Copy Number Variations (CNVs) Account for 10.8% of Pathogenic Variants in Patients Referred for Hereditary Cancer Testing.

BACKGROUND/AIM: Germline copy number variation (CNV) is a type of genetic variant that predisposes significantly to inherited cancers. Today, next-generation sequencing (NGS) technologies have contributed to multi gene panel analysis in clinical practice. MATERIALS AND METHODS: A total of 2,163 patients were screened for cancer susceptibility, using a solution-based capture method. A panel of 52 genes was used for targeted NGS. The capture-based approach enables computational analysis of CNVs from NGS data. We studied the performance of the CNV module of the commercial software suite SeqPilot (JSI Medical Systems) and of the non-commercial tool panelcn.MOPS. Additionally, we tested the performance of digital multiplex ligation-dependent probe amplification (digitalMLPA). RESULTS: Pathogenic/likely pathogenic variants (P/LP) were identified in 464 samples (21.5%). CNV accounts for 10.8% (50/464) of pathogenic variants, referring to deletion/duplication of one or more exons of a gene. In patients with breast and ovarian cancer, CNVs accounted for 10.2% and 6.8% of pathogenic variants, respectively. In colorectal cancer patients, CNV accounted for 28.6% of pathogenic/likely pathogenic variants. CONCLUSION: In silico CNV detection tools provide a viable and cost-effective method to identify CNVs from NGS experiments. CNVs constitute a substantial percentage of P/LP variants, since they represent up to one of every ten P/LP findings identified by NGS multigene analysis; therefore, their evaluation is highly recommended to improve the diagnostic yield of hereditary cancer analysis.

Comprehensive tumor molecular profile analysis in clinical practice.

BACKGROUND: Tumor molecular profile analysis by Next Generation Sequencing technology is currently widely applied in clinical practice and has enabled the detection of predictive biomarkers of response to targeted treatment. In parallel with targeted therapies, immunotherapies are also evolving, revolutionizing cancer therapy, with Programmed Death-ligand 1 (PD-L1), Microsatellite instability (MSI), and Tumor Mutational Burden (TMB) analysis being the biomarkers employed most commonly. METHODS: In the present study, tumor molecular profile analysis was performed using a 161 gene NGS panel, containing the majority of clinically significant genes for cancer treatment selection. A variety of tumor types have been analyzed, including aggressive and hard to treat cancers such as pancreatic cancer. Besides, the clinical utility of immunotherapy biomarkers (TMB, MSI, PD-L1), was also studied. RESULTS: Molecular profile analysis was conducted in 610 cancer patients, while in 393 of them a at least one biomarker for immunotherapy response was requested. An actionable alteration was detected in 77.87% of the patients. 54.75% of them received information related to on-label or off-label treatment (Tiers 1A.1, 1A.2, 2B, and 2C.1) and 21.31% received a variant that could be used for clinical trial inclusion. The addition to immunotherapy biomarker to targeted biomarkers' analysis in 191 cases increased the number of patients with an on-label treatment recommendation by 22.92%, while an option for on-label or off-label treatment was provided in 71.35% of the cases. CONCLUSIONS: Tumor molecular profile analysis using NGS is a first-tier method for a variety of tumor types and provides important information for decision making in the treatment of cancer patients. Importantly, simultaneous analysis for targeted therapy and immunotherapy biomarkers could lead to better tumor characterization and offer actionable information in the majority of patients. Furthermore, our data suggest that one in two patients may be eligible for on-label ICI treatment based on biomarker analysis. However, appropriate interpretation of results from such analysis is essential for implementation in clinical practice and accurate refinement of treatment strategy.

Objective response rate assessment in oncology: Current situation and future expectations.

