Purpose The aim of the study was to evaluate the clinical implication of multigene panel testing of beyond BRCA genes in Korean patients with BRCA1/2 mutation-negative breast cancer.
Materials and Methods Between 2016 and 2019, a total of 700 BRCA1/2 mutation-negative breast cancer patients received comprehensive multigene panel testing and genetic counseling. Among them, 347 patients completed a questionnaire about cancer worry, genetic knowledge, and preference for the method of genetic tests during pre- and post-genetic test counseling. The frequency of pathogenic and likely pathogenic variants (PV/LPV) were analyzed.
Results At least one PV/LPV of 26 genes was found in 76 out of 700 patients (10.9 %). The rate for PV/LPV was 3.4% for high-risk genes (17 PALB2, 6 TP53, and 1 PTEN). PV/LPVs of clinical actionable genes for breast cancer management, high-risk genes and other moderate-risk genes such as ATM, BARD1, BRIP, CHEK2, NF1, and RAD51D, were observed in 7.4%. Patients who completed the questionnaire showed decreased concerns about the risk of additional cancer development (average score, 4.21 to 3.94; p < 0.001), influence on mood (3.27 to 3.13; p < 0.001), influence on daily functioning (3.03 to 2.94; p=0.006); and increased knowledge about hereditary cancer syndrome (66.9 to 68.8; p=0.025) in post-test genetic counseling. High cancer worry scales (CWSs) were associated with age ≤ 40 years and the identification of PV/LPV. Low CWSs were related to the satisfaction of the counselee.
Conclusion Comprehensive multigene panel test with genetic counseling is clinically applicable. It should be based on interpretable genetic information, consideration of potential psychological consequences, and proper preventive strategies.
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Cancer Res Treat. 2020;52(3):680-688. Published online January 28, 2020
Purpose
Recent studies revealed the BRCA1 c.5339T>C, p.Leu1780Pro variant (L1780P) is highly suggested as a likely pathogenic. The aim of this study was to evaluate clinicopathologic features of L1780P with breast cancer (BC) using multicenter data from Korea to reinforce the evidence as a pathogenic mutation and to compare L1780P and other BRCA1/2mutations using Korean Hereditary Breast Cancer (KOHBRA) study data.
Materials and Methods
The data of 54 BC patients with L1780P variant from 10 institutions were collected and the clinicopathologic characteristics of the patients were reviewed. The hereditary breast and/or ovarian cancer–related characteristics of the L1780P variant were compared to those of BC patients in the KOHBRA study.
Results
The median age of all patients was 38 years, and 75.9% of cases showed triple-negative breast cancer. Comparison of cases with L1780P to carriers from the KOHBRA study revealed that the L1780P patients group was more likely to have family history (FHx) of ovarian cancer (OC) (24.1% vs. 19.6% vs. 11.2%, p < 0.001 and p=0.001) and a personal history of OC (16.7% vs. 2.9% vs. 1.3%, p=0.003 and p=0.001) without significant difference in FHx of BC and bilateral BC. The cumulative risk of contralateral BC at 10 years after diagnosis was 31.9%, while the cumulative risk of OC at 50 years of age was 20.0%. Patients with L1780P showed similar features with BRCA1 carriers and showed higher penetrance of OC than patients with other BRCA1 mutations.
Conclusion
L1780P should be considered as a pathogenic mutation. Risk-reducing salpingo-oophorectomy is highly recommended for women with L1780P.
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Purpose
Next-generation sequencing (NGS) allows simultaneous sequencing of multiple cancer susceptibility genes and may represent a more efficient and less expensive approach than sequential testing. We assessed the frequency of germline mutations in individuals with epithelial ovarian cancer (EOC), using multi-gene panels and NGS.
Materials and Methods
Patients with EOC (n=117) with/without a family history of breast or ovarian cancer were recruited consecutively, from March 2016 toDecember 2016.GermlineDNAwas sequenced using 35-gene NGS panel, in order to identify mutations. Upon the detection of a genetic alteration using the panel, results were cross-validated using direct sequencing.
