Utilization and Outcomes of Multigene Panel Testing in Patients With Pancreatic Ductal Adenocarcinoma.

PURPOSE: Guidelines recommend germline genetic testing (GT) for patients with pancreatic ductal adenocarcinoma (PDAC). This study aims to evaluate the utilization and outcomes of multigene panel GT in patients with PDAC. METHODS: This retrospective, multisite study included patients with PDAC diagnosed between May 2018 and August 2020 at Mayo Clinic Arizona, Florida, and Minnesota. Discussion, uptake, and outcomes of GT were compared before (May 1, 2018-May 1, 2019) and after (August 1, 2019-August 1, 2020) the guideline update, accounting for a transition period. RESULTS: The study identified 533 patients with PDAC, with 321 (60.2%) preguideline and 212 (39.8%) postguideline. Patient characteristics did not differ between the preguideline and postguideline periods. GT was discussed in 34.3% (110 of 321) of preguideline and 39.6% (84 of 212) of postguideline patients (odds ratio [OR], 1.26 [95% CI, 0.88 to 1.80]) and subsequently performed in 80.9% (89 of 110) of preguideline and 75.0% (63 of 84) of postguideline patients (OR, 1.10 [95% CI, 0.75 to 1.61]). Of 152 tested patients, 26 (17.1%) had a pathogenic variant (PV), of whom 17 (11.2%; 17 of 152) were PDAC-associated. Over the entire study period, GT was more likely in younger patients (65 v 70 years; P < .001), those seen by a medical oncologist (82.9% v 69.0%; P < .001), and those surviving more than 12 months from diagnosis (70.4% v 43.4%; P < .001). Demographics and personal/family cancer history were comparable between patients with and without a PDAC PV. CONCLUSION: GT remains underutilized despite National Comprehensive Cancer Network guideline recommendations. Given the poor prognosis of PDAC and potential implications of GT, efforts to increase utilization are needed to provide surveillance and support to both patients with PDAC and at-risk family members.

Germline BRCA testing in pancreatic cancer: improving awareness, timing, turnaround, and uptake.

Prognosis is generally poor for patients with pancreatic ductal adenocarcinoma. However, patients with germline BRCA1 or BRCA2 mutations (gBRCAm) may benefit from first-line platinum-based chemotherapy and maintenance therapy with the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib following at least 16 weeks of first-line platinum-based chemotherapy without disease progression. Germline breast cancer gene (BRCA) testing is therefore important to ensure that patients receive the most effective treatment. In addition, testing for other DNA damage response gene mutations beyond gBRCAm may also guide treatment decisions. However, clinical pathways for genetic testing are often suboptimal, leading to delays in treatment initiation or missed opportunities for personalized therapy. Barriers to testing include low rates of referral and uptake, delays to referral and slow result turnaround times, cost, and biopsy and assay limitations if somatic testing is performed, leading to the requirement for subsequent dedicated germline testing. Low rates of referral may result from lack of awareness among physicians of the clinical value of testing, coupled with low confidence in interpreting test results and poor availability of genetic counseling services. Among patients, barriers to uptake may include similar lack of awareness of the clinical value of testing, anxiety regarding the implications of test results, lack of insurance coverage, fear of negative insurance implications, and socioeconomic factors. Potential solutions include innovative approaches to testing pathways, including 'mainstreaming' of testing in which BRCA tests are routinely arranged by the treating oncologist, with the involvement of genetic counselors if a patient is found to have a gBRCAm. More recently, the utility of multigene panel analyses has also been explored. Access to genetic counseling may also be improved through initiatives such as having a genetic counseling appointment for all new patient visits and telemedicine approaches, including the use of telephone consultations or DVD-assisted counseling. Educational programs will also be beneficial, and cost effectiveness is likely to improve as the number of targeted treatments increases and when the earlier detection of tumors in family members following cascade testing is considered.