The tumor objective response rate (ORR) is an important parameter to demonstrate the efficacy of a treatment in oncology. The ORR is valuable for clinical decision making in routine practice and a significant end-point for reporting the results of clinical trials. World Health Organization and Response Evaluation Criteria in Solid Tumors (RECIST) are anatomic response criteria developed mainly for cytotoxic chemotherapy. These criteria are based on the visual assessment of tumor size in morphological images provided by computed tomography (CT) or magnetic resonance imaging. Anatomic response criteria may not be optimal for biologic agents, some disease sites, and some regional therapies. Consequently, modifications of RECIST, Choi criteria and Morphologic response criteria were developed based on the concept of the evaluation of viable tumors. Despite its limitations, RECIST v1.1 is validated in prospective studies, is widely accepted by regulatory agencies and has recently shown good performance for targeted cancer agents. Finally, some alternatives of RECIST were developed as immune-specific response criteria for checkpoint inhibitors. Immune RECIST criteria are based essentially on defining true progressive disease after a confirmatory imaging. Some graphical methods may be useful to show longitudinal change in the tumor burden over time. Tumor tissue is a tridimensional heterogenous mass, and tumor shrinkage is not always symmetrical; thus, metabolic response assessments using positron emission tomography (PET) or PET/CT may reflect the viability of cancer cells or functional changes evolving after anticancer treatments. The metabolic response can show the benefit of a treatment earlier than anatomic shrinkage, possibly preventing delays in drug approval. Computer-assisted automated volumetric assessments, quantitative multimodality imaging in radiology, new tracers in nuclear medicine and finally artificial intelligence have great potential in future evaluations.

Predictive and Prognostic Factors in Ovarian and Uterine Carcinosarcomas.

BACKGROUND: Prognostic factors and the standard treatment approach for gynaecological carcinosarcomas have not yet been clearly defined. Although carcinosarcomas are more aggressive than pure epithelial tumours, they are treated similarly. Serous/clear cell and endometrioid components may be predictive factors for the efficacy of adjuvant chemotherapy (CT) or radiotherapy (RT) or RT in patients with uterine and ovarian carcinosarcomas. Heterologous carcinosarcomas may benefit more from adjuvant CT. AIMS: We aimed to define the prognostic and predictive factors associated with treatment options in ovarian (OCS) and uterine carcinosarcoma (UCS). STUDY DESIGN: Retrospective cross-sectional study. METHODS: We retrospectively reviewed the medical records of patients with ovarian and uterine carcinosarcoma from 2000 to 2013, and 127 women were included in this study (24 ovarian and 103 uterine). Patients admitted to seventeen oncology centres in Turkey between 2000 and December 2013 with a histologically proven diagnosis of uterine carcinosarcoma with FIGO 2009 stage I-III and patients with sufficient data obtained from well-kept medical records were included in this study. Stage IV tumours were excluded. The patient records were retrospectively reviewed. Data from 104 patients were evaluated for this study. RESULTS: Age (≥70 years) was a poor prognostic factor for UCS (p=0.036). Pelvic±para aortic lymph node dissection did not affect overall survival (OS) (p=0.35). Macroscopic residual disease was related with OS (p<0.01). The median OS was significantly longer in stage I-II patients than stage III patients (p=0.03). Adjuvant treatment improved OS (p=0.013). Adjuvant radiotherapy tended to increase the median OS (p=0.075). However, this tendency was observed in UCS (p=0.08) rather than OCS (p=0.6).Adjuvant chemotherapy had no effect on OS (p=0.15).Adjuvant radiotherapy significantly prolonged the median OS in patients with endometrioid component (p=0.034). A serous/clear cell component was a negative prognostic factor (p=0.035). Patients with serous/clear cell histology for whom adjuvant chemotherapy was applied had significantly longer OS (p=0.019), and there was no beneficial effect of adjuvant radiotherapy (p=0.4). Adjuvant chemotherapy was effective in heterologous tumours (p=0.026). In multivariate analysis, the stage and chemotherapy were prognostic factors for all patients. Age was an independent prognostic factor for UCS. However, serous/clear cell histology and radiotherapy tended to be significant prognostic factors. CONCLUSION: The primary location, the histological type of sarcomatous and the epithelial component may be predictive factors for the efficacy of chemotherapy or radiotherapy in UCS and OCS.

Clinicopathologic characteristics, treatment outcomes, and prognostic factors of primary thoracic soft tissue sarcoma: A multicenter study of the Anatolian Society of Medical Oncology (ASMO).

