Women with BRCA 1/2 pathogenic/likely pathogenic variants (P/LPVs) have a high lifetime risk of developing breast and ovarian cancer. The aim of the retrospective study is to analyze the rate, ...longitudinal trends, and effectiveness of prophylactic risk-reducing mastectomy (RRM) and salpingo-oophorectomy (RRSO) on the incidence of breast and ovarian cancer. We analyzed data from 496 unaffected BRCA1/2 carriers with a median follow-up of 6.0 years. A statistically significant increase of RRM (12% vs. 29%) and RRSO (31% vs. 42%) was observed when comparing periods 2005-2012 and 2013-2020 (p < 0.001). BC developed in 15.9% of BRCA1/2 carriers without RRM vs. 0.6% of BRCA1/2 carriers after RRM (HR 20.18, p < 0.001). OC was diagnosed in 4.3% vs. 0% of BRCA1/2 carriers without vs. after RRSO (p < 0.001). Data shows a high effectiveness and significant increase of prophylactic surgeries over 20 years period in a central European population of BRCA1/2 carriers. Unnafected female carriers of BRCA1 and BRCA2 pathogenic/likely pathogenic variants (P/LPVs) are at higher risk of breast cancer (BC) and ovarian cancer (OC). In the retrospective single-institution study in the Czech Republic, we analyzed the rate, longitudinal trends, and effectiveness of prophylactic risk-reducing mastectomy (RRM) and risk-reducing salpingo-oophorectomy (RRSO) on the incidence of BC and OC in BRCA1/2 carriers diagnosed between years (y) 2000 to 2020. The study included 496 healthy female BRCA1/2 carriers. The median follow-up was 6.0 years. RRM was performed in 156 (31.5%, mean age 39.3 y, range 22-61 y) and RRSO in 234 (47.2%, mean age 43.2 y, range 28-64 y) BRCA1/2 carriers. A statistically significant increase of RRM (from 12% to 29%) and RRSO (from 31% to 42%) was observed when comparing periods 2005-2012 and 2013-2020 (p < 0.001). BC developed in 15.9% of BRCA1/2 carriers without RRM vs. 0.6% of BRCA1/2 carriers after RRM (HR 20.18, 95% CI 2.78- 146.02; p < 0.001). OC was diagnosed in 4.3% vs. 0% of BRCA1/2 carriers without vs. after RRSO (HR not defined due to 0% occurrence in the RRSO group, p < 0.001). Study results demonstrate a significant increase in the rate of prophylactic surgeries in BRCA1/2 healthy carriers after 2013 and the effectiveness of RRM and RRSO on the incidence of BC and OC in these populations.
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Background: Trifluridine/tipiracil (T) and regorafenib (R) are indicated for patients with refractory mCRC. Currently, no biomarkers are used to select which patient will benefit ...from which treatment. Methods: We retrospectively evaluated 212 patients who received T and/or R. Different factors associated with progression-free survival (PFS) and overall survival (OS) were analyzed. Results: T received 132, R 52, both drugs 28 patients. Median age was 64 (range 28-83), male 64%, PS 0 37%, median line of treatment 3, characteristic was similar between treatment groups. Median follow-up was 16.5 months. Median OS for T was 10.2, for R 6.9 months, P = 0.03. Factors significantly associated with OS were: ≥ 24 months from diagnosis of mCRC (0.49, P < 0.001), PS 0 (HR 1.54, P = 0.007), baseline WBC < 8 × 10
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/L (HR 0.47, P < 0.001), normal baseline CRP (HR 0.47, P < 0.001), ≥ 3 months from last therapy (fluoropyrimidine for T, anti-VEGF for R) (HR 0.66, P = 0.006). We developed a scoring system TASREG from these factors, 1 point for each factor, the overall score was the sum of these points and patients were divided into 3 groups: high risk group with 0 to 1 point, intermediate with 2 to 3, favorable with 4 or more points. OS for all patients according to risk group was 4.6 for high risk, 7.9 intermediate, 11.8 months favorable risk (P < 0.001). Score was also significant for T and R group evaluated separately. Score was also significant for PFS. Factors associated with OS specific for T were neutropenia G≥2 (HR 0.34, P < 0.001); for R normal baseline LDH (HR 0,40. P < 0.001), no liver metastases (HR 0.45, P = 0.002), non-synchronous disease (HR 0,40, P < 0.001). Conclusions: We could find factors associated with better outcomes for both treatment groups and factors specific for T or R. TASREG is simple prognostic tool for patients with refractory mCRC.
