed with solid tumours at 21 different medical centres in Turkey. Remarkably, 67.9% of the patients exhibited metastasis at the time of diagnosis. We utilized an OncoDNA (Gosselies, Belgium) platform (OncoDEEP) integrating next-generation sequencing with additional tests to harvest complex molecular profiling data. The results were analyzed in relation with two specific outcomes: (i) the impact on therapeutic decisions, including formulation or modifications, and (ii) associated treatment response. RESULTS: Out of the 228 patients with final molecular profiling results, 118 (50.4%) had their treatment modified, whilst the remaining 110 (47.0%) did not. The response rates were comparable, with 3.9 versus 3.4% for complete response, 13.6 versus 29.3% for partial response, 66.9 versus 51.7% for progressive disease and 15.5 versus 15.5% for stable disease for treatments informed and not informed by complex molecular profiling, respectively (P = 0.16). CONCLUSION: Our real-world findings highlight the significant impact of complex molecular profiling on the treatment decisions made by oncologists for a substantial portion of patients with advanced solid tumours. Regrettably, no significant advantage was detected in terms of treatment response or disease control rates.

Association of PD-1 and PDL-1 gene polymorphisms with colorectal cancer risk and prognosis.

BACKGROUND: Programmed Cell Death-1 (PD-1) together with Programmed Death Ligand 1 (PDL-1) have crucial roles in anti-tumor immune response, cancer susceptibility and prognosis. Since PD-1 and PDL-1 have been considered as important genetic risk factors in cancer development and their functions can be affected by polymorphic sites, we investigated the effects of PD-1 rs2227981, rs2227982, rs36084323 and PDL-1 rs2282055, rs822336 gene polymorphisms on colorectal cancer (CRC) risk and prognosis in Turkish subjects. METHODS AND RESULTS: Our study group consisted of 5-FU or Capacitabine prescribed CRC diagnosed patients and healthy controls. Genotype analyses of PD1 and PDL-1 polymorphisms were performed with Agena MassARRAY platform. rs36084323 CT genotype frequency was found to be higher in controls compared to cases (p < 0.001). rs36084323 CT genotype was highly associated with reduced CRC risk compared to CC genotype (OR 0.068, 95% CI 0.022-0.211, p < 0.001). In adjusted analysis, rs2282055 GG genotype was found to be associated with reduced CRC risk (OR 0.271, 95% CI 0.078-0.940, p = 0.040). rs2282055 TT genotype was found to be related to longer progression-free (Bonferroni corrected Log rank p = 0.013) and overall survival (Bonferroni corrected Log rank p = 0.009) to that of GG genotypes. Patients with rs822336 GC+CC genotypes showed longer overall survival times compared to GG (Log rank p = 0.044). CONCLUSIONS: According to our results, PD-1 rs822336 G > C polymorphism might be useful in predicting CRC prognosis. PDL-1 rs2282055 T > G polymorphism might be useful in predicting both CRC risk and prognosis. Further studies should be conducted in larger and different populations to clear the roles of PD-1 and PDL-1 polymorphisms in CRC risk and prognosis.

The value of plasma netrin-1 in non-small cell lung cancer patients as diagnostic and prognostic biomarker.

Netrin-1 is found to be elevated and purposive as a diagnostic biomarker in many human cancers. We evaluated serum netrin-1 concentrations in patients with advanced non-small cell lung cancer compared with those in a healthy group. Thirty patients with advanced non-small cell lung cancer and 30 healthy people were included in the study. Serum netrin-1 concentrations were measured by quantitative ELISA method in both groups. The mean serum netrin-1 concentrations were found to be significantly higher in patients with non-small cell lung cancer than in healthy controls. The mean serum netrin-1 concentrations were found to be significantly higher in patients with non-small cell lung cancer before the beginning of chemotherapy when compared after the completion of the third cycle. Our results represented that netrin-1 concentrations elevated in advanced non-small cell lung cancer compared to a healthy control group, and netrin-1 concentrations decreased with chemotherapy.

