Navigating Precision Oncology: Insights from an Integrated Clinical Data and Biobank Repository Initiative across a Network Cancer Program.

Advancing cancer treatment relies on the rapid translation of new scientific discoveries to patient care. To facilitate this, an oncology biobank and data repository program, also referred to as the "Moonshot" program, was launched in 2021 within the Integrated Network Cancer Program of the Allegheny Health Network. A clinical data program (CDP) and biospecimen repository were established, and patient data and blood and tissue samples have been collected prospectively. To date, the study has accrued 2920 patients, predominantly female (61%) and Caucasian (90%), with a mean age of 64 ± 13 years. The most common cancer sites were the endometrium/uterus (12%), lung/bronchus (12%), breast (11%), and colon/rectum (11%). Of patients diagnosed with cancer, 34% were diagnosed at stage I, 25% at stage II, 26% at stage III, and 15% at stage IV. The CDP is designed to support our initiative in advancing personalized cancer research by providing a comprehensive array of patient data, encompassing demographic characteristics, diagnostic details, and treatment responses. The "Moonshot" initiative aims to predict therapy responses and clinical outcomes through cancer-related biomarkers. The CDP facilitates this initiative by fostering data sharing, enabling comparative analyses, and informing the development of novel diagnostic and therapeutic methods.

Germline pathogenic variants in cancer risk genes among patients with thyroid cancer and suspected predisposition.

PURPOSE: Multigene panels allow simultaneous testing of genes involved in cancer predisposition. Thyroid cancer (TCa) is a component tumor of several cancer predisposition syndromes, but the complete landscape of germline variants predisposing to TCa remains to be determined. METHODS: Clinical information and genetic test results were reviewed from over 170,000 individuals who had multigene panel testing for hereditary cancer at a single diagnostic laboratory. Germline pathogenic and likely pathogenic variants ("pathogenic variants") were examined among individuals with TCa. A cohort with breast cancer (BCa) was examined to serve as a comparison group and to determine the added contribution of TCa to the ascertainment of genetic risk. RESULTS: Of 3134 individuals with TCa, 291 (9.3%) were found to have one or more pathogenic variant(s). Among 904 individuals with TCa alone, 7.5% had one or more pathogenic variant(s), similar to those with BCa alone (8.4%). In all groups, CHEK2 was the gene with the highest number of pathogenic variants identified, with a significantly increased frequency among individuals with a history of both thyroid and BCa compared to BCa alone. CONCLUSIONS: A high prevalence of germline pathogenic variants was observed among individuals with TCa referred for hereditary cancer genetic testing, even in the absence of other cancer diagnoses. These data suggest that TCa may be an under-recognized component of cancer predisposition syndromes.

Splicing profile by capture RNA-seq identifies pathogenic germline variants in tumor suppressor genes.

Germline variants in tumor suppressor genes (TSGs) can result in RNA mis-splicing and predisposition to cancer. However, identification of variants that impact splicing remains a challenge, contributing to a substantial proportion of patients with suspected hereditary cancer syndromes remaining without a molecular diagnosis. To address this, we used capture RNA-sequencing (RNA-seq) to generate a splicing profile of 18 TSGs (APC, ATM, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, MLH1, MSH2, MSH6, MUTYH, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, and TP53) in 345 whole-blood samples from healthy donors. We subsequently demonstrated that this approach can detect mis-splicing by comparing splicing profiles from the control dataset to profiles generated from whole blood of individuals previously identified with pathogenic germline splicing variants in these genes. To assess the utility of our TSG splicing profile to prospectively identify pathogenic splicing variants, we performed concurrent capture DNA and RNA-seq in a cohort of 1000 patients with suspected hereditary cancer syndromes. This approach improved the diagnostic yield in this cohort, resulting in a 9.1% relative increase in the detection of pathogenic variants, demonstrating the utility of performing simultaneous DNA and RNA genetic testing in a clinical context.

Facilitated referral pathway for genetic testing at the time of ovarian cancer diagnosis: uptake of genetic counseling and testing and impact on patient-reported stress, anxiety and depression.