AXIN2-related oligodontia-colorectal cancer syndrome with cleft palate as a possible new feature.

BACKGROUND: Pathogenic variants in AXIN2 have been associated with tooth agenesis, colon polyps, and colon cancer. Given the rare nature of this phenotype, we set out to collect additional genotypic and phenotypic information. METHODS: Data were collected via a structured questionnaire. Sequencing was performed in these patients mostly due to diagnostic purpose. A little more than half of the AXIN2 variant carriers were identified by NGS; other six were family members. RESULTS: Here, we report 13 individuals with a heterozygous AXIN2 pathogenic/likely pathogenic variant who have a variable expression of oligodontia-colorectal cancer syndrome (OMIM 608615) or oligodontia-cancer predisposition syndrome (ORPHA 300576). Three individuals from one family also had cleft palate, which might represent a new clinical feature of AXIN2 phenotype, also given the fact that AXIN2 polymorphisms have been found in association with oral clefting in population studies. AXIN2 has already been added to multigene cancer panel tests; further research should be conducted to determine whether it should be added to cleft lip/palate multigene panels. CONCLUSION: More clarity about oligodontia-colorectal cancer syndrome, about the variable expression, and associated cancer risks is needed to improve clinical management and to establish guidelines for surveillance. We collected information about the surveillance that was advised, which might support clinical management of these patients.

Patient uptake of updated genetic testing following uninformative BRCA1 and BRCA2 results.

Advances have dated the genetic testing initially offered to evaluate for hereditary breast and ovarian cancer risks. Previous research has demonstrated that many patients have not updated testing. This study reviewed the incidence of additional analysis after an uninformative BRCA1/2 result and offered updated testing with limited barriers to those who had not completed. After viewing an educational video and providing informed consent, eligible patients were mailed a saliva collection kit to complete an 84-gene hereditary cancer panel at no personal cost. A total of 704 patients had completed BRCA1/2 only testing between 2001 and 2020. Fifteen percent (N = 102) of the 671 patients with an uninformative BRCA1/2 result had already completed expanded testing. Most, 74 of 102 (73%), had been rereferred to medical genetics during a clinical visit related to cancer care. Those who had already completed additional testing were more likely to have a personal history of cancer (92% vs. 79%, p = 0.002) and live locally (p = 0.032). Invitation to complete updated testing through this study was sent to 372 people, and 116 (31%) consented to participate. For 142 of the 256 who did not proceed with testing through the study, proof of receipt of research information was available. In total, 22 pathogenic variants were reported in 21 of the 226 patients with updated testing from before and including our study: ATM (4), CHEK2 (4), LZTR1 (1), MUTYH (3), NBN (1), NF1 (1), NTHL1 (1), PALB2 (4), PMS2 (1), RAD50 (1), and SPINK1 (1). Many potential barriers of retesting were eliminated by removing personal costs or travel requirements. Still, only about 30% of patients agreed to participate, and a significant portion elected not to proceed. Future research could focus on the discovery of other factors that dissuade patients and what measures may better inform them on potential benefits.

Germline Cancer Susceptibility Gene Testing in Unselected Patients With Colorectal Adenocarcinoma: A Multicenter Prospective Study.

BACKGROUND & AIMS: Hereditary factors play a role in the development of colorectal cancer (CRC). Identification of germline predisposition can have implications on treatment and cancer prevention. This study aimed to determine the prevalence of pathogenic germline variants (PGVs) in CRC patients using a universal testing approach, association with clinical outcomes, and the uptake of family variant testing. METHODS: We performed a prospective multisite study of germline sequencing using a more than 80-gene next-generation sequencing platform among CRC patients (not selected for age or family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018, and March 31, 2020. RESULTS: Of 361 patients, the median age was 57 years (SD, 12.4 y), 43.5% were female, 82% were white, and 38.2% had stage IV disease. PGVs were found in 15.5% (n = 56) of patients, including 44 in moderate- and high-penetrance cancer susceptibility genes. Thirty-four (9.4%) patients had incremental clinically actionable findings that would not have been detected by practice guideline criteria or a CRC-specific gene panel. Only younger age at diagnosis was associated with the presence of PGVs (odds ratio, 1.99; 95% CI, 1.12-3.56). After a median follow-up period of 20.7 months, no differences in overall survival were seen between those with or without a PGV (P = .2). Eleven percent of patients had modifications in their treatment based on genetic findings. Family cascade testing was low (16%). CONCLUSIONS: Universal multigene panel testing in CRC was associated with a modest, but significant, detection of heritable mutations over guideline-based testing. One in 10 patients had changes in their management based on test results. Uptake of cascade family testing was low, which is a concerning observation that warrants further study.