BACKGROUND: Soft tissue sarcomas (STSs) are rare malignant tumors of embryogenic mesoderm origin. Primary thoracic STSs account for a small percentage of all STSs and limited published information is available. This study aimed to identify the prognostic factors for thoracic STSs and evaluate the disease's clinical outcomes. METHODS: The medical records of 109 patients with thoracic STSs who were treated between 2003 and 2013 were retrospectively reviewed. Patients' survival rates were analyzed and potential prognostic factors evaluated. RESULTS: The median follow-up period was 29 months (range: 1-121 months). STSs were most frequently localized on the chest wall (n = 42; 38.5%) and lungs (n = 42; 38.5%). The most common histological types were malignant fibrous histiocytoma (n = 23; 21.1%), liposarcoma (n = 17; 15.6%), and leiomyosarcoma (n = 16; 14.7%). The median survival time of all patients was 40.3 months (95% confidence interval, 14.22-66.37 months), with one and five-year survival rates of 93.4% and 63.5%, respectively. Univariate analysis of all groups revealed that metastatic stage, unresectability, tumor diameter of >10 cm, tumor location other than the chest wall, and grade 3 diseases were predictable of poor survival. However, only grade 3 diseases and tumor location other than the chest wall were confirmed by multivariate analysis as poor prognostic factors. CONCLUSIONS: Primary thoracic STSs are rarely seen malignant tumors. Our results indicated that patients with low-grade tumors and those localized on the chest wall often experienced better survival outcomes.

KRAS discordance between primary and metastatic tumor in patients with metastatic colorectal carcinoma.

PURPOSE: Adding targeted therapies to chemotherapy in metastatic colorectal cancer (CRC) improves response rates and survival. KRAS is a predictive indicator for anti-epidermal growth factor receptor (EGFR) treatments. The most important reasons for KRAS discordance are intratumoral heterogeneity and incorrect mutation analysis. Evaluating the status of KRAS in primary and metastatic lesions becomes even more crucial to ensure efficient usage of anti-EGFR treatments. METHODS: Patients with metastatic CRC, whose primary disease and liver and/or lung metastases were operated, were retrospectively evaluated, and KRAS assessment was performed on 31 patients who were suitable for DNA analysis. Pyrosequencing with polymerase chain reaction (PCR) was used for KRAS analysis. RESULTS: The median age of 31 patients diagnosed with rectal cancer (N=13) and colon cancer (N=18) was 63 years (range 33-73). Metastasectomy locations included the liver (N=27), lung (N=3), and both lung and liver (N=1). KRAS discordance was detected in 22% (7/31) of the patients. While 3 patients with detected discordance had mutated KRAS in the primary material, wild type KRAS was detected in their liver or lung lesions. On the other hand, while 4 patients had wild type KRAS in the primary material, mutated KRAS was determined in their liver or lung lesions. The McNemar test revealed no significant discordance between primary and metastatic disease (p=1.00). No progression free survival (PFS) difference was detected between patients with determined discordance and patients with undetermined discordance (10.6 vs 14.7 months, p=0.719). CONCLUSION: This is the first study to evaluate KRAS discordance between primary and metastasis in CRC patients, who underwent metastasectomy, together with survival data. In the literature and recent studies with large patient numbers in which modern KRAS tests were used, the KRAS discordance rate varies between 3-12%. In our study, a higher KRAS discordance (22%) was detected, and no survival difference was determined between patients with or without discordance. In recent years, the rising interest in borderline resectable disease may bring forward discussions related to which material the KRAS status should be analyzed.

Sequential therapy and prognostic factors in metastatic renal cell carcinoma: single centre experience.

PURPOSE: In advanced stage renal cell cancer (RCC), overall survival (OS) of patients has been prolonged due to targeted therapies. To date, there are several prognostic risk models that have been developed for metastatic RCC (mRCC). The purpose of this study was to evaluate the outcomes of the sequential therapy (IFN-α, tyrosine kinase inhibitors/TKIs, m-TOR inhibitor) and prognostic factors in patients with mRCC, especially those with bone metastasis. METHODS: We retrospectively examined the data of 82 patients with pathologically proven mRCC who were followed-up and treated at the Medical Oncology Clinic of the Dr A.Y Oncology Hospital between 2005 and 2013. RESULTS: Median OS was 23 months in all patients with mRCC and 20 months in patients treated with TKIs. According to MSKCC and HENG risk classifications, median OS differed between the groups (p=0.02, p<0.001, respectively). Median OS was lower in patients with isolated bone metastasis compared to those with lung metastasis (16 vs 24 months, p=0.25). Median OS improved with increasing number of sequential therapies (p=0.08). CONCLUSION: This study confirmed the correlation between MSKCC and HENG risk models and survival data. Additionally, it was shown that increase of the number of therapeutic lines in sequential therapy prolonged survival and that bone metastases were negative prognostic factors.

Comparison the efficacy of second-line modified EOX (epirubicin, oxaliplatin, and capecitabine) and irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) regimens in metastatic gastric cancer patients that progressed on first-line modified docetaxel and cisplatin plus fluorouracil (DCF) regimen.