BACKGROUND: Timely genetic testing at ovarian cancer diagnosis is essential as results impact front line treatment decisions. Our objective was to determine rates of genetic counseling and testing with an expedited genetics referral pathway wherein women with newly-diagnosed ovarian cancer are contacted by a genetics navigator to facilitate genetic counseling. METHODS: Patients were referred for genetic counseling by their gynecologic oncologist, contacted by a genetics navigator and offered appointments for genetic counseling. Patients completed quality of life (QoL) surveys immediately pre- and post-genetic assessment and 6 months later. The primary outcome was feasibility of this pathway defined by presentation for genetic counseling. RESULTS: From 2015 to 2018, 100 patients were enrolled. Seventy-eight had genetic counseling and 73 testing. Median time from diagnosis to genetic counseling was 34 days (range 10-189). Among patients who underwent testing, 12 (16%) had pathogenic germline mutations (BRCA1-7, BRCA2-4, MSH2-1). Sixty-five patients completed QoL assessments demonstrating stress and anxiety at time of testing, however, scores improved at 6 months. Despite the pathway leveling financial and logistical barriers, patients receiving care at a public hospital were less likely to present for genetic counseling compared to private hospital patients (56% versus 84%, P = 0.021). CONCLUSIONS: Facilitated referral to genetic counselors at time of ovarian cancer diagnosis is effective, resulting in high uptake of genetic counseling and testing, and does not demonstrate a long term psychologic toll. Concern about causing additional emotional distress should not deter clinicians from early genetics referral as genetic testing can yield important prognostic and therapeutic information.

Recontact practices of cancer genetic counselors and an exploration of professional, legal, and ethical duty.

The duty to recontact continues to be revisited in the field of clinical genetics and is currently relevant for cancer genetic counseling given the transition from single-gene to multi-gene panel testing. We recruited cancer genetic counselors through the National Society of Genetic Counselors list-serv to complete an online survey assessing current practices and perspectives regarding recontacting patients about diagnostic genetic tests. Forty-one percent of respondents reported that they have recontacted patients to offer updated (new) diagnostic genetic testing (40/97). A majority (61%, 17/28), of genetic counselors who reported recontact specifically for panel testing indicated that the availability of management recommendations for genes not previously tested routinely was an important factor in the decision to recontact. All respondents who recontacted patients reported "improved patient care" as a perceived benefit. Respondents indicated that recontact is mostly a patient responsibility (49%), followed by a shared responsibility between the provider and patient (43%). Few respondents (2%) reported a uniform ethical duty to recontact patients regarding new and updated testing, while the majority (89%) felt that there was some degree of ethical duty. A greater percentage of those who reported past recontact practices reported intention to recontact in the future (p = 0.001). There is little consensus among the genetic counselor respondents about how to approach the recontacting of patients to offer updated genetic testing.

Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma.

BACKGROUND: The objective of this study was to investigate the prevalence of pathogenic germline variants (PGVs) in 32 cancer susceptibility genes in individuals with newly diagnosed pancreatic ductal adenocarcinoma (PDAC). A key secondary objective was to evaluate how often PGVs would have been undetected with existing genetic testing criteria. METHODS: From May 2016 through May 2017, this multicenter cohort study enrolled consecutive patients aged 18 to 89 years with histologically confirmed PDAC diagnosed within the previous 12 weeks. Demographics, medical histories, and 3-generation pedigrees were collected from participants who provided samples for germline DNA analysis. RESULTS: Four hundred nineteen patients were deemed eligible, 302 were enrolled, and 298 were included in the final cohort. Clinically actionable variants were reported in 29 PDAC patients (9.7%), with 23 (7.7%) having a PGV associated with an increased risk for PDAC. Six of 23 individuals (26%) with PDAC-associated gene mutations did not meet currently established genetic testing criteria. According to guideline-based genetic testing, only 11 of the 23 PGVs (48%) in known PDAC genes would have been detected. Six additional patients (2%) had PGVs associated with an increased risk for other cancers. CONCLUSIONS: These findings support the significant prevalence of PGVs associated with PDAC and the limitations of current paradigms for selecting patients for genetic testing, and they thereby lend support for universal germline multigene genetic testing in this population.

Differences in TP53 Mutation Carrier Phenotypes Emerge From Panel-Based Testing.

