Chandra, Shruti

Abstract Pancreatic neuroendocrine neoplasm (panNEN) is a rare malignancy and the second most common type of pancreatic cancer after pancreatic ductal adenocarcinoma (PDAC), but its etiology is poorly understood. We investigated whether the risk factors of panNEN are concordant with those known for PDAC. We performed the largest case-control study to date on panNENs, comprising 927 sporadic nonfunctional panNEN cases and 1807 frequency-matched controls, using data from the Mayo Clinic Biospecimen Resource for Pancreas Research. We assessed associations for obesity, first-degree family history of pancreatic cancer, cigarette smoking, overall type II diabetes mellitus (T2DM), new-onset T2DM (<1 year before panNEN diagnosis), longstanding T2DM (≥5 years), alcohol intake and aspirin use. Multivariable logistic regression was used to calculate odds ratios and 95% confidence intervals (CIs). Our results show that overall T2DM (OR = 1.71, 95% CI: 1.37–2.14) and new-onset T2DM (OR = 2.65, 95% CI: 1.92–3.69) are associated with higher odds of panNEN, but not longstanding T2DM (OR = 1.29, 95% CI: 0.94–1.75). A non-significant elevated odds of panNEN was observed among participants with a positive family history of pancreatic cancer (OR = 1.44, 95% CI: 0.96–2.14). Alcohol use was inversely related to panNEN (OR = 0.52, 95% CI: 0.42–0.66, ever-vs-never). No association was observed for smoking, obesity or aspirin use. These findings indicate that overall T2DM and new-onset T2DM are associated with higher odds of panNEN. Unlike PDAC, alcohol use was inversely related to panNEN, and we found no associations for cigarette smoking, obesity or aspirin use. These results indicate differences in the risk factor profiles of panNEN and PDAC.

ImportanceIncreased cancer risk in first-degree relatives of probands with pancreatic ductal adenocarcinoma (PDAC probands) who carry pathogenic or likely pathogenic germline variants (PGVs) in cancer syndrome–associated genes encourages cascade genetic testing. To date, unbiased risk estimates for the development of cancers on a gene-specific basis have not been assessed.ObjectiveTo quantify the risk of development of PDAC and extra-PDAC among first-degree relatives of PDAC probands who carry a PGV in 1 of 9 cancer syndrome–associated genes—ATM, BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2, and CDKN2A.Design, Setting, and ParticipantsThis case series focused on first-degree relatives of PDAC probands carrying PGVs in specific cancer syndrome–associated genes. The cohort comprised clinic-ascertained patients enrolled in the Mayo Clinic Biospecimen Resource for Pancreas Research registry with germline genetic testing. In total, 234 PDAC probands carrying PGVs were drawn from the prospective research registry of 4562 participants who had undergone genetic testing of cancer syndrome–associated genes. Demographic and cancer-related family histories were obtained by questionnaire. The data were collected from October 1, 2000, to December 31, 2021.Main Outcomes and MeasuresFor the PDAC probands, the genetic test results of the presence of PGVs in 9 cancer syndrome–associated genes were obtained by clinical testing. Cancers (ovary, breast, uterus or endometrial, colon, malignant melanoma, and pancreas) among first-degree relatives were reported by the probands. Standardized incidence ratios (SIRs) were used to estimate cancer risks among first-degree relatives of PDAC probands carrying a PGV.ResultsIn total, 1670 first-degree relatives (mean [SD] age, 58.1 [17.8] years; 853 male [51.1%]) of 234 PDAC probands (mean [SD] age, 62.5 [10.1] years; 124 male [53.0%]; 219 [94.4%] White; 225 [98.7%] non-Hispanic or non-Latino]) were included in the study. There was a significantly increased risk of ovarian cancer in female first-degree relatives of probands who had variants in BRCA1 (SIR, 9.49; 95% CI, 3.06-22.14) and BRCA2 (SIR, 3.72; 95% CI, 1.36-8.11). Breast cancer risks were higher with BRCA2 variants (SIR, 2.62; 95% CI, 1.89-3.54). The risks of uterine or endometrial cancer (SIR, 6.53; 95% CI, 2.81-12.86) and colon cancer (SIR, 5.83; 95% CI, 3.70-8.75) were increased in first-degree relatives of probands who carried Lynch syndrome mismatch repair variants. Risk of PDAC was also increased for variants in ATM (SIR, 4.53; 95% CI, 2.69-7.16), BRCA2 (SIR, 3.45; 95% CI, 1.72-6.17), CDKN2A (SIR, 7.38; 95% CI, 3.18-14.54), and PALB2 (SIR, 5.39; 95% CI, 1.45-13.79). Melanoma risk was elevated for first-degree relatives of probands with CDKN2A variants (SIR, 7.47; 95% CI, 3.97-12.77).Conclusions and RelevanceIn this case series, the presence of PGVs in 9 cancer syndrome–associated genes in PDAC probands was found to be associated with increased risk of 6 types of cancers in first-degree relatives. These gene-specific PDAC and extra-PDAC cancer risks may provide justification for clinicians to counsel first-degree relatives about the relevance and importance of genetic cascade testing, with the goal of higher uptake of testing.