Gastric cancer is often diagnosed in advanced stage. Palliative chemotherapy or best supportive care is recommended for patients with metastatic gastric patients. In several clinical trials, palliative chemotherapy improved overall survival (OS) and progression-free survival (PFS), but the survival benefit of second-line chemotherapy was demonstrated in small cohort studies. The main aim of our study was to compare retrospectively the efficacy of second-line modified EOX (epirubicin, oxaliplatin and capecitabine) [mEOX] and irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) regimens in metastatic gastric cancer patients that progressed on first-line modified docetaxel-cisplatin-fluorouracil (DCF) regimen. Metastatic gastric cancer patients who progressed on modified DCF regimens were included. A total 105 patients were included to this study; 55 and 50 patients were treated with mEOX and FOLFIRI regimens, respectively. The clinicopathological and demographic characteristics of all patients were collected from the medical charts. Kaplan-Meier survival analysis was carried out for PFS and OS. The median follow-up of our study was 16 (4-85) months. In both groups, all of the patients were treated with first-line mDCF. Median cycle of second-line chemotherapy was 3 (1-8) and 3.5 (1-6) in EOX and FOLFIRI groups, respectively (P = 0.44). Overall response rate was observed in 34.6 % and 42.0 % of patients second-line chemotherapy in mEOX and FOLFIRI arms, respectively (P = 0.17). Median PFS was 5.5 and 6.3 months in mEOX and FOLFIRI arms, respectively (P = 0.98). Median OS was 6.9 and 7.0 months in mEOX and FOLFIRI arms, respectively, from the time of beginning second-line chemotherapy protocol (P = 0.89). As compared with FOLFIRI regimen, mEOX regimen was associated with less neutropenia, thrombocytopenia and anemia. Dose reduction and dose delay were significantly higher in FOLFIRI group compared to mEOX group (P < 0.001). In our trial, triplet regimens mEOX and FOLFIRI regimens have similar efficacy as second-line treatment for patients with metastatic gastric cancer. FOLFIRI regimen was associated with more hematological toxicity.

Treatment and prognostic factors in primary peritoneal carcinoma: a multicenter study of the Anatolian Society of Medical Oncology (ASMO).

BACKGROUND: In this study, we aimed to evaluate the clinicopathological characteristics and prognosis of patients with primary peritoneal carcinoma (PPC), and the effectiveness and toxicity of first-line platinum/taxane combination therapy. PATIENTS AND METHODS: We retrospectively evaluated 79 patients with PPC, who were treated and followed up between December 2001 and August 2012 at 10 medical oncology clinics. RESULTS: All patients were female, with a median age of 63 years (range 34-79 years). Histopathological diagnoses included primary peritoneal serous carcinoma (PPSC) (n = 69) and mixed epithelial carcinoma of the peritoneum (MEC) (n = 10). Patients received first-line treatment with carboplatin/paclitaxel (n = 67) or cisplatin/paclitaxel (n = 12) combination therapy. Overall response rate, median progression-free survival, and median survival time in the paclitaxel/carboplatin group and the paclitaxel/cisplatin group were 74.6 vs. 75%, 15.6 vs. 37.8 months, and 41 vs. 70.3 months, respectively. In multivariate analysis, favorable prognostic factors were: ECOG performance status 0 (p < 0.001) and optimal cytoreduction (p = 0.03). CONCLUSION: PPC is a rare, heterogeneous disease. ECOG performance status and optimal cytoreduction are important prognostic factors regarding survival rates. Platinum/taxane combination therapy is an effective and tolerable regimen in this patient group.

Gastric carcinoma with bone marrow metastasis: a case series.

Gastric cancer is a major cause of cancer-related mortality. At the time of diagnosis, majority of the patients usually have unresectable or metastatic disease. The most common sites of metastases are the liver and the peritoneum, but in the advanced stages, there may be metastases to any region of the body. Bone marrow is an important metastatic site for solid tumors, and the prognosis in such cases is poor. In gastric cancer cases, bone marrow metastasis is usually observed in younger patients and in those with poorly differentiated tumors. Prognosis is worsened owing to the poor histomorphology as well as the occurrence of pancytopenia. The effect of standard chemotherapy is unknown, as survival is limited to a few weeks. This report aimed to evaluate 5 gastric cancer patients with bone marrow metastases to emphasize the importance of this condition.