Germline Cancer Susceptibility Gene Testing in Unselected Patients with Hepatobiliary Cancers: A Multi-Center Prospective Study.

Data from germline testing in unselected patients with hepatobiliary cancers are limited. Identification of germline predisposition can have important implications on cancer treatment and family counseling. To determine prevalence of pathogenic germline variants (PGV) in patients with hepatobiliary cancer, we undertook a prospective multi-site study of germline sequencing using a >80-gene next-generation sequencing platform among patients with hepatobiliary cancers receiving care at Mayo Clinic Cancer Centers between April 1, 2018 and March 31, 2020. Patients were not selected on the basis of stage, family cancer history, ethnicity, or age. Family cascade testing was offered at no cost. Of 205 patients, the median age was 65 years, 58.5% were male, 81% were White, and 64.4% had cholangiocarcinoma, 21.5% hepatocellular carcinoma, 7.8% gallbladder cancer, and 4.3% carcinoma of ampulla of Vater. PGV were found in 15.6% (n = 32) of patients, including 23 (71%) in moderate and high penetrance cancer susceptibility genes. A total of 75% of patients with a positive result would not have been detected using guidelines for genetic evaluation. Prevalence of PGV was 15.7% in intrahepatic cholangiocarcinoma, 17% in extrahepatic cholangiocarcinoma, 15.9% in hepatocellular cancer, and 33% in carcinoma of ampulla of Vater. On the basis of these genetic findings, 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Universal multi-gene panel testing in hepatobiliary cancers was associated with detection of heritable mutations in over 15% of patients most of whom would not have been tested using current guidelines. Germline testing should be considered in all patients with hepatobiliary cancers. PREVENTION RELEVANCE: Universal multi-gene testing in hepatobiliary cancers was associated with heritable mutations in over 15% of patients, most of whom would not have been tested using current guidelines. 55% were potentially eligible for approved precision therapy and/or clinical treatment trials. Germline testing should be considered in all patients with hepatobiliary cancers.

Clinical Impact of Pathogenic Germline Variants in Pancreatic Cancer: Results From a Multicenter, Prospective, Universal Genetic Testing Study.

INTRODUCTION: To report the prevalence and outcomes of unselected pancreatic cancer (PC) patients with pathogenic/likely pathogenic germline variants (PGVs) detected using a universal testing approach. METHODS: We undertook a prospective, multisite study of germline sequencing using a >80 gene next-generation sequencing platform among 250 patients with PC (not selected for age or family history of cancer) between April 1, 2018, and March 31, 2020. Demographic, tumor characteristics, and clinical outcomes were compared between PGV carriers and noncarriers. RESULTS: Of 250 patients, the mean age was 65 years (SD 8.7), 56% was male, 83.6% was White, and 65.6% had advanced disease (stages III and IV). PGVs were found in 15.2% (N = 38) of patients, and 2 patients had more than 1 PGV. Variants of uncertain significance were found in 44.4% (N = 111). Family history of cancer (odds ratio: 2.36, 95% confidence interval: 1.14-5.19, P = 0.025) was associated with a higher risk of PGV. In a median follow-up of 16.5 months, the median overall survival was 16.8 months in PGV carriers compared with 16.5 months in noncarriers (hazard ratio: 0.51, 95% confidence interval: 0.25-1.01, P = 0.05). Higher levels of carbohydrate antigen 19-9 and advanced disease stages (III and IV) were associated with worse outcomes in both groups. Overall, 68% of PGV carriers had mutations in homologous recombination repair genes, including BRCA1, BRCA2, PALB2, ATM, CHEK2, NBN, and RAD51C. DISCUSSION: Universal multigene panel testing in PC reveals that 1 in 6 patients are carriers of PGV. Multigene germline testing should be used to aid in treatment selection, prognostication, and familial cancer counseling.

