Multigene Panel Testing Research Articles

Genetic testing outcome disparities in minority racial and ethnic sub-populations within a hereditary breast and ovarian cancer program serving a diverse, urban-based population (191)

Genetic testing outcome disparities in minority racial and ethnic sub-populations within a hereditary breast and ovarian cancer program serving a diverse, urban-based population (191)

Comprehensive Germline Genomic Profiling of Patients with Ovarian Cancer: A Cross-Sectional Study

Abstract Introduction Ovarian cancer is the third most common cancer among Indian women. The data on the hereditary predisposition of these cancers and the clinical outcomes of those with pathogenic mutations is meager in India. Objective The aim of the current study was to analyze the germline-genetic profile, clinicopathological characteristics, and outcomes of patients with ovarian cancer who were referred for genetic counseling at our Institute. Materials and Methods It was a cross-sectional observational study. Patients with histological diagnosis of carcinoma ovary at our institute who were referred for genetic counseling from July 2017 to June 2020 were included in the study. All patients underwent pretest counseling. Most patients underwent multigene panel testing with reflex multiplication ligation-dependent probe amplification for large genomic rearrangements, while some received testing for BRCA1 and BRCA2 only. The variants were classified as pathogenic or benign based on American College of Medical Genetics (ACMG) guidelines. Data regarding the demographic profile, clinical characteristics, histopathological findings, family history, treatment received, and outcomes were extracted from the medical record system files. Results One hundred and one patients were referred to the genetic clinic and underwent genetic counseling. All patients were advised for genetic testing; however, only 72 (71%) underwent testing. A multigene panel testing was done in 51 (70%) patients, and only BRCA1 and BRCA2 genes were tested in 21 (30%). Among the 72 patients who underwent a genetic test, the median age was 47 years (range, 28–82). The most common histopathology was serous (90%), while 85% were diagnosed having stage 3 and 4 ovarian cancer. A pathogenic/likely pathogenic (P/LP) BRCA or non-BRCA mutation was detected in 32 (44%) patients. Six patients (8%) had a variant of unknown significance (VUS). Among P/LP mutations, 85% were in the BRCA gene (75% in BRCA1 and 10% in BRCA2), while 15% were in non-BRCA gene mutations (RAD51, PALB2, MER11, HMMR). Disease-free survival and overall survival were not different in mutation-positive and mutation-negative cohorts. Conclusions We report 44% P/LP mutations in this selected cohort of patients with carcinoma ovaries. BRCA mutations constituted 85% of all the mutations, while 15% of mutations were in non-BRCA genes.

Spectrum and management of breast cancer patients with variant of uncertain significance mutations at a tertiary care centre in North India.

BackgroundThe spectrum and significance of Variants of Uncertain Significance (VUS) mutations in breast cancer predisposition genes is poorly defined in the Indian population.MethodsAll new female breast cancer patients from 1 March 2019 to 28 February 2020 were screened. Those providing informed consent and without previous genetic testing were recruited. Multigene panel testing (107 genes) by next-generation sequencing was performed for all patients. Descriptive statistics was used to describe the spectrum of VUS mutations.ResultsOut of 236 patients recruited in the study, a VUS was detected in 89 patients (37.71%). VUS pathogenic ratio was 2.02. A total of 121 different VUS mutations in 40 different genes were detected. Fourteen patients (15.7%) had a VUS in high penetrance genes and 36 VUS mutations (29.8%) were detected in one of the genes involved in homologous recombination repair pathway. No therapeutic interventions were done based on VUS.ConclusionsIn this large prospective study of genetic determinants of breast cancer from India, a high prevalence of VUS (37.71%) was detected with 15.7% patients having a VUS in high penetrance genes. More evidence needs to be generated from larger multicentric studies to better understand the implications of these genetic variants and enable their reclassification.

Significance of the Multi-gene Panel myRisk in Japan.

Hereditary tumors are estimated to account for approximately 5-10% of all tumors. In Europe and the United States, multi-gene panel testing (MGPT) is the standard method used for identifying potential causative genes. However, MGPT it is still not widely used in Japan. The aim of this study was to assess the risk of hereditary tumors in Japanese cancer patients using germline MGPT and provide an overview of MGPT in the Japanese medical system. We used the myRiskTM, a 35-gene panel that determines the risk for eight hereditary cancers: breast, ovarian, gastric, colorectal, prostate, pancreatic, malignant melanoma, and endometrial cancers. From June 2019 to March 2020, 21 patients who were suspected to have hereditary tumors were included, based on their family or medical history. Pathogenic variants were found in 7 patients [BRCA1 (5), MSH6 (1), TP 53 (1)]. In this study, despite the small number of participants, we were able to show the significance of MGPT in Japan. Therefore, MGPT should be used for evaluating hereditary tumors in clinical practice.