Prognostic factors for recurrence-free survival in patients with HER2-positive early-stage breast cancer treated with adjuvant trastuzumab.

BACKGROUND: The objective of this study was to identify prognostic factors affecting the recurrence-free survival (RFS) in patients who received a 52-week trastuzumab therapy for HER2-positive early stage breast cancer (EBC). PATIENTS AND METHODS: The medical records of all patients with EBC from 10 centers were analyzed. Pathologic and clinical tumor characteristics were evaluated in 424 female patients who received 52 weeks of adjuvant trastuzumab for HER2-positive EBC. Survival was estimated using the Kaplan-Meier method. Univariate analyses of RFS were performed with the log-rank test. Independent prognostic and predictive factors affecting RFS were assessed by Cox regression analysis. RESULTS: Median follow-up time was 33.1 months (range 9.2-75.9 months). 3-year RFS and overall survival were 87 and 97%, respectively. In multivariate analysis, patients aged 70 years or over (p = 0.017, relative risk (RR) 2.7, 95% confidence interval (CI) 1.19-6.13), patients with > 9 positive lymph nodes (p = 0.001, RR 2.52, 95% CI 1.42-4.46), and those with progesterone receptor-negative tumors (p = 0.006, RR 2.33, 95% CI 1.27-4.27) had worse RFS. CONCLUSION: In spite of a 52-week adjuvant trastuzumab treatment, classic poor prognostic factors for invasive EBC remained as such in patients with HER2-positive EBC.

Yttrium-90 transarterial radioembolization and capecitabine in hepatocellular carcinoma with portal vein involvement.

Hepatocellular carcinoma (HCC) with portal vein tumor thrombus is considered an advanced stage disease. Non-surgical local and systemic therapies are the only treatment options available. To analyze the survival and toxicity outcomes of systemic treatment concurrent with yttrium-90 transarterial radioembolization in HCC with liver-limited disease and portal vein involvement with Child-Pugh B liver reserve. The medical records of 22 patients who underwent yttrium-90 transarterial radioembolization concomitant with capecitabine chemotherapy as first-line treatment between 2014 and 2019 were retrospectively reviewed. Twenty-two patients were included in the study. Grade 3 to 4 side effects were evaluated, and hepatic encephalopathy developed in 1 patient after yttrium-90 transarterial radioembolization. In the fourth month of radiological evaluation, 11 patients had a partial response (50%), 5 patients had stable disease (22.7%), and 6 patients (27.3%) developed progressive disease. The median survival time was 21 months. Combined treatment with yttrium-90 transarterial radioembolization and capecitabine may be an effective and safe treatment option. Treatment was associated with a median overall survival of 21 months and a disease control rate of 72.7% at 4 months in patients with inoperable HCC.

Netrin-1 concentrations in patients with advanced gastric cancer and its relation with treatment.

CONTEXT: Netrin-1 is found to be elevated and usable as a diagnostic biomarker in many human cancers. OBJECTIVES: We evaluated serum Netrin-1 concentrations in patients with advanced gastric cancer compared with those in a healthy group. MATERIAL AND METHODS: Thirty patients with advanced gastric cancer and thirty healthy people were included in the study. Serum netrin-1 concentrations were measured by quantitative ELISA method in both groups. RESULTS: The mean serum Netrin-1 concentrations were found to be significantly higher in patients with gastric cancer than in healthy controls. The mean serum Netrin-1 concentrations were found to be significantly higher in patients with gastric cancer before the beginning of chemotherapy when compared after the completion of third cycle. DISCUSSION AND CONCLUSION: Our results indicated that netrin-1 concentrations elevated in advanced gastric cancer compared to a healthy control group and netrin-1 concentrations decreased with chemotherapy.

Investigation of DPYD, MTHFR and TYMS polymorphisms on 5-fluorouracil related toxicities in colorectal cancer.

