Association of Family Cancer History With Pathogenic Variants in Specific Breast Cancer Susceptibility Genes

PURPOSE Family cancer history is an important component of genetic testing guidelines that estimate which patients with breast cancer are most likely to carry a germline pathogenic variant (PV). However, we do not know whether more extensive family history is differentially associated with PVs in specific genes. METHODS All women diagnosed with breast cancer in 2013-2017 and reported to statewide SEER registries of Georgia and California were linked to clinical genetic testing results and family history from two laboratories. Family history was defined as strong (suggestive of PVs in high-penetrance genes such as BRCA1/2 or TP53, including male breast, ovarian, pancreatic, sarcoma, or multiple female breast cancers), moderate (any other cancer history), or none. Among established breast cancer susceptibility genes ( ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53), we evaluated PV prevalence according to family history extent and breast cancer subtype. We used a multivariable model to test for interaction between affected gene and family history extent for ATM, BRCA1/2, CHEK2, and PALB2. RESULTS A total of 34,865 women linked to genetic results. Higher PV prevalence with increasing family history extent ( P < .001) was observed only with BRCA1 (3.04% with none, 3.22% with moderate, and 4.06% with strong history) and in triple-negative breast cancer with PALB2 (0.75% with none, 2.23% with moderate, and 2.63% with strong history). In a multivariable model adjusted for age and subtype, there was no interaction between family history extent and PV prevalence for any gene except PALB2 ( P = .037). CONCLUSION Extent of family cancer history is not differentially associated with PVs across established breast cancer susceptibility genes and cannot be used to personalize genes selected for testing.

Prevalence of Germline Pathogenic Variants in Cancer Predisposing Genes in Czech and Belgian Pancreatic Cancer Patients

(1) Background: The proportion and spectrum of germline pathogenic variants (PV) associated with an increased risk for pancreatic ductal adenocarcinoma (PDAC) varies among populations. (2) Methods: We analyzed 72 Belgian and 226 Czech PDAC patients by multigene panel testing. The prevalence of pathogenic variants (PV) in relation to personal/family cancer history were evaluated. PDAC risks were calculated using both gnomAD-NFE and population-matched controls. (3) Results: In 35/298 (11.7%) patients a PV in an established PDAC-predisposition gene was found. BRCA1/2 PV conferred a high risk in both populations, ATM and Lynch genes only in the Belgian subgroup. PV in other known PDAC-predisposition genes were rarer. Interestingly, a high frequency of CHEK2 PV was observed in both patient populations. PV in PDAC-predisposition genes were more frequent in patients with (i) multiple primary cancers (12/38; 32%), (ii) relatives with PDAC (15/56; 27%), (iii) relatives with breast/ovarian/colorectal cancer or melanoma (15/86; 17%) but more rare in sporadic PDAC (5/149; 3.4%). PV in homologous recombination genes were associated with improved overall survival (HR = 0.51; 95% CI 0.34–0.77). (4) Conclusions: Our analysis emphasizes the value of multigene panel testing in PDAC patients, especially in individuals with a positive family cancer history, and underlines the importance of population-matched controls for risk assessment.

Circulating tumor cells demonstrate a positive biomarker in head and neck squamous cell carcinoma (HNSCC) in tobacco consuming population of Bangladesh.