A clinician's guide for counseling patients on results of a multigene pharmacogenomic panel.

This article explores approaches to pharmacogenomic counseling for patients who have undergone multigene panel testing by describing the collective experience of 5 institutions. Multigene panel pharmacogenomic testing has the potential to unlock a myriad of information about a patient's past, present, and future drug response. The multifaceted nature of drug response coupled with the complexity of genetic results necessitates some form of patient education through pharmacogenomic counseling. Published literature regarding disclosure of pharmacogenomic test results is limited. This article compares the counseling practices of pharmacists from 5 different institutions with pharmacogenomics clinics whose experience represents perspectives ranging from academia to community clinical environments. Overarching counseling themes discussed during result disclosure center around (1) pharmacogenomic results, (2) gene-drug interactions, (3) gene-drug-drug interactions, (4) drug changes (5) future, familial, or disease-risk implications, (6) updates in the interpretation and application of pharmacogenomic results, (7) gauging patient comprehension, and (8) sharing results and supplemental information. Dedicating time to counseling patients on the results of a multigene pharmacogenomic panel is important given the lifelong applications of a test that is generally performed only once. The content and methods of disclosing test results shared by the experiences of pharmacists at 5 different institutions serve as guide to be further refined as research addresses effective communication strategies that enhance patient comprehension of pharmacogenomic results.

Implementing universal upfront multi-gene panel testing in endometrial cancer: From cost to practical considerations

ObjectivesThe routine use of upfront universal germline genetic testing among patients with newly diagnosed endometrial cancer (EC) has been proposed to improve diagnosis of Lynch syndrome (LS) and discover pathogenic variants (PVs) in other cancer susceptibility genes. We propose an algorithm prioritizing upfront multi-gene panel testing (MGPT) for newly diagnosed EC patients. MethodsA decision analysis compared the cost of the current algorithm of universal mismatch repair (MMR) immunohistochemistry (IHC) for all EC cases to a new MGPT algorithm that employs upfront MGPT for all EC cases and reserves MMR IHC for the recurrent setting. The increase in the number of LS diagnoses using upfront MGPT, and the number of patients with PVs in BRCA1 and BRCA2 are also estimated. ResultsThe MGPT algorithm demonstrated a cost savings of $259 per patient. Assuming 66,950 new cases of EC per year, this would represent $17.1 M of cost savings per year. When applied to all new diagnoses of EC in one year, the MGPT algorithm identified 660 (1%) additional cases of LS that would have been missed with the current algorithm. An additional 660 (1%) EC patients with BRCA1 or BRCA2 PVs would be diagnosed only through implementation of universal MGPT. ConclusionsThe use of universal upfront MGPT is a practical consideration for patients with newly diagnosed EC for cost savings and improved diagnosis of highly penetrant cancer syndromes. Incorporation of germline genetic testing in the upfront setting represents an opportunity to improve access to genetic counseling and testing, and ultimately an avenue to achieve equity and improve the lives of our patients with EC and their families.

Germline Testing in a Cohort of Patients at High Risk of Hereditary Cancer Predisposition Syndromes: First Two-Year Results from South Italy.

Germline pathogenic variants (PVs) in oncogenes and tumour suppressor genes are responsible for 5 to 10% of all diagnosed cancers, which are commonly known as hereditary cancer predisposition syndromes (HCPS). A total of 104 individuals at high risk of HCPS were selected by genetic counselling for genetic testing in the past 2 years. Most of them were subjects having a personal and family history of breast cancer (BC) selected according to current established criteria. Genes analysis involved in HCPS was assessed by next-generation sequencing (NGS) using a custom cancer panel with high- and moderate-risk susceptibility genes. Germline PVs were identified in 17 of 104 individuals (16.3%) analysed, while variants of uncertain significance (VUS) were identified in 21/104 (20.2%) cases. Concerning the germline PVs distribution among the 13 BC individuals with positive findings, 8/13 (61.5%) were in the BRCA1/2 genes, whereas 5/13 (38.4%) were in other high- or moderate-risk genes including PALB2, TP53, ATM and CHEK2. NGS genetic testing showed that 6/13 (46.1%) of the PVs observed in BC patients were detected in triple-negative BC. Interestingly, the likelihood of carrying the PVs in the moderate-to-high-risk genes calculated by the cancer risk model BOADICEA was significantly higher in pathogenic variant carriers than in negative subjects. Collectively, this study shows that multigene panel testing can offer an effective diagnostic approach for patients at high risk of hereditary cancers.