Aim: To investigate the association of DPYD, MTHFR and TYMS polymorphisms on 5-fluorouracil (5-FU) related toxicities and patient survival. Materials & methods: A total of 103 colorectal cancer patients prescribed 5-FU were included in the study. Genotyping was conducted for several DPYD, MTHFR and TYMS polymorphisms using a microarray analyzer. Results: DPYD 496A>G polymorphism was found to be significantly associated with 5-FU related grade 0-2, but not severe toxicities (p = 0.02). Furthermore, patients with DPYD 85TC and CC genotypes had longer progression and overall survival times compared to TT genotypes in our study group (log rank = 6.60; p = 0.01 and log rank = 4.40; p = 0.04, respectively). Conclusion: According to our results, DPYD 496AG and GG genotypes might be protective against severe adverse events compared to the AA genotype. Another DPYD polymorphism, 85T>C, may be useful in colorectal cancer prognosis. Further studies for both polymorphisms should be conducted in larger populations to achieve accurate results.

5-fluorouracil (5-FU) is a widely used drug for chemotherapy in colorectal cancer. In this study, we investigated the relationship between the severity of 5-FU induced adverse events and several variations in DPYD, MTHFR and TYMS genes, which encode the enzymes involved in 5-FU metabolism in a total of 103 colorectal patients. We also examined the relationship between the polymorphisms and progression-free and overall survival times of the patients in our study group. Among the variations, DPDY 496A>G polymorphism was found to be associated with 5-FU induced adverse events. Also, the DPYD 85T>C polymorphism was detected to be associated with longer progression-free and overall survival times.

Investigation of Vascular Endothelial Growth Factor Polymorphisms on Risk, Metastasis, Laterality, and Prognosis of Colorectal Cancer in Turkish Subjects.

Objectives: Tumor angiogenesis is known to support the spread and invasion of tumor cells, allow distant organ metastasis and to result in poorer prognoses and increased mortality. Since vascular endothelial growth factor-A (VEGF-A) is the major regulator of angiogenesis, in the present study the associations of the VEGF-A +405G>C and -460C>T polymorphisms with risk, primary tumor location, prognosis and metastasis of colorectal cancer (CRC) were investigated in Turkish subjects. Material and Methods: A total of 153 subjects consist of 74 controls and 79 CRC diagnosed patients were included in the study. VEGF-A +405G>C and -460C>T polymorphisms were analyzed using the Agena MassARRAY platform. Results: The VEGF +405GC+CC genotypes were found to be significantly associated with left colon cancer (unadjusted OR = 5.208 95% CI: 1.064-25.496, p = 0.04). The VEGF -460TT and CT+TT genotypes were associated with reduced liver metastasis risk (OR = 0.080 95% CI: 0.009-0.689 p = 0.02 and OR = 0.191 95% CI: 0.039-0.925, p = 0.04, respectively). Patients with the VEGF +405GG genotype showed longer progression-free survival in response to bevacizumab treatment (Log rank = 6.92, p = 0.03). Conclusion: According to our results, the VEGF +405G>C and -460C>T polymorphisms were found to be associated with CRC prognosis, sidedness and metastases. Our findings need to be replicated in further studies.

Evaluation of Bevacizumab in Advanced Small Bowel Adenocarcinoma.

BACKGROUND: Small bowel adenocarcinomas (SBAs) are rarely seen tumors. Data regarding the use of chemotherapy together with bevacizumab in patients with advanced SBA are lacking. The aim of this study was the evaluation of treatment with bevacizumab in advanced SBA. MATERIALS AND METHODS: Twenty-eight patients from 5 centers with a diagnosis of advanced SBA who received first-line treatments with modified FOLFOX6 (mFOLFOX6; oxaliplatin, leucovorin, and 5-fluorouracil) and FOLFIRI (leucovorin, 5-fluorouracil, and irinotecan) chemotherapy regimens were involved in the study. All patients were divided into 2 groups; those who received bevacizumab together with these chemotherapy regimens (Chemo+Bev group) and those who did not receive bevacizumab (Chemo group). RESULTS: The median progression-free survival (PFS) and overall survival (OS) times of all population were 8.7 months and 16.9 months, respectively. The overall response rate was 43.7% in the Chemo group and 58.3% in the Chemo+Bev group. The median PFSs in the Chemo and Chemo+Bev groups were found to be 7.7 months and 9.6 months, respectively, and the median OSs were 14.8 months and 18.5 months, respectively. There was not a significant difference between the groups in terms of overall response rate, PFS, and OS. CONCLUSION: Although there was no significant difference in any of the outcomes, use of bevacizumab together with chemotherapy is a more effective treatment approach compared with chemotherapy alone, and it does not cause an excess of significant toxicity.