Comparison of Universal Genetic Testing vs Guideline-Directed Targeted Testing for Patients With Hereditary Cancer Syndrome.

IMPORTANCE: Hereditary factors play a key role in the risk of developing several cancers. Identification of a germline predisposition can have important implications for treatment decisions, risk-reducing interventions, cancer screening, and germline testing. OBJECTIVE: To examine the prevalence of pathogenic germline variants (PGVs) in patients with cancer using a universal testing approach compared with targeted testing based on clinical guidelines and the uptake of cascade family variant testing (FVT). DESIGN, SETTING, AND PARTICIPANTS: This prospective, multicenter cohort study assessed germline genetic alterations among patients with solid tumor cancer receiving care at Mayo Clinic cancer centers and a community practice between April 1, 2018, and March 31, 2020. Patients were not selected based on cancer type, disease stage, family history of cancer, ethnicity, or age. EXPOSURES: Germline sequencing using a greater than 80-gene next-generation sequencing platform. MAIN OUTCOMES AND MEASURES: Proportion of PGVs detected with a universal strategy compared with a guideline-directed approach and uptake of cascade FVT in families. RESULTS: A total of 2984 patients (mean [SD] age, 61.4 [12.2] years; 1582 [53.0%] male) were studied. Pathogenic germline variants were found in 397 patients (13.3%), including 282 moderate- and high-penetrance cancer susceptibility genes. Variants of uncertain significance were found in 1415 patients (47.4%). A total of 192 patients (6.4%) had incremental clinically actionable findings that would not have been detected by phenotype or family history-based testing criteria. Of those with a high-penetrance PGV, 42 patients (28.2%) had modifications in their treatment based on the finding. Only younger age of diagnosis was associated with presence of PGV. Only 70 patients (17.6%) with PGVs had family members undergoing no-cost cascade FVT. CONCLUSIONS AND RELEVANCE: This prospective, multicenter cohort study found that universal multigene panel testing among patients with solid tumor cancer was associated with an increased detection of heritable variants over the predicted yield of targeted testing based on guidelines. Nearly 30% of patients with high-penetrance variants had modifications in their treatment. Uptake of cascade FVT was low despite being offered at no cost.

Case report expanding the germline AXIN2- related phenotype to include olfactory neuroblastoma and gastric adenoma.

BACKGROUND: Pathogenic AXIN2 variants cause absence of permanent teeth (hypodontia), sparse hair and eye brows (ectodermal dysplasia), and gastrointestinal polyps and cancer. Inheritance is autosomal dominant with variable penetrance. Only twenty- five patients have been reported from five families. A Mayo Clinic pilot program tested 3009 newly diagnosed cancer patients for pathogenic germline variants in 83 hereditary cancer genes, including AXIN2. We found only one patient with a pathogenic AXIN2 variant. CASE PRESENTATION: The proband was a 49 year-old female who came to Otolaryngology clinic complaining of right-sided nasal obstruction. Biopsy of identified nasal polyp revealed olfactory neuroblastoma (esthesioneuroblastoma). Surgical resection with gross, total tumor resection was followed by radiation therapy. The patient enrolled in a clinical pilot of genetic testing and a pathogenic variant in AXIN2, c.1822del (p.Leu608Phefs*81) (NM_004655.3) was found. She was seen in Medical Genetics clinic and found to have a personal history of hypodontia. Her eyebrows, hair, and nails were all normal. She underwent upper endoscopy and colonoscopy. A four mm gastric adenoma was found and removed. CONCLUSIONS: This is the first case reported on a patient with a pathogenic, germline AXIN2 variant and an olfactory neuroblastoma or a gastric adenoma. We propose that these could be features of the AXIN2 phenotype. The known association between gastric adenomas and familial adenomatous polyposis, the other Wnt/beta-catenin disorder, supports the hypothesis that pathogenic AXIN2 variants increase risk as well. As the odds of a chance co-occurrence of a pathogenic AXIN2 variant and an olfactory neuroblastoma are so rare, it is worth exploring potential causation. We are building a clinical registry to expand understanding of the AXIN2 phenotype and request any clinicians caring for patients with pathogenic AXIN2 variants to contact us.