e18011 Background: Tobacco consumption accounts for 1.6 million deaths annually in the South East Asia Region (SEAR). Notably, amongst 10-20% of the global population consuming the betel quid and tobacco, about 81% concentration is in SEAR regions, including India and Bangladesh. The prevalence of HNSCC in these regions is rising alarmingly. For example, HNCs account for 23% of total 156775 cancer incidences in Bangladesh. Liquid biopsy tools are unavailable and expensive for most patients in this region. However, early cancer detection using tumor biomarkers, for example, Circulating Tumor Cells (CTCs) is highly implicated. Furthermore, such biomarkers are being validated and have potential for screening of high-risk patients, such as genetic predisposition, tobacco consumption, etc. We report the first observational study in HNSCC patients in Bangladesh correlating the presence of CTCs to chronic tobacco consumption. Methods: The study involved 70 cancer patients and 10 healthy volunteers (no prior cancer history). 87% of the patients had a specified history of chronic tobacco consumption. CTCs were isolated in 1.5 ml of blood using OncoDiscover Liquid Biopsy Test, which is clinically approved by the Drug Controller General of India, that contains an enriching anti-EPCAM antibody immunomagnetic kit. CTCs are qualified as CK18+, DAPI+and CD45-. Subsequently, CTCs were imaged using Zeiss Axio Observer 7 and quantified for Mean Fluorescence Intensity (MFI) for clinicopathological parameters; age/gender, HNSCC sub-population, and CTC distribution. Results: This is the 1st study on Bangladesh phenotype accounting for the presence of CTCs in HNSCC patients. In this population, 34 males (66%) and 10 females (52%) accounted for 91 CTCs. CTC distribution was 0 to 6 with mean and median ̃ 2.02 and 2, respectively. 25 patients (17 males, 8 females) were negative for any CTCs. Interestingly, 02 patients exhibited CTC clusters indicative of aggressive metastasis in which 01 patient had no prior tobacco usage or family cancer history. There was no correlation between CTC presence in males (66 %) and females (52 %). Healthy volunteer samples exhibited no false positives. The MFI values ranged between 23 and 766, with mean and median MFI values were 157 and 96, respectively, indicative of CK overexpression on CTCs of HNSCC patients. Conclusions: HNSCC patients with a history of chronic tobacco consumption in Bangladesh correlated the presence of CTCs in 64 % of the cases. Prospectively, CTCs may be validated as a biomarker for screening chronic tobacco users in Bangladesh to detect early cancers and HNSCC. Clinical trial information: BMRC/Grants/2018/99 (1-100).

Risk factors of Pancreatic Cancer in Vietnam: A Matched Case–Control Hospital-Based Study

Background: Data about the risk factors and pancreatic cancer in developing countries remain limited. We investigated for the first time the role of a number of risk factors (family cancer history, smoking, alcohol consumption, diabetes, inflammation disease, HBV infection) associated with pancreatic cancer among Vietnamese patients. Methods: We included all patients hospitalized at 4 Northern Vietnamese hospitals (Vietnam National Cancer Hospital, Bach Mai, Viet Duc, Thai Nguyen) and diagnosed with pancreatic cancer during the period from 2017 to 2019. Risk factors of eligible patients were collected and assessed the associations using a matched control study and logistic regression model analysis. Results: We identified 196 patients with diagnosis of pancreatic cancer of which 114 males and 82 females. The average age of the patient at the time of diagnosis was 58.28 years (standard deviation of 12.94, ranging from 25 to 87). Most of patients were diagnosed at advanced stage (85%). Smoking, diabetes, inflammation disease significantly increased the cancer risks (OR and 95% CI were 2.42 (1.38-4.37), 3.09 (1.54-6.68), 2.21 (1.42-3.45), respectively). HBV infection demonstrated a significant link with pancreatic cancer in univariate model (OR = 2.94 (1.08-9.36)), but not in multivariate model. However, cancer family history and alcohol drinkers did not show any significantly increased risk related to pancreatic cancer. Conclusions: Our finding showed smoking, diabetes, inflammation disease significantly increased the risk of pancreatic cancer in Vietnam.

Lung cancer screening with low-dose computed tomography at a tertiary hospital in Anhui, China and secondary analysis of trial data