Assessment of tumor characteristics and factors affecting survival in patients with primary metastatic breast carcinoma: a Multicenter Study of the Anatolian Society of Medical Oncology.

Primary metastatic breast cancer (PMBC) comprises 3-10% of all BCs. PMBC is a heterogeneous disease. To date, little is known about the tumor characteristics, treatment results, and overall survival (OS) of patients with PMBC. Patients were considered to have PMBC if distant metastasis was evident within 3 months of the initial diagnosis of BC. Between September 2007 and April 2013, 466 PMBC patients were included in this study and analyzed retrospectively. The median age of the patients was 50 (18-90) years. Bone/soft tissue metastases were more frequent in the hormone receptor (HR)(+) human epidermal growth factor receptor (HER)2(-) group compared with the HR(-)HER2(-) and HR(-)HER2(+) groups (p < 0.001), whereas visceral organ metastasis was more frequent in the HR(-)HER2(-) and HR(-)HER2(+) groups (p < 0.001). The OS was affected by Eastern Cooperative Oncology Group performance status, tumor histology, receptor status, and the site of metastasis (p < 0.001, p < 0.001, p < 0.001, and p = 0.011, respectively). According to the first-line systemic treatment choices of the patients, the longest median OS was observed in the HR(+)HER2(+) group who received hormonotherapy combined with trastuzumab after chemotherapy (86 months, 95% CI 23.8-148.1) and the shortest median OS was observed in the HR(-)HER2(-) group who received chemotherapy only (24 months, 95% CI 17.9-30.0) (p < 0.001). Bisphosphonate therapy or radiotherapy had no significant effect on OS (p = 0.733, 0.603). In multivariate analysis, hormonotherapy, chemotherapy + trastuzumab, trastuzumab + hormonotherapy following chemotherapy, and surgery were the most important prognostic factors for OS, respectively (p < 0.001, p = 0.025, p = 0.027, p = 0.029). The general characteristics of the primary tumor are important for the prognosis and survival of patients with PMBC. Interestingly, patients who underwent primary breast tumor surgery, even those at the metastatic stage upon admission, had the longest survival.

Clinical outcomes in patients who received lapatinib plus capecitabine combination therapy for HER2-positive breast cancer with brain metastasis and a comparison of survival with those who received trastuzumab-based therapy: a study by the Anatolian Society of Medical Oncology.

PURPOSE: In this study, we investigated the effect of lapatinib plus capecitabine treatment in HER2-positive breast cancer patients with brain metastasis. METHODS: Of 405 metastatic breast cancer patients with brain metastases at referral centers in Turkey, 46 were treated with lapatinib plus capecitabine only after the development of brain metastasis. Patients who only received trastuzumab-based therapy after the development of brain metastases were accepted as the historic control group for survival analyses (n = 65). Patients who received both drugs consecutively or sequentially were excluded from the analyses (n = 34). RESULTS: Median age among 46 patients who received lapatinib plus capecitabine therapy was 45 years (27-76), and median time for development of brain metastases was 11.9 months (0-69 months). Twenty-six out of 38 patients who received lapatinib plus capecitabine and had extracranial metastasis showed partial response or stable diseases (68.4 %). Grade 3-4 toxicity was observed in eight patients (17.3 %). Median overall survival (OS) in patients treated with lapatinib plus capecitabine was significantly increased compared to that in patients treated with trastuzumab-based therapy (19.1 vs. 12 months, respectively, p = 0.039). The incidence of cerebral death was slightly decreased in patients who received lapatinib plus capecitabine compared to those who received trastuzumab-based therapy (32 vs. 43.4 %, p = 0.332). In the multivariate analysis, lapatinib plus capecitabine therapy remained an independent positive predictor for survival [odds ratio (OR), 0.57; p = 0.02]. DISCUSSION: Although this retrospective multicenter study had several limitations, the results suggest that undergoing lapatinib plus capecitabine therapy after the diagnosis of brain metastasis may further improve survival compared to undergoing only trastuzumab-based therapy.