Hereditary Cancer Syndromes-A Primer on Diagnosis and Management: Part 1: Breast-Ovarian Cancer Syndromes.

Cancer is the second leading cause of death in both men and women in the United States, with colorectal cancer and breast cancer being two of the most frequent cancer types. Hereditary causes occurring due to pathogenic sequence variants and defects in certain genes makes up roughly 5% of all colorectal cancers and breast-ovarian cancers. High-risk hereditary predisposition syndromes have been associated with a substantially increased lifetime risk for the development of colorectal cancers and breast-ovarian cancers depending on the genetic syndrome, and many people also carry an increased risk of several other cancers compared with the general population. The aim of this review was to provide comprehensive literature on the most commonly encountered hereditary predisposition syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, hamartomatous polyposis, and breast-ovarian cancer conditions. This will be presented as a 2-part series: the first part will cover the breast-ovarian cancer syndromes, and the second will focus on the inherited colorectal cancer and polyposis conditions.

Hereditary Cancer Syndromes-A Primer on Diagnosis and Management, Part 2: Gastrointestinal Cancer Syndromes.

Hereditary causes due to mutations and defects in certain genes account for roughly 5% to 10% of all colorectal cancers. These inherited syndromes have been associated with a 60% to 100% lifetime risk for development of colorectal cancer, depending on the genetic syndrome, and many also carry an increased risk for multiple extracolonic malignancies. In this second part of a review series on hereditary cancer syndromes, the focus will be to provide guidance on the features and management of the most commonly encountered hereditary colorectal cancers and polyposis conditions including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and hamartomatous polyposis.

A novel variant in FN1 in a family with fibronectin glomerulopathy.

Glomerulopathy with fibronectin deposits (GFND) is a rare glomerular disorder. We report a 28-year-old male diagnosed with GFND by mass spectrometry on kidney biopsy tissue. Whole-exome sequencing (WES) identified that a previously undescribed FN1 gene mutation (c.3051G > T, p.W1017C) was likely responsible for this patient's fibronectin glomerulopathy. We discuss the implications of this novel variant of FN1 and the importance of WES to identify a mutation in a gene of interest.

Diagnostic Yield From Screening Asymptomatic Individuals at High Risk for Pancreatic Cancer: A Meta-analysis of Cohort Studies.