Identification of Lynch Syndrome in Patients with Endometrial Cancer Based on a Germline Next Generation Sequencing Multigene Panel Test.

Simple SummaryLynch Syndrome (LS) is a hereditary cancer syndrome caused by an autosomal dominant mutation in one of the DNA mismatch repair (MMR) genes. Understanding the clinical traits of endometrial cancer, which is one of the most frequent as well as the earliest diagnosed cancer types of LS-associated cancers, has the potential to offer tailored screening programs and lifesaving interventions. Whereas most large-scale studies of LS-associated endometrial cancers are based on cohorts in Western countries, studies from a predominantly Korean population are relatively few. We conducted a multi-center, retrospective study of patients with endometrial cancer who underwent germline multigene panel testing that included MMR genes. Based on the analysis of 204 patients with endometrial cancer who underwent germline multigene panel testing, we investigated the prevalence of LS and non-LS mutation and the relative contribution of each MMR gene mutation that, in composite, led to the clinical phenotype of LS-associated endometrial cancer patients in a predominantly Korean population.We aimed to investigate the prevalence and relative contributions of LS and non-LS mutations in patients with endometrial cancer in Korea. We retrospectively reviewed the medical records of 204 patients diagnosed with endometrial cancer who underwent a germline next generation sequencing multigene panel test covering MLH1, MSH2, MSH6, PMS2, and EPCAM at three tertiary centers. Thirty patients (14.7%) with pathogenic mutations (12 MLH1; 6 MSH2; 10 MSH6; 2 PMS2) and 20 patients (9.8%) with 22 unclassified variants (8 MLH1; 8 MSH2; 2 MSH6; 3 PMS2; 1 EPCAM) were identified. After excluding four close relatives of a proband, the prevalence of LS was 13.0% (26/200). Patients with LS were more likely than those with sporadic cancer to be younger at diagnosis (48 vs. 53 years, p = 0.045) and meet the Amsterdam II criteria (66.7 vs. 3.5%, p < 0.001). Non-endometrioid histology was more prevalent in patients with MSH6 or PMS2 mutations (41.7%) than those with MLH1 or MSH2 mutations (5.6%, p = 0.026). In this pre-selected cohort of endometrial cancer patients who underwent next generation sequencing, the prevalence of LS was 13%, thus supporting the use of gene panel testing for endometrial cancer patients.

Experiences of individuals with a variant of uncertain significance on genetic testing for hereditary cancer risks: a mixed method systematic review.

The expansion of Multi-Gene Panel Testing (MGPT) has led to increased detection of variants of uncertain significance (VUS) among individuals with personal or family history of cancer. However, having a VUS result can impact on emotional and psychological wellbeing and cause challenges for non-geneticist healthcare providers. The purpose of this mixed methods systematic review was to examine what is currently known about the experiences of individuals with a VUS on genetic testing for inherited cancer susceptibility. The initial search was conducted in June 2020 using PUBMED, CINAHL, Web of Science, and PsychInfo according to the Joanna Briggs methodology for systematic reviews. A total of 18 studies met the inclusion criteria. Studies included in this review identified a range of emotional reactions to a VUS result, a general lack of understanding of a VUS result and its implications, frustration with a lack of healthcare provider knowledge, and a need for clear communication with healthcare providers. This review identified critical gaps in current knowledge to guide genetic counseling praxis, specifically in the knowledge of communication patterns and methods of improving communication with healthcare providers and family members and preferred risk management strategies. This will help to improve the counseling process and the management of care during and after genetic testing.

Prevalence of Cancer Predisposition Germline Variants in Male Breast Cancer Patients: Results of the German Consortium for Hereditary Breast and Ovarian Cancer.