Abstract RAD18 is an E3 ubiquitin ligase that prevents replication fork collapse by promoting DNA translesion synthesis and template switching. Besides this classical role, RAD18 has been implicated ...in homologous recombination; however, this function is incompletely understood. Here, we show that RAD18 is recruited to DNA lesions by monoubiquitination of histone H2A at K15 and counteracts accumulation of 53BP1. Super-resolution microscopy revealed that RAD18 localizes to the proximity of DNA double strand breaks and limits the distribution of 53BP1 to the peripheral chromatin nanodomains. Whereas auto-ubiquitination of RAD18 mediated by RAD6 inhibits its recruitment to DNA breaks, interaction with SLF1 promotes RAD18 accumulation at DNA breaks in the post-replicative chromatin by recognition of histone H4K20me0. Surprisingly, suppression of 53BP1 function by RAD18 is not involved in homologous recombination and rather leads to reduction of non-homologous end joining. Instead, we provide evidence that RAD18 promotes HR repair by recruiting the SMC5/6 complex to DNA breaks. Finally, we identified several new loss-of-function mutations in RAD18 in cancer patients suggesting that RAD18 could be involved in cancer development.
Alternative pre-mRNA splicing increases transcriptome plasticity by forming naturally-occurring alternative splicing variants (ASVs). Alterations of splicing processes, caused by DNA mutations, ...result in aberrant splicing and the formation of aberrant mRNA isoforms. Analyses of hereditary cancer predisposition genes reveal many DNA variants with unknown clinical significance (VUS) that potentially affect pre-mRNA splicing. Therefore, a comprehensive description of ASVs is an essential prerequisite for the interpretation of germline VUS in high-risk individuals.
To identify ASVs in a gene of interest, we have proposed an approach based on multiplex PCR (mPCR) amplification of all theoretically possible exon-exon junctions and subsequent characterization of size-selected and pooled mPCR products by next-generation sequencing (NGS). The efficiency of this method is illustrated by a comprehensive analysis of BRCA1 ASVs in human leukocytes, normal mammary, and adipose tissues and stable cell lines.
We revealed 94 BRCA1 ASVs, including 29 variants present in all tested samples. While differences in the qualitative expression of BRCA1 ASVs among the analyzed human tissues were minor, larger differences were detected between tissue and cell line samples.
Compared with other ASV analysis methods, this approach represents a highly sensitive and rapid alternative for the identification of ASVs in any gene of interest.
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•Fast mPCR/NGS-based analysis of mRNA splicing variants proposed•Performance tested by the analysis of BRCA1 alternative splicing variants (ASVs)•94 different BRCA1 ASVs involving all splicing biotypes identified•Expression of BRCA1 ASVs in human leukocytes, mammary and adipose tissues analyzed•Method suitable for the analysis of mRNA splicing variants in any gene of interest
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Background: TAS-102 is effective in refractory mCRC and significantly improved survival versus placebo. Currently no predictive biomarkers are established and used in clinical ...practice. Methods: We analyzed data of 160 patients treated with TAS-102 in real clinical practice in Czech Republic. Different factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated. Results: Baseline patients’ characteristics: median age 66 years (range 28-83), 106 patients were male (66.3 %), ECOG PS 0 had 38.1 %, RAS wt 45 %. Anti-VEGF treatment had 83.1 %, anti-EGFR 43.8 %. Median number of TAS-102 treatment line was 3 (range, 2 – 8), median TAS-102 cycles 3 (range 1 – 27). At the time of analysis 15 % continued in treatment, 73.7 % discontinued due to progression, 6.9 % due to toxicity, 3.8 % decided to discontinue in treatment. Median PFS was 3.3 months (95% CI, 3.0 – 3.5), and median OS 10.2 months (95% CI, 8.9 – 11.8). Factors significantly associated with PFS and/or OS were: PS, time from diagnosis of mCRC, initiation of TAS-102 treatment > 3 months from last fluoropyrimidine, baseline CRP, WBC, neutrophils count, monocytes count, NLR, neutropenia ≥ G2, diarrhea ≥ G1, thrombocytopenia ≥ G2, required TAS-102 dose reduction and cycle delay. We developed a scoring system TAScore from factors at the beginning of treatment (PS 0, initiation of TAS-102 > 3 months from fluoropyrimidine, time from diagnosis of mCRC, baseline CRP, WBC, monocytes count < 0.5 × 10
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/L). For each factor patient received 1 point, the overall score was the sum of these points and patients were divided into 3 groups: high risk group with 0 to 1 point, intermediate with 2 to 3, favorable with 4 or more points. OS according to risk group was: 5.7 months for high risk (11 patients), 8.7 for intermediate (63), 12.8 for favorable (59) (P < 0.0001). TAScore was also associated with PFS: 2.4 months for high risk, 2.9 intermediate and 3.9 for favorable risk group (P < 0.0001). Conclusions: TAS-102 is effective in patients with refractory mCRC. We propose simple scoring system TAScore to help with precise patient selection at the beginning of TAS-102 treatment.