Results
Thirty-eight patients (32.5%) had 39 pathogenic or likely pathogenic mutations in eight genes, including BRCA1 (n=21), BRCA2 (n=10), BRIP1 (n=1), CHEK2 (n=2), MSH2 (n=1), POLE (n=1), RAD51C (n=2), and RAD51D (n=2). Among 64 patients with a family history of cancer, 27 (42.2%) had 27 pathogenic or likely pathogenic mutations, and six (9.3%) had mutations in genes other than BRCA1/2, such as CHECK2, MSH2, POLE, and RAD51C. Fifty-five patients (47.0%) were identified to carry only variants of uncertain significance.
Conclusion
Using the multi-gene panel test, we found that, of all patients included in our study, 32.5% had germline cancer-predisposing mutations. NGS was confirmed to substantially improve the detection rates of a wide spectrum of mutations in EOC patients compared with those obtained with the BRCA1/2 testing alone.
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Cancer Res Treat. 2017;49(4):1127-1139. Published online February 6, 2017
Purpose
Metastatic biliary tract cancer (mBTC) has a dismal prognosis. In this study, an independent dataset of patients with mBTC was used to implement and validate a routine clinico-laboratory parameter-based scoring model for risk group identification.
Materials and Methods
From September 2006 to February 2015, 482 patients with mBTC were assigned randomly (ratio, 7:3) into investigational (n=340) and validation datasets (n=142). The continuous variables were dichotomized using a normal range or the best cutoff values determined using the Contal and O'Quigley statistical methods. Following a Cox’s proportional hazard model, the scoring model was derived by summing the rounded chi-square scores for the factors identified by multivariate analysis.
Results
The performance status (Eastern Cooperative Oncology Group 3-4), hypoalbuminemia (< 3.4 mg/dL), carcinoembryonic antigen (≥ 9 ng/mL), neutrophil-to-lymphocyte ratio (≥ 3.0), and carbohydrate antigen 19-9 (≥ 120 U/mL) were identified as independent prognosticators (Harrell’s C index, 0.682; integrated area under the curve, 0.653). Survival was clearly correlated with the risk groups (low, intermediate, and high, 14.0, 7.3, and 2.3 months, respectively; p < 0.001). The prognosis was also discriminative in the validation data set (median survival, 16.7, 7.5, and 1.9 months, respectively; p < 0.001). Chemotherapy did not offer any survival benefits for high-risk patients.
Conclusion
These proposed prognostic criteria for mBTC can facilitate accurate patient risk stratification and treatment-related decision-making.
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Purpose
Comparison of variant frequencies in the general population has become an essential part of the American College of Medical Genetics and Genomics (ACMG) standards and guidelines for interpreting sequence variants. We determined the optimal number of relevant ethnic controls that should be used to accurately calculate the odds ratio (OR) of genetic variants.
Materials and Methods
Using the ACMG guidelines, we reclassified BRCA1 and BRCA2 mutations and variants of unknown significance in 745 Korean patients susceptible to hereditary breast and ovarian cancer compared with 1,314 Korean population controls.
Results
We observed that the ORs were falsely inflated when we analyzed several variants using non-Korean population data. Our simulation indicated that the number of controls needed for the lower limit of a 95% confidence interval to exceed 1.0 varied according to the frequency of the variant in each patient group, with more than 820 controls needed for a variant existing in 1% of cases. Using a sufficient number of relevant population data, we could efficiently classify variants and identified the BRCA1 p.Leu1780Pro mutation as a possible pathogenic founder mutation in Korean patients.
Conclusion
Our study suggests that BRCA1 p.Leu1780Pro is a novel pathogenic mutation found in Korean patients. We also determined the optimal number of relevant ethnic controls needed for accurate variant classification according to the ACMG guidelines.
Citations
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Purpose
The purpose of this study was to investigate the clinical features of epithelial ovarian cancer (EOC) patients according to BRCA1/2 mutation status (mutation, variant of uncertain significance [VUS], or wild type).
Materials and Methods
We analyzed 116 patients whose BRCA1/2 genetic test results were available for mutation type and clinical features, including progression-free survival (PFS), overall survival (OS), and response rate. These characteristics were compared according to BRCA1/2 mutation status.