Simple SummaryMale breast cancer (mBC) is a rare disease associated with a high prevalence of pathogenic germline variants (PVs) in the BRCA2 gene. However, data regarding other breast cancer (BC) predisposition genes are limited or conflicting. We investigated the prevalence of PVs in BRCA1/2 and 23 other cancer predisposition genes using an overall study sample of 614 patients with mBC. A high proportion of patients with mBC carried pathogenic germline variants in BRCA2 (23.0%, 142/614) and BRCA1 (4.6%, 28/614). A BRCA1/2 PV prevalence of 11.0% was identified in patients with mBC without a family history of breast and/or ovarian cancer. Patients with BRCA1/2 PVs did not show an earlier disease onset than those without. Case-control analyses revealed significant associations of protein-truncating variants in BRCA1, BRCA2, CHEK2, PALB2, and ATM with mBC. Our findings support the benefit of multi-gene panel testing in patients with mBC.Male breast cancer (mBC) is associated with a high prevalence of pathogenic variants (PVs) in the BRCA2 gene; however, data regarding other BC predisposition genes are limited. In this retrospective multicenter study, we investigated the prevalence of PVs in BRCA1/2 and 23 non-BRCA1/2 genes using a sample of 614 patients with mBC, recruited through the centers of the German Consortium for Hereditary Breast and Ovarian Cancer. A high proportion of patients with mBC carried PVs in BRCA2 (23.0%, 142/614) and BRCA1 (4.6%, 28/614). The prevalence of BRCA1/2 PVs was 11.0% in patients with mBC without a family history of breast and/or ovarian cancer. Patients with BRCA1/2 PVs did not show an earlier disease onset than those without. The predominant clinical presentation of tumor phenotypes was estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, and HER2-negative (77.7%); further, 10.2% of the tumors were triple-positive, and 1.2% were triple-negative. No association was found between ER/PR/HER2 status and BRCA1/2 PV occurrence. Comparing the prevalence of protein-truncating variants (PTVs) between patients with mBC and control data (ExAC, n = 27,173) revealed significant associations of PTVs in both BRCA1 and BRCA2 with mBC (BRCA1: OR = 17.04, 95% CI = 10.54–26.82, p < 10−5; BRCA2: OR = 77.71, 95% CI = 58.71–102.33, p < 10−5). A case-control investigation of 23 non-BRCA1/2 genes in 340 BRCA1/2-negative patients and ExAC controls revealed significant associations of PTVs in CHEK2, PALB2, and ATM with mBC (CHEK2: OR = 3.78, 95% CI = 1.59–7.71, p = 0.002; PALB2: OR = 14.77, 95% CI = 5.02–36.02, p < 10−5; ATM: OR = 3.36, 95% CI = 0.89–8.96, p = 0.04). Overall, our findings support the benefit of multi-gene panel testing in patients with mBC irrespective of their family history, age at disease onset, and tumor phenotype.

Applications for pharmacogenomics in pharmacy practice: A scoping review.

Pharmacogenomics (PGx) can provide valuable pharmacokinetic and pharmacodynamic information for the pharmacist's assessment of drug therapy, especially within medication therapy management (MTM) services. However, no review has comprehensively mapped the pharmacists' use of PGx in practice-based research. Doing so would allow future researchers, practitioners, and policy-makers to identify the ideal populations and settings for PGx implementation within the pharmacy. The purpose of this review is to identify the evidence to date of PGx use in pharmacy practice. A scoping review was conducted to find all studied non-oncologic pharmacy practices incorporating PGx testing. Search terms were applied to 5 databases and relevant journals. Characteristics of patients, pharmacy settings, genetic tests, and outcomes were summarized to determine models most likely to benefit patients. The search identified 43 studies on the use of PGx by pharmacists published between 2007 and 2020. CYP2C19 testing with antiplatelets was the most studied model, found in both community and institutional settings. It also was the most actionable test: approximately 30% of patients have polymorphisms indicating a need for alternative antiplatelets, and identifying these patients can reduce morbidity and mortality by more than 50%. As technology shifts, broader studies using multi-gene panel tests within MTM demonstrate an approximate 50% decrease in emergency visits and hospitalizations in elderly polypharmacy patients. Clinical benefit or drug-gene interactions are also found in other cardiovascular, psychiatric, analgesic, and gastrointestinal indications. No evaluations of actual costs or of pharmacist prescribing within pharmacy-based PGx have been performed. Facilitators towards successful PGx implementation included pharmacist education, collaboration with other healthcare providers, and the use of clinical decision software. Pharmacogenomic testing has demonstrated feasibility and improved medication outcomes in pharmacy practice, including in the community pharmacy. Further PGx research should be directed towards pharmacist prescribing, pharmacist education, and pharmacoeconomics.

P38-1 The clinical result of cancer multi-gene panel testing in Anjo Kosei Hospital

P38-1 The clinical result of cancer multi-gene panel testing in Anjo Kosei Hospital

Germline Pathogenic Variant Prevalence Among Latin American and US Hispanic Individuals Undergoing Testing for Hereditary Breast and Ovarian Cancer: A Cross-Sectional Study.