Use of knee height for the estimation of stature in elderly Turkish people and their relationship with cardiometabolic risk factors.

The determination of the approximately truest value in height measurement is important in many fields, but it is difficult to perform true measurements, especially in the elderly individuals. We planned to investigate the following items in geriatric Turkish population: to calculate the decrease in height with advancing age by using the standing height measurement and estimated height derived from the knee height; to evaluate the significance of difference between the two measurement methods in the calculation of body mass index (BMI) and waist/height ratio (WHtR); to determine the cut-off value of WHtR according to estimated height in elderly individuals. We studied 551 cases aged between 19 and 97 years. Knee height was measured using a sliding caliper in a sitting position. Linear regression analysis was carried out to derive predictive equations for the estimation of stature with adults (≤ 50 years of age) according to the gender. This equation was then used to estimate height among elderly subjects. Of the cases, 60.3% were <60 years (mean: 48.75 ± 7.50); 39.7% of the cases were >60 years (mean: 69.51 ± 7.12). Estimated BMI (EBMI) measurements in the females and males >60 years were in average 1.23 kg/m(2) and 0.92 kg/m(2) higher than their real BMIs, respectively. EBMI measurements in the females <60 years were 0.32 kg/m(2) higher than their real BMIs (p<0.01). There is a statistically significant difference between WHtR in the females of both age groups, and in the males >60 years, as compared to our estimated WHtR (EWHtR) measurements (p<0.01). The cut-off point of WHtR was 0.61 and 0.58 in the female and male cases of >60 years in our study, respectively. WHtR seemed to be a better anthropometric index that could predict most cardiometabolic risk factors in our study. EWHtR emerged to be a better cardiometabolic risk index especially in the elderly group.

Nine-week trastuzumab treatment versus 52-week trastuzumab treatment for HER2-positive early-stage breast cancer.

PURPOSES: Trastuzumab is known to be effective for early and advanced stages of breast cancer but optimal duration for early-stage breast cancer (EBC) is not well known. We evaluated the efficacy and toxicity of 9- and 52-week trastuzumab therapy for EBC retrospectively. METHODS: In this multicenter study, the medical records of all patients with EBC were analyzed in 8 centers retrospectively. Totally consecutive, 479 female patients who received trastuzumab in the adjuvant treatment were evaluated for disease-free survival (DFS), overall survival (OS), efficacy, and toxicity. RESULTS: There were 181 (37.8 %) and 298 (62.2 %) patients in the 9- and 52-week trastuzumab groups, respectively. Median follow-up was 30.6 months (5.7-68.9) in the 9-week trastuzumab group and 29.3 months (5.9-59.6) in the 52-week trastuzumab group. Thirty-six month DFS was 90 and 85 % (P = 0.132) in the 9- and 52-week trastuzumab treatment groups, respectively, and 36-month OS was 96 and 97 % in the 9- and 52-week trastuzumab groups, respectively (P = 0.779). Symptomatic cardiotoxicity was observed in 1 (0.6 %) patient in the 9-week trastuzumab group and in 4 (1.3 %) patients in the 52-week trastuzumab group. CONCLUSIONS: In this study, similar outcomes were found in the 9- and 52-week trastuzumab treatment groups.

Comparison of epicardial adipose tissue (EAT) thickness and anthropometric measurements in metabolic syndrome (MS) cases above and under the age of 65.