Objective: Lung cancer screening with low-dose computed tomography (LDCT) partly reduces cancer-specific mortality. However, few data have described this specific population for screening in mainland China. Here, we conducted a population-based screening program in Anhui, China. Methods: 9084 individuals were participating in the screening program for lung cancer in Anhui province from 1 June 2014 to 31 May 2017. LDCT was offered to all participants who joined the program. Results: Of 9084 individuals undergoing LDCT, we detected 54 lung cancers (0.594%). The age with the highest rate was 61–65 years (up to 1.016%), followed by 56–60 (0.784%). Most patients (98.1%, 53/54) were in stage I–II (early stage), and only one was in stage III (advanced stage). Adenocarcinoma, squamous cell carcinoma and small cell lung cancer accounted for 57.4% (31/54), 37% (20/54) and 5.6% (3/54) of the individuals, respectively. Notably, There were 4,102 never smokers in our study. The median age was 63 years. Males and females accounted for 53.4 and 46.6%, respectively. Among the 4102 never smokers, 96 participants had a positive family cancer history. Additionally, we detected 20 lung cancers (0.488%), slightly lower than the whole rate 0.594%. Finally, our data showed that age, smoking, family cancer history and features of nodules were risk factors for lung cancer. Conclusion: Our study qualified the efficiency of LDCT to detect early-stage lung cancers in Anhui, China. Further establishment of appropriate lung cancer screening methods specifically for individuals in China is warranted. Advances in knowledge: We evaluated the performance of lung cancer screening for asymptomatic populations using LDCT in Anhui, an eastern inland province of China. Our study qualified the efficiency of LDCT to detect early-stage lung cancers in Anhui, China.

Association between prostate cancer characteristics and BRCA1/2-associated family cancer history in a Japanese cohort

In addition to breast, ovarian, and pancreatic cancers, BRCA1/2 genes have been associated with prostate cancer (PC). However, the role of BRCA1/2-associated family cancer history (FCH) has remained unexplored in treating these four cancer types as a homogenous pathophysiological group. We aimed to clarify the relationship between BRCA1/2-associated FCH and PC, and to assess its relationship with cancer aggressiveness. Patient characteristics, positive family history of BRCA1/2-associated cancer, and cancer characteristics (Gleason score, prostate specific antigen level at diagnosis, and clinical tumor stage) were analyzed. Among the 1,985 eligible candidates, 473 (23.83%) patients had adequately detailed FCH, obtained via questionnaire, and were thus included in the study. BRCA1/2-associated FCH was observed in 135 (28.54%) patients with PC (68, 14.38%), breast (44, 9.30%), pancreatic (31, 6.55%), or ovarian (8, 1.69%) cancers. BRCA1/2-associated FCH was not significantly associated with high Gleason score (≥ 8). Patients with BRCA-associated FCH were less likely to present with high clinical tumor stage, and no difference was observed in prostate-specific antigen level, presence of metastatic lesions at diagnosis, or likelihood of high-risk classification between patients with and without BRCA-associated FCH. This is the first report of BRCA1/2-associated FCH in Japanese men, indicating that family history did not affect the severity or aggressiveness of PC.

Smoking and Family Cancer History Are Associated With Sarcomas in A Japanese Population Study

Background: Sarcoma is a rare cancer, and it is also the cause of the development of various kinds of sarcomas, such as gene abnormalities, which has recently becoming evident due to advances of genetic testing. The approach to solve the origin of diseases is essential to elucidate both the external environmental factors and the internal genetic factors. However, the lifestyle habits, lifestyle-related diseases, personal and family cancer history of sarcoma patients remain unclear.Methods: A total of 1320 sarcoma patients were enrolled in this study. A questionnaire on lifestyle habits, life-style diseases, and the patient’s personal and family cancer history was completed at presentation. A total of 1320 controls were selected by propensity score matching for age and gender. Smoking, drinking, obesity, hypertension, dyslipidemia and diabetes mellitus were compared. In addition, we investigated the incidence of a personal and family cancer history in sarcoma patients. Results: A smoking habit was the only independent risk factor for high-grade soft tissue sarcoma development in adults ≥20 years old (n=952), excluding low-grade and intermediate malignant soft tissue tumors (Odds ratio [OR], 2.45; 95% confidence interval [CI] 1.88-3.20, p<0.001). The ORs of high-grade liposarcoma and undifferentiated pleomorphic sarcoma (UPS) were 2.56 and 3.00, respectively. Eight percent of sarcoma patients had a personal history of another cancer. Thirty percent of soft tissue sarcoma patients had a family history of cancer in a first-degree relatives (malignant peripheral nerve sheath tumor, 52%; leiomyosarcoma, 46%). Conclusions: We confirmed that a smoking habit were associated with the development of high-grade soft tissue sarcomas. A family history of cancer might be associated with certain soft tissue sarcomas, but a further investigation will be necessary.