To report on pathogenic germline variants detected among individuals undergoing genetic testing for hereditary breast and/or ovarian cancer (HBOC) from Latin America and compare them with self-reported Hispanic individuals from the United States. In this cross-sectional study, unrelated individuals with a personal/family history suggestive of HBOC who received clinician-ordered germline multigene sequencing were grouped according to the location of the ordering physician: group A, Mexico, Central America, and the Caribbean; group B, South America; and group C, United States with individuals who self-reported Hispanic ethnicity. Relatives who underwent cascade testing were analyzed separately. Among 24,075 unrelated probands across all regions, most were female (94.9%) and reported a personal history suggestive of HBOC (range, 65.0%-80.6%); the mean age at testing was 49.1 ± 13.1 years. The average number of genes analyzed per patient was highest in group A (A 63 ± 28, B 56 ± 29, and C 40 ± 28). Between 9.1% and 18.7% of patients had pathogenic germline variants in HBOC genes (highest yield in group A), with the majority associated with high HBOC risk. Compared with US Hispanics individuals the overall yield was significantly higher in both Latin American regions (A v C P = 1.64×10-9, B v C P < 2.2×10-16). Rates of variants of uncertain significance were similar across all three regions (33.7%-42.6%). Cascade testing uptake was low in all regions (A 6.6%, B 4.5%, and C 1.9%). This study highlights the importance of multigene panel testing in Latin American individuals with newly diagnosed or history of HBOC, who can benefit from medical management changes including targeted therapies, eligibility to clinical trials, risk-reducing surgeries, surveillance and prevention of secondary malignancy, and genetic counseling and subsequent cascade testing of at-risk relatives.

Identification of novel susceptibility genes for non-syndromic cleft lip with or without cleft palate using NGS-based multigene panel testing.

For non-syndromic cleft lip with or without cleft palate (ns-CL/P), the proportion of heritability explained by the known risk loci is estimated to be about 30% and is captured mainly by common variants identified in genome-wide association studies. To contribute to the explanation of the "missing heritability" problem for orofacial clefts, a candidate gene approach was taken to investigate the potential role of rare and private variants in the ns-CL/P risk. Using the next-generation sequencing technology, the coding sequence of a set of 423 candidate genes was analysed in 135 patients from the Polish population. After stringent multistage filtering, 37 rare coding and splicing variants of 28 genes were identified. 35% of these genetic alternations that may play a role of genetic modifiers influencing an individual's risk were detected in genes not previously associated with the ns-CL/P susceptibility, including COL11A1, COL17A1, DLX1, EFTUD2, FGF4, FGF8, FLNB, JAG1, NOTCH2, SHH, WNT5A and WNT9A. Significant enrichment of rare alleles in ns-CL/P patients compared with controls was also demonstrated for ARHGAP29, CHD7, COL17A1, FGF12, GAD1 and SATB2. In addition, analysis of panoramic radiographs of patients with identified predisposing variants may support the hypothesis of a common genetic link between orofacial clefts and dental abnormalities. In conclusion, our study has confirmed that rare coding variants might contribute to the genetic architecture of ns-CL/P. Since only single predisposing variants were identified in novel cleft susceptibility genes, future research will be required to confirm and fully understand their role in the aetiology of ns-CL/P.

Predictors of germline status for hereditary melanoma: 5 years of multi-gene panel testing within the Italian Melanoma Intergroup

BackgroundThe incidence of cutaneous melanoma is increasing in Italy, in parallel with the implementation of gene panels. Therefore, a revision of national genetic assessment criteria for hereditary melanoma may be needed. The aim of this study was to identify predictors of susceptibility variants in the largest prospective cohort of Italian high-risk melanoma cases studied to date.Materials and methodsFrom 25 Italian centers, we recruited 1044 family members and germline sequenced 940 cutaneous melanoma index cases through a shared gene panel, which included the following genes: CDKN2A, CDK4, BAP1, POT1, ACD, TERF2IP, MITF and ATM. We assessed detection rate according to familial status, region of origin, number of melanomas and presence and type of non-melanoma tumors.ResultsThe overall detection rate was 9.47% (5.53% analyzing CDKN2A alone), ranging from 5.14% in sporadic multiple melanoma cases (spoMPM) with two cutaneous melanomas to 13.9% in familial cases with at least three affected members. Three or more cutaneous melanomas in spoMPM cases, pancreatic cancer and region of origin predicted germline status [odds ratio (OR) = 3.23, 3.15, 2.43, P < 0.05]. Conversely, age > 60 years was a negative independent predictor (OR = 0.13, P = 0.008), and was the age category with the lowest detection rate, especially for CDKN2A. Detection rate was 19% when cutaneous melanoma and pancreatic cancer clustered together.ConclusionsGene panel doubled the detection rate given by CDKN2A alone. National genetic testing criteria may need a revision, especially regarding age cut-off (60) in the absence of strong family history, pancreatic cancer and/or a high number of cutaneous melanomas.