EAT is a new index of cardiac and visceral obesity. Waist circumference (WC) measurement is not fully reliable in the determination of visceral adipose tissue (VAT), especially in elderly individuals. Studies on the reflection of the intra-abdominal fat mass by the EAT mass surrounding the heart were performed. Our purpose in this study was to determine the relation between the MS criteria and EAT in MS cases and especially to compare anthropometric measures between non-geriatric patients under the age of 65, and geriatric ones over the age of 65 years. The study was performed during the years 2008 and 2009 on 120 cases; 66.7% of them were under the age of 65 and 33.3% of the cases were 65-year old or older. All of the patients were diagnosed as MS by the International Diabetes Federation (IDF) criteria. They were randomized as per the application order and included to the study. Each subject underwent transthoracic two-dimensional (2D) guided M-mode echocardiogram. We measured epicardial fat thickness on the 1/3 section close to the ventricle basis adjacent to the free wall of right ventricle from both the parasternal long axis (LA) and parasternal short axis (SA) views. Multiple regression analysis showed that WC, systolic blood pressure (SBP) and age were the strongest independent variables correlated with EAT (p<0.001). We also determined a significant correlation between low-density lipoprotein-cholesterol (LDL-C) and EAT (p<0.05). Our data show that EAT-measurement by echocardiography is an efficient method in determination of visceral adiposity and shall be taken into consideration especially when advanced age groups are in question.

[Effects of different statins, ezetimibe/simvastatin combination on hsCRP levels in unstable angina pectoris and non-ST elevation myocardial infarction patients: a randomized trial]. / Kararsiz anjina pektoris ve ST-elevasyonsuz miyokart enfarktüslü hastalarda degisik statinlerin, ezetimib/simvastatin kombinasyonunun hsCRP düzeyleri üzerine etkileri: randomize bir çalisma.

OBJECTIVE: The aim of our study was to evaluate the effects of two different statins and a statin/ezetimibe combination on high sensitive C-reactive protein (hsCRP) values, which were given at high doses in the early period of acute coronary syndromes. METHODS: A total of 150 patients with non-ST elevation myocardial infarction and unstable angina pectoris were enrolled to our prospective, randomized, single-blind study. Patients were divided into three groups by block randomization method. One group received 20 mg/day atorvastatin, one group received 10 mg/day rosuvastatin and the other group received 10 mg/day ezetimibe/simvastatin combination therapy, which was initiated within the first 24 hours of admission. Follow-up duration was 2 months . Biochemical investigations and hsCRP levels (by nephelometric method) were performed with 138 patients evaluated at baseline, 10th and 60th days of therapy. Decreases of hsCRP levels were analyzed with one-way MANOVA and repeated measures of ANOVA methods. Post-hoc Tukey HSD test was performed for finding the different group, when the difference was detected between the groups. RESULTS: Tenth day hsCRP levels in ezetimibe/simvastatin group was significantly lower than the other groups (p<0.001). Further, after 60 days of follow-up a significant reduction was seen in hsCRP levels in ezetimib/simvastatin group (in ezetimibe/simvastatin group the mean hsCRP was reduced from 38.4±15.0 mg/L to 2.4±1.3 mg/L, in atorvastatin group the mean hsCRP was reduced from 27.3±11.7 mg/L to 4.1±2.4 mg/L and in rosuvastatin group the mean hsCRP was reduced from 22.0±6.9 mg/L to 3.6±1.7 mg/L (F (1.1, 148.2) = 746.9, p<0.01 and the difference between drugs; F (2.2, 148.2) = 32.1, p<0.01). No side effects related to drugs were seen during follow-up in all three treatment groups. CONCLUSION: This study showed that ezetimibe/simvastatin 10 mg/day combination treatment was superior to atorvastatin 20 mg/day and rosuvastatin 10 mg/day treatment in reducing the inflammatory markers when high dose statins was started in the early period of unstable angina and non ST elevation myocardial infarction.