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Background: TAS-102 significantly improved progression free survival (PFS) and overall survival (OS) versus placebo in patients with treatment refractory mCRC. We analyzed potential ...predictive and prognostic factors in patients treated with TAS-102 in real-world practice. Methods: We retrospectively evaluated the clinical data of 129 patients who received TAS-102. Different factors associated with PFS and OS were analyzed. Results: Baseline characteristics were: median age 67 (range 37-83), male 63.6%, ECOG PS 0 in 40.3% and 1 in 59.7%. Primary tumor location: right 20.2%, left 79.2%, wt RAS 45%. Median number of TAS-102 treatment line 3 (range 2-8). Prior treatment: anti-EGFR 45%, anti-VEGF 83%, and regorafenib 20.9%. Median follow-up was 9.4 months. The median number of cycles of TAS-102 was 3 (range 1-14). Best achieved response was SD in 23%. Median PFS was 3.3 months and OS was 11.1 months. Any ≥ grade 3 AE was in 45%, the most common ≥ grade 3 AEs were neutropenia (40.2%), anemia (6.2%), thrombocytopenia (4.7%), febrile neutropenia (2.3%), diarrhea (1.6%), nausea (1.6%), and asthenia (1.6%). Dose reduction was needed in 29.5% and cycle delay in 53.5%. Factors significantly associated with longer PFS were: initiation of TAS-102 treatment more than 3 months from last fluoropyrimidine therapy (p = 0.022, HR 0.633), normal baseline CRP level (p = 0.004, HR 0.479), baseline WBC < 8 × 10
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/L (p = 0.025, HR 0.641), monocytes < 0.5 × 10
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/L (p = 0.016, HR 0.522), neutropenia ≥ grade 2 during treatment (p < 0.0001, HR 0.349), TAS-102 dose reduction during treatment (p < 0.0001, HR 0.397), and TAS-102 cycle delay (p < 0.0001, HR 0.402). Factors associated with longer OS were normal CRP (p = 0.001, HR 0.295), normal LDH (p = 0.006, HR 0.422), WBC < 8 × 10
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/L (p = 0.0001, HR 0.357), monocytes < 0.5 × 10
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/L (p = 0.016, HR 0.373), neutropenia ≥ G2 during treatment (p = 0.0002, HR 0.343), TAS-102 cycle delay (p = 0.002, HR 0.421), wt RAS (p = 0.05, HR 0.578). Conclusions: This analysis confirms that TAS-102 is effective in patients with refractory mCRC treated in a real-world setting. Factors associated with better outcomes were baseline CRP, WBC, monocytes, and neutropenia, dose reduction and cycle delays during the treatment.
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Background: Right-sided location of primary colorectal carcinoma is associated with worse prognosis and predicts worse outcome of treatment of metastatic disease. Prognostic role of ...KRAS status in 1
st
-line treatment with anti-VEGF of mCRC remains controversial. We aim to study prognostic role of KRAS in the context of primary tumor location for anti-VEGF-based therapy of mCRC. Methods: Data from 3 national comprehensive cancer centers in the Czech Republic were collected prospectively from 01/2009 - 09/2015. A retrospective analysis of outcomes of 1059 pts with mCRC with known KRAS status was performed. Patients were treated with 1st-line bevacizumab (bev) plus FOLFOX or CapOx, irrespective of the KRAS status (all-RAS since 2015). The primary objective of our retrospective analysis was assessment of OS and PFS in right-sided primary tumors in connection with KRAS status. OS and PFS were calculated using the Kaplan-Meier method. Results: KRAS mutation was significantly more common in right- vs left-sided mCRC. Unlike in left-sided subgroup, both PFS and OS was poor in right-sided subgroup irrespective of KRAS status. Targeted therapy in subsequent lines of treatment was evenly spread among primary location subgroups. 769 (71.4%) patients were treated by CTx alone. Conclusions: Known KRAS status (Table) is not relevant for the treatment with 1
st
-line anti-VEGF plus CTx in righ-sided primary tumors. Table: see text
Epithelioid sarcoma is a rare soft-tissue sarcoma typically presenting itself as a subcutaneous or deep dermal mass in distal portions of the extremities of adolescents and young adults. They are ...frequently mistaken for ulcers, abscesses, or infected warts resistant to standard medical treatment. Patients often develop multiple local recurrences with subsequent metastases. We report a case of a 66-year-old patient with chronic leg ulcer who died of generalization of an epithelioid sarcoma.
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