Spectrum of germline pathogenic variants using a targeted next generation sequencing panel and genotype-phenotype correlations in patients with suspected hereditary breast cancer at an academic medical centre in Pakistan

BackgroundBreast cancer is the most common malignancy in women, affecting over 1.5 million women every year, which accounts for the highest number of cancer-related deaths in women globally.Hereditary breast cancer (HBC), an important subset of breast cancer, accounts for 5–10% of total cases. However, in Low Middle-Income Countries (LMICs), the population-specific risk of HBC in different ethnicities and the correlation with certain clinical characteristics remain unexplored.MethodsRetrospective chart review of patients who visited the HBC clinic and proceeded with multi-gene panel testing from May 2017 to April 2020.Descriptive and inferential statistics were used to analyze clinical characteristics of patients. Fisher’s exact, Pearson’s chi-squared tests and Logistic regression analysis were used for categorical variables and Wilcoxon rank-sum test were used for quantitative variables. For comparison between two independent groups, Mann-Whitney test was performed. Results were considered significant at a p value of < 0.05.ResultsOut of 273 patients, 22% tested positive, 37% had a VUS and 41% had a negative genetic test result. Fifty-five percent of the positive patients had pathogenic variants in either BRCA1 or BRCA2, while the remaining positive results were attributed to other genes. Patients with a positive result had a younger age at diagnosis compared to those having a VUS and a negative result; median age 37.5 years, IQR (Interquartile range) (31.5–48). Additionally, patients with triple negative breast cancer (TNBC) were almost 3 times more likely to have a positive result (OR = 2.79, CI = 1.42–5.48 p = 0.003). Of all patients with positive results, 25% of patients had a negative family history of breast and/or related cancers.ConclusionsIn our HBC clinic, we observed that our rate of positive results is comparable, yet at the higher end of the range which is reported in other populations. The importance of expanded, multi-gene panel testing is highlighted by the fact that almost half of the patients had pathogenic or likely pathogenic variants in genes other than BRCA1/2, and that our test positivity rate would have only been 12.8% if only BRCA1/2 testing was done. As the database expands and protocol-driven referrals are made across the country, our insight about the genetic architecture of HBC in our population will continue to increase.

Abstract 5517: Addition of PD-1 antibody camrelizumab overcame resistance to trastuzumab plus chemotherapy in a HER2-positive, metastatic gallbladder cancer patient

Abstract HER2 amplification/overexpression is a common driver in a variety of cancers including gallbladder cancer (GBC). For patients with metastatic GBC, chemotherapy remains the standard of care with limited efficacy. The combination of HER2 antibody trastuzumab plus chemotherapy is the frontline treatment option for patients with HER2-positive breast/gastric cancer. Recently, this regime also showed antitumor activity in HER2-positive GBC. However, resistance to this regime represents a clinical challenge. Camrelizumab is a novel PD-1 antibody approved for Hodgkin lymphoma and hepatocellular carcinoma in China. Here we presented a HER2-positive metastatic GBC patient who was refractory to trastuzumab plus chemotherapy but experienced significant clinical benefit after the addition of camrelizumab. A 69-year-old male GBC patient was found disease progression in the lung six month after operation, staged IV (T3N0M1). Immunohistochemical (IHC) staining was positive for HER2 (3+) and negative for PD-L1 in both primary and pulmonary lesions. Chemotherapy including S-1 plus gemcitabine, as well as oxaliplatin plus paclitaxel consecutive failed, with a new lesion discovered in the liver. Genomic profiling with a multi-gene NGS panel testing (Onco Panscan࣪, Genetron Health) of the pulmonary lesion showed the presence of TP53 S241Y, ARID2 R273*, EGFR E872K mutations, HER2 amplification (fold change, 8.7), and high tumor mutational burden (TMB 10.33). He was treated with trastuzumab in combination with afatinib and capecitabine. Unfortunately, progressive disease in the lung and brain was observed after two cycles. Due to progression of disease and high TMB of the pulmonary biopsy, also based on the reported activity of PD-1 antibody plus trastuzumab in trastuzumab-resistant, advanced HER2-positive breast cancer, a triplet regime of camrelizumab, trastuzumab, and oxaliplatin was administered. The lesions of the lung, liver, and brain completely regressed after five cycles. From cycle 8 of maintance regime, an anti-angiogenic agent apatinib was added to treat reactive cutaneous capillary endothelial proliferation (RCCEP), the most common immune-related adverse event (irAE) related to camrelizumab, with complete regression after four months. Currently, the patient remains in remission. Our case highlights the potential of immunotherapy in combination with HER2-targeted therapy in HER2-positive GBC. We also demonstrated that immune-related adverse events (irAEs) associated with camrelizumab can be managed with an anti-VEGF agent apatinib. This case not only highlights the importance of irAE management in patients treated with camrelizumab, but also demonstrates the potential of PD-1 antibody plus trastuzumab in HER2-positive GBCs who have developed resistance to chemotherapy and trastuzumab-based targeted therapy. Citation Format: Dong Yan, Xiaomo Li, Li Wang, Yurong Cheng, Si Liu. Addition of PD-1 antibody camrelizumab overcame resistance to trastuzumab plus chemotherapy in a HER2-positive, metastatic gallbladder cancer patient [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5517.