Introduction: Endoscopic full-thickness resection (EFTR) is a promising technique that allows for a minimally invasive resection of mucosal and submucosal lesions in the gastrointestinal (GI) tract. The data regarding the efficacy and safety of performing EFTR of upper GI lesions using a full-thickness resection device (FTRD) is limited. Hence, we performed a systematic review and meta-analysis of the studies that evaluated this technique. Methods: We performed a comprehensive systematic search of multiple electronic databases and conference proceedings that reported outcomes of EFTR using the FTRD system. The weighted pooled rates of technical success, complete (R0) resection, adverse events (AE), and residual or recurrent lesions were analyzed with 95% CI using the random effects model. Results: Eight studies with a total of 139 patients who underwent EFTR of upper GI lesions were included in the study. The pooled, weighted rate of technical success was 88.2% (95% CI: 81.4-92.7%, I 2 : 0). The R0 resection rate was 70.7% (95% CI: 62.5-77.8%, I 2 : 0). Overall AE rates were 22.1% (95% CI: 15.8-30.1%, I 2 : 0), however, most of the AEs were minor. Of the patients who had follow-up endoscopies, the residual and/or recurrent lesion rate was 6.1% (95% CI: 2.4-14.4%, I 2 : 0). Heterogeneity in the analysis was low. Conclusions: EFTR using the FTRD seems to be effective and safe with acceptable R0 resection rates and low recurrence rates. Further prospective studies are required to validate our results and to compare various modalities of endoscopic resection with this single-step EFTR device.

Abstract Increased pancreatic cancer (PC) risk in first-degree relatives (FDRs) of PC patients with germline pathogenic/likely pathogenic variants (PLPV) is a motivator for cascade genetic testing. To date, unbiased FDR risk estimates for gene-specific risks of genetic cancer syndrome-associated cancers are unknown. These estimates would enhance genetic counseling of at-risk FDRs in families where the PC proband has been found to carry a PLPV. Study Aim: To objectively quantify gene-specific risks of six relevant cancers among FDRs of PC patients with germline PLPV in ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, and PMS2. Methods: In the prospective, clinic-based Mayo Clinic Biospecimen Resource for Pancreas Research registry, 4,562 PC patients had previously undergone germline genetic testing for pancreatic cancer-associated genes through either research studies or clinical testing. Of these, 234 PC probands were found to carry PLPV among 9 genes of interest and had provided detailed demographic and cancer data on their FDRs by questionnaire. We focused on six cancer types (ovary, breast, uterus, pancreas, colon, and malignant melanoma) in FDRs as reported by the probands. Standardized incidence ratios estimated risk by gene of six cancers among FDRs of PC patients carrying PLPV. Results: 1,670 FDRs (mean age 58.1+17.8SD; 48.9% female) were included in the study. We found significantly increased risk of ovarian cancer in female FDRs of PC probands who carry PLPV in BRCA1 (SIR 9.49, 95%CI:3.06-22.14) or BRCA2 (3.72, 95%CI:1.36-8.11), and breast cancer risks were higher with BRCA2 (2.62, 95%CI:1.89-3.54). Uterine cancer risk was increased in FDRs of PC probands who carry PLPV for Lynch Syndrome mismatch repair (MMR) (6.53, 95%CI:2.81-12.86). PC risk was also increased (ATM 4.53, 95% CI:2.69-7.16; BRCA2 3.45, 95%CI:1.72-6.17; CDKN2A 7.38, 95%CI:3.18-14.54; PALB2 5.39, 95%CI:1.45-13.79). Increased colon cancer risk was observed in FDRs of probands who carried MMR PLPV (5.83, 95%CI:3.70-8.75), while melanoma risk was elevated for FDRs of probands with CDKN2A PLPV (7.47, 95%CI:3.97-12.77). Conclusion: PLPV in nine syndrome-associated genes in PC probands are associated with increased risk of six cancers in FDRs in PC families. The findings underscore the importance of risk estimation of various other cancers in PC families for screening, early detection, and intervention. The gene-specific quantified cancer risks for FDRs of PC patients with syndrome-associated germline PLPV can inform counseling regarding extra-PC risks when considering cascade genetic testing. Citation Format: Xuan Chen, Kari Rabe, Margaret Meyer, Jennnifer Kemppainen, Masayasu Horibe, Shruti Chandra, Shounak Majumder, Gloria Petersen. Gene-specific risk of syndrome-associated cancers in first-degree relatives of pancreatic cancer patients with pathogenic/likely pathogenic variants [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A033.

Abstract Background and study aims Palliative treatment of malignant gastric outlet obstruction (GOO) has conventionally been with surgical gastrojejunostomy (SGJ). Advent of devices like lumen apposing metal stents has made endoscopic ultrasound-guided gastroenterostomy (EUS-GE) a potential alternative to SGJ for these patients. We performed a systematic review and meta-analysis of studies that compared outcomes of EUS-GE versus SGJ. Methods We performed a comprehensive systematic search of multiple electronic databases and conference proceedings through January 2021 and identified six studies that compared outcomes of EUS-GE versus SGJ in the management of malignant GOO. The rates of technical success, clinical success, and AEs were analyzed, and pooled odds ratios were calculated using random effects model. Results Six studies were included in our analysis with a total of 484 patients, of which 291 underwent EUS-GE and 193 underwent SGJ. The technical success rate of SGJ was superior to EUS-GE (OR = 0.195; 95 %CI:0.054–0.702; P = 0.012; I2 = 0). The clinical success of EUS-GE was statistically similar to SGJ (OR = 1.566; 95 %CI:0.585–4.197; P = 0.372; I2 = 46.68 %). EUS-GE had significantly fewer AEs compared to SGJ (OR = 0.295; 95 %CI:0.172–0.506; P < 0.005; I2 = 0). Among studies which reported reintervention rates, EUS-GE was statistically similar to SGJ (OR = 0.587; 95 %CI:0.174–1.979; P = 0.390, I2 = 54.91). Minimal to moderate heterogeneity was noted in the analyses. Conclusions EUS-GE has equivalent clinical success and reintervention rates, but significantly lower adverse events compared to SGJ. When feasible, EUS-GE appears to be an effective and safe alternative to SGJ for palliative management of malignant GOO.