Results
Thirty-seven (37/116, 31.9%) BRCA1/2 mutations were identified (BRCA1, 30; BRCA2, 7). Mutation of c.3627_3628insA (p.Leu1209_Glu1210?fs) in BRCA1 was observed in five patients (5/37, 13.5%). Twenty-five patients had BRCA1/2 VUSs (25/116, 21.6%). Personal histories of breast cancer were observed in 48.6% of patients with BRCA1/2 mutation (18/37), 16.0% of patients with BRCA1/2 VUS (4/25), and 7.4% of patients with BRCA wild type (4/54) (p < 0.001). Patients with BRCA1/2 mutation showed longer OS than those with BRCA1/2 wild type (p=0.005). No significant differences were detected in PFS, OS, or response rates between patients with BRCA1/2 VUS and BRCA1/2 mutation (p=0.772, p=0.459, and p=0.898, respectively).
Conclusion
Patientswith BRCA1/2 mutation had longer OS than thosewith BRCA1/2wild type. Patients with BRCA1/2 mutation and BRCA1/2 VUS displayed similar prognoses.
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Purpose
This study focused on implementation of a prognostic scoring index based on clinico-laboratory parameters measured routinely on admission in metastatic pancreatic cancer patients.
Materials and Methods
Records from 403 patients of metastatic disease were analyzed retrospectively. Continuous variables were dichotomized according to the normal range or the best cut-off values statistically determined by Contal and O’Quigley method, and then analyzed in association with prognosis—overall survival (OS), using Cox’s proportional hazard model. Scores were calculated by summing the rounded chi-square scores for the factors that emerged in the multivariate analysis.
Results
Performance status, hemoglobin, leucocyte count, neutrophil-lymphocyte ratio, and carcinoembryonic antigen were independent factors for OS. When patients were divided into three risk groups according to these factors, median survival was 11.7, 6.2, and 1.3 months for the low, intermediate, and high-risk groups, respectively (p < 0.001). Palliative chemotherapy has a significant survival benefit for low and intermediate-risk patients (median OS; 12.5 months vs. 5.9 months, p < 0.001 and 8.0 months vs. 2.0 months, p < 0.001, respectively).
Conclusion
We advocate the use of a multivariable approach with continuous variables for prognostic modeling. Our index is helpful in accurate patient risk stratification and may aid in treatment selection.
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Neutrophil-to-lymphocyte ratio as prognostic indicator in gastrointestinal cancers: a systematic review and meta-analysis Randy C. Bowen, Nancy Ann B. Little, Joshua R. Harmer, Junjie Ma, Luke G. Mirabelli, Kyle D. Roller, Andrew Mackay Breivik, Emily Signor, Alec B. Miller, Hung T. Khong Oncotarget.2017; 8(19): 32171. CrossRef
PURPOSE The aims of this study are to find out whether the sequence of chemotherapeutic regimens including second- and third-line taxane and irinotecan influences the survival of patients with unresectable gastric carcinoma and to identify clinical characteristics of patients with improved response. MATERIALS AND METHODS Fifty gastric carcinoma patients who were treated by third-line sequential chemotherapy between November 2004 and July 2010 were enrolled in this study.
Their overall survival (OS) and time to progression (TTP) were set up as primary and secondary end points. For the sequence of chemotherapy regimen, two arms were used. Arm A was defined as 5-fluorouracil (5-FU)+cisplatin (FP) or folinic acid, 5-FU and oxaliplati (FOLFOX), followed by folinic acid, 5-FU and irinotecan (FOLFIRI), and paclitaxel or docetaxel plus 5-FU, with or without epirubicin. Arm B was defined as FP or FOLFOX, followed by paclitaxel or docetaxel plus 5-FU, and FOLFIRI. RESULTS The median OS of all patients was 16.0 months (95% confidence interval, 13.6 to 18.3 months), which is longer than historical control of patients who did not receive third-line chemotherapy. The sequence of second and third-line regimen, including irinotecan and taxane, did not present significant difference in OS or TTP after failure of 5-FU with platinum chemotherapy. In survival analysis of patients' clinicopathologic characteristics, poor prognosis was shown in patients with poorly differentiated histologic features, elevated serum carcinoembryonic level, and shorter TTP of first line chemotherapy. CONCLUSION It is possible for patients to respond differently to chemotherapy due to differences in clinical features and underlying gene expression profiles.
Development of individualized chemotherapy regimens based on gene expression profiles is warranted.
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