Abstract LB163: Germline pathogenic variants in melanoma patients

Abstract Background: The etiology of melanoma has generally been thought to be exposure to UV radiation (sun and sun tanning lamps). However, the percent of melanoma patients harboring a germline PV is not well studied so we undertook this study to determine the number of patients with melanoma who have a PV. Methods: Patient data was obtained from the Informed Genetically Annotated Patient (iGAP) Registry, an IRB-approved multi-center longitudinal, observational study designed to capture genetic test results and the patient’s outcome over time. A sequential series of unselected melanoma patients presenting to a single surgical oncologist’s office for treatment underwent multigene panel testing. Additionally, patients who had already undergone multigene panel testing for another reason (breast cancer) were included. The cohort was analyzed overall and in two subgroups: melanoma patients who also had a history of breast cancer and melanoma patients who have never had breast cancer. Demographics collected include age at diagnosis, race, other cancers, stage of melanoma, and thickness of melanoma. Results: There were 170 patients, most were Caucasian (one Black, one Asian) and the average age was 60.9 years. There were 11 patients with a history of prior melanoma. There were 39 males and 131 females. Stages ranged from zero to four with a majority of them stage one. Average thickness was 2.1 mm. The overall group (170 patients) had 29 (17.06%) with a PV (one patient with melanoma and breast cancer had three PVs). The following table lists the PVs (see Table 1). There were 56 patients with melanoma and breast cancer, eight (14.3%) of which had a PV. In the melanoma without breast cancer group (n = 114), had 21 (17.5%) had a PV. Conclusions: The cost of germline genetic testing with large panels has fallen precipitously making testing more available for many cancer patients. There have been attempts to define a group of factors in patients with melanoma who should be offered germline testing but with mixed results. Our cohort of melanoma patients (with or without breast cancer) has a PV rate of 17% suggesting that all patients with melanoma should be offered germline genetic testing. Guidelines restricting testing are no longer justified. Table 1. Melanoma PVs Melanoma without Breast Cancer PVs Melanoma with Breast Cancer PVs MUTYH-Monoallelic 3 BLM 2 CHEK2/1100delC 3 ATM 1 NTHL1 2 BRCA1 1 CDKN2A/p16 2 CHEK2 1 SDHA 2 CHEK2/1100delC 1 ATM 2 MITF 1 MITF 2 MUTYH-Biallelic/Compound Heterozygous 1 PMS2 1 NF1 1 MUTYH-Biallelic/Compound Heterozygous 1 PTEN 1 MSH3 1 FH 1 BRCA2 1 Total Melanoma w/o Breast Cancer PVs 21 Total Melanoma w/Breast Cancer PVs 10 Citation Format: Peter Beitsch, Chloe Wernecke, Kelly Bontempo, Brenna Bentley, Pat Whitworth, Rakesh Patel. Germline pathogenic variants in melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB163.