BACKGROUND & AIMS: There have been few studies of abdominal imaging screening of individuals at high risk for pancreatic cancer (based on family history or genetic variants). We performed a meta-analysis of prospective cohort studies to determine the diagnostic yield and outcomes of abdominal imaging screening for asymptomatic individuals at high risk. METHODS: Through a systematic review of multiple electronic databases and conference proceedings through July 2017, we identified prospective cohort studies (>20 patients) of asymptomatic adults determined to be at high-risk of pancreatic cancer (lifetime risk >5%, including specific genetic-associated conditions) who were screened by endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) to detect pancreatic lesions. Our primary outcome was identification of high-risk pancreatic lesions (high-grade pancreatic intraepithelial neoplasia, high-grade dysplasia, or adenocarcinoma) at initial screening, and overall incidence during follow up. Summary estimates were reported as incidence rates per 100 patient-years. RESULTS: We identified 19 studies comprising 7085 individuals at high risk for pancreatic cancer; of these, 1660 patients were evaluated by EUS and/or MRI. Fifty-nine high-risk lesions were identified (43 adenocarcinomas: 28 during the initial exam and 15 during follow-up surveillance) and 257 patients underwent pancreatic surgery. Based on our meta-analysis, the overall diagnostic yield screening for high-risk pancreatic lesions was 0.74 (95% CI, 0.33-1.14), with moderate heterogeneity among studies. The number needed to screen to identify 1 patient with a high-risk lesion was 135 (95% CI, 88-303). The diagnostic yield was similar for patients with different genetic features that increased risk, and whether patients were screened by EUS or MRI. CONCLUSIONS: Based on meta-analysis, 135 patients at high-risk for pancreatic cancer must be screened to identify 1 patient with a high-risk pancreatic lesion. Further studies are needed to determine whether screening reduces mortality and is cost effectiveness for individuals at high-risk of pancreatic cancer.

Advanced Genetic Testing Comes to the Pain Clinic to Make a Diagnosis of Paroxysmal Extreme Pain Disorder.

UNLABELLED: Objective. To describe the use of an advanced genetic testing technique, whole exome sequencing, to diagnose a patient and their family with a SCN9A channelopathy. Setting. Academic tertiary care center. Design. CASE REPORT: Case Report. A 61-year-old female with a history of acute facial pain, chronic pain, fibromyalgia, and constipation was found to have a gain of function SCN9A mutation by whole exome sequencing. This mutation resulted in an SCN9A channelopathy that is most consistent with a diagnosis of paroxysmal extreme pain disorder. In addition to the patient being diagnosed, four siblings have a clinical diagnosis of SCN9A channelopathy as they have consistent symptoms and a sister with a known mutation. For treatment, gabapentin was ineffective and carbamazepine was not tolerated. Nontraditional therapies improved symptoms and constipation resolved with pelvic floor retraining with biofeedback. Conclusion. Patients with a personal and family history of chronic pain may benefit from a referral to Medical Genetics. Pelvic floor retraining with biofeedback should be considered for patients with a SCN9A channelopathy and constipation.

Outcome of Whole Exome Sequencing for Diagnostic Odyssey Cases of an Individualized Medicine Clinic: The Mayo Clinic Experience.

OBJECTIVE: To describe the experience and outcome of performing whole-exome sequencing (WES) for resolution of patients on a diagnostic odyssey in the first 18 months of an individualized medicine clinic (IMC). PATIENTS AND METHODS: The IMC offered WES to physicians of Mayo Clinic practice for patients with suspected genetic disease. DNA specimens of the proband and relatives were submitted to WES laboratories. We developed the Genomic Odyssey Board with multidisciplinary expertise to determine the appropriateness for IMC services, review WES reports, and make the final decision about whether the exome findings explain the disease. This study took place from September 30, 2012, to March 30, 2014. RESULTS: In the first 18 consecutive months, the IMC received 82 consultation requests for patients on a diagnostic odyssey. The Genomic Odyssey Board deferred 7 cases and approved 75 cases to proceed with WES. Seventy-one patients met with an IMC genomic counselor. Fifty-one patients submitted specimens for WES testing, and the results have been received for all. There were 15 cases in which a diagnosis was made on the basis of WES findings; thus, the positive diagnostic yield of this practice was 29%. The mean cost per patient for this service was approximately $8000. Medicaid supported 27% of the patients, and 38% of patients received complete or partial insurance coverage. CONCLUSION: The significant diagnostic yield, moderate cost, and notable health marketplace acceptance for WES compared with conventional genetic testing make the former method a rational diagnostic approach for patients on a diagnostic odyssey.