Abstract LB561: Germline mutational profiling of TNBCs in an Indian cohort

Abstract Breast cancer is the most common cancer in Indian women with a high incidence of triple negative breast cancer (TNBC), an aggressive subtype of breast cancer associated with poor prognosis. The high TNBC prevalence (&amp;gt;25%) in India as compared to the western population (10-15%) remains to be a challenge in clinical management. The association of germline BRCA1/2 mutations in TNBCs is well-established as a predisposing factor for hereditary breast cancer risk. However, these studies are predominantly from germline profiling of TNBCs representative of western population. Therefore, we aimed to investigate the germline profiles of breast cancer patients in India using a multi-institutional TNBC cohort based on ACMG consensus multi-gene NGS panel. Of 193 TNBC patients, we identified 57 pathogenic mutations (diagnostic yield = 29.53%) from various genes of which BRCA1 (41/57, 71.93%) and BRCA2 (8/57, 14.03%) were most commonly mutated. We observed a high prevalence of BRCA1 mutations (41/193, 21.24%) and BRCA2 mutations (8/193, 4.14%) in our cohort as compared to published literature. Additionally, 8 pathogenic mutations were also reported in non-BRCA cancer pre-disposing genes associated with the HR pathway like ATM, CHEK2, PALB2. 10 novel mutations were identified in 3 genes namely BRCA1, BRCA2 and PALB2. The most common type of mutations was found to be frame-shift which may cause protein truncation and loss of function. Furthermore, we identified 48 variants of unknown significance (24.9%) of which about 7% were in the BRCA1/2 genes. Data mining from global databases like TCGA, Genome Asia indicated that the novel mutations were unique to the Indian population compared to the germline profiles of different ethnicities. Our study confirms the major contribution of BRCA1/2 genes in TNBCs as reported in the literature. A high percentage of the women were found to be associated with young age onset which may be attributed to BRCA mutations. We have also assessed the association of clinicopathological parameters such as tumor grade, stage, recurrence to the germline mutational status. Our analysis shows significant association of germline mutational status with family history thus underlin the importance of multi-gene panel testing as recommended by NCCN guidelines. Moreover, our results also emphasize the need for designing/implementing guidelines specific to Indian population. In summary our results indicate that Indian TNBCs have a high prevalence of BRCA1/2 mutations. Large scale studies in future are warranted to validate these preliminary findings. Citation Format: Chaitanyanand Koppiker, Ashwini Bapat, Siddharth Gahlaut, Naveen Luke, Jisha John, Rupa Mishra, Aishwarya Konnur, Namrata Namewar, Ruhi Reddy, Shaheen Shaikh, Rituja Banale, Smeeta Nare, Laleh Busheri, Asha Reddy, Ashraf Mannan, Sabarinathan Radhakrishnan, Selvi Radhakrishna, Santosh Dixit. Germline mutational profiling of TNBCs in an Indian cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB561.

Clinical characteristics and genetic testing outcome of suspected hereditary peripheral nerve sheath tumours in a tertiary cancer institution in Singapore

BackgroundPeripheral Nerve Sheath Tumors (PNST) are a diverse group of mostly benign tumours uncommon in the general population. About 5–10% of PNSTs are hereditary, predominantly arising from germline variants in NF1, NF2, SMARCB1, or LZTR1 gene.MethodsWe reviewed the clinical characteristics and genetic testing results of patients referred to the NCIS Adult Cancer Genetics Clinic for suspected hereditary PNST.Results3,001 patients suspected to have various hereditary cancer syndromes were evaluated between year 2000 to March 2021. 13 (0.4%) were clinically diagnosed to have hereditary PNSTs. The majority were male (54%), with a median age at presentation to the genetics clinic of 29 years (range 19–48). 11/13 (85%) patients had multiple PNSTs, 12/13 (92%) had young onset PNSTs, 5/13 (38.5%) had personal and family history of PNST. 11/13 patients (85%) had clinical features of neurofibromatosis type 1 (NF1) including one patient who also fulfilled clinical criteria of neurofibromatosis type 2 (NF2); 2/13 (14%) had multiple schwannomas. Four patients underwent multi-gene panel testing, including one patient with clinical NF1, one patient who met both clinical NF1 and NF2 criteria, and two patients with multiple schwannomas. The patient with clinical features of NF1 was heterozygous for a pathogenic c. 2033dup variant in the NF1 gene. The patient with both NF1/NF2 features was heterozygous for a novel c.732 T > A nonsense variant in the NF2 gene. The two patients with multiple schwannomas were heterozygous for a pathogenic/likely pathogenic variant in the LZTR1 gene and are the first LZTR1-positive schwannomatosis patients reported in Asia.ConclusionHereditary PNSTs are rare referrals to an adult cancer genetics clinic. NF1 is the most common PNST seen. LZTR1 variants may be the underlying cause in Asian patients with multiple schwannomatosis.