Background: Li-Fraumeni syndrome (LFS) has traditionally been identified by single-gene testing (SGT) of TP53 triggered by clinical criteria, but the widespread use of multigene panel tests (MGPTs) has upended this paradigm. We sought to compare the personal and family cancer histories of TP53-positive result (TP53+) carriers who were identified by either MGPT or SGT. Methods: Of 44 310 individuals who underwent testing of TP53 in a single clinical diagnostic laboratory between 2010 and 2014, 44 086 (40 885 MGPT and 3201 SGT) met study eligibility criteria. Personal cancer histories were available for 38 938 subjects. The frequency of germline TP53 results and various phenotypic manifestations were compared according to test type. All statistical tests were two-sided. Results: MGPT TP53+ individuals (n = 126) had an older median age at first cancer than SGT TP53+ carriers (n = 96; women: median = 36 vs 28 years, P < .001; and men: median = 40 vs 15 years, P = .004). The median age of breast cancer diagnosis was 40 years in MGPT TP53+ women vs 33 years in SGT TP53+ women (P < .001). In both cohorts, childhood and LFS core cancers, and for women, multiple primary cancers (not multiple breast tumors), were associated with TP53+ results. Established LFS testing criteria were less often met by MGPT TP53+ individuals. Conclusions: MGPT TP53+ individuals differ in phenotype from those ascertained through SGT and are notably older at cancer diagnosis and less likely to meet LFS clinical criteria. These findings suggest that LFS may have a greater phenotypic spectrum than previously appreciated. This has implications for the counseling of MGPT TP53+ individuals. Prospective follow-up of these individuals and families is needed to re-evaluate cancer risks.

Patient and genetic counselor perceptions of in-person versus telephone genetic counseling for hereditary breast/ovarian cancer.

Telephone genetic counseling (TC) for high-risk women interested in BRCA1/2 testing has been shown to yield positive outcomes comparable to usual care (UC; in-person) genetic counseling. However, little is known about how genetic counselors perceive the delivery of these alternate forms of genetic counseling. As part of a randomized trial of TC versus UC, genetic counselors completed a 5-item genetic counselor process questionnaire (GCQ) assessing key elements of pre-test sessions (information delivery, emotional support, addressing questions and concerns, tailoring of session, and facilitation of decision-making) with the 479 female participants (TC, N = 236; UC, N = 243). The GCQ scores did not differ for TC vs. UC sessions (t (477) = 0.11, p = 0.910). However, multivariate analysis showed that participant race/ethnicity significantly predicted genetic counselor perceptions (ß = 0.172, p < 0.001) in that the GCQ scores were lower for minorities in TC and UC. Exploratory analyses suggested that GCQ scores may be associated with patient preference for UC versus TC (t (79) = 2.21, p = 0.030). Additionally, we found that genetic counselor ratings of session effectiveness were generally concordant with patient perceptions of the session. These data indicate that genetic counselors perceive that key components of TC can be delivered as effectively as UC, and that these elements may contribute to specific aspects of patient satisfaction. However, undefined process differences may be present which account for lower counselor perceptions about the effectiveness of their sessions with minority women (i.e., those other than non-Hispanic Whites). We discuss other potential clinical and research implications of our findings.

Rescreening for genetic mutations using multi-gene panel testing in patients who previously underwent non-informative genetic screening.

OBJECTIVE: The availability of next-generation sequencing and identification of multiple cancer-related genes has caused a shift away from single gene testing towards multi-gene panel testing for hereditary cancer syndromes. However, the utility of panels in individuals who previously underwent non-informative genetic screening has yet to be evaluated. We aim to evaluate the use of rescreening and results of multi-gene panels in this rescreened population. METHODS: We reviewed the medical records for patients who had previously undergone genetic testing and then underwent multi-gene panel testing at a single institution between 9/2013 and 11/2014. RESULTS: One hundred and twenty-seven patients with prior genetic testing underwent multi-gene panels. One hundred and four patients (82%) had a history of cancer and 118 (93%) had at least one family member with cancer. On primary testing, no pathogenic mutations were detected and 10 patients (8%) were found to have variants of uncertain significance (VUS). On repeat multi-gene panel testing, nine patients (7%) were found to have a pathogenic mutation and 53 patients (42%) were VUS not identified on prior testing. CONCLUSIONS: Seven percent of patients with non-informative primary testing were found to have a pathogenic mutation with multi-gene panels, suggesting that there is a potential benefit to be gained from rescreening. However, 42% of patients were found to have new VUS with panels, a result that can cause patients anxiety without clear clinical implications.

Patient experiences living with pancreatic cancer risk.

BACKGROUND: Pancreatic cancer (PancCa) is recognized as a component of many well-described hereditary cancer syndromes. Minimal research has focused on patient needs and experiences living with this risk. PURPOSE: To understand the meaning and experience of living with familial PancCa risk and to explore experiences related to screening and prevention of PancCa. METHODS: Participants underwent semi-structured, in-depth interviews. Adults without PancCa and who met familial or hereditary risk criteria were eligible. Thematic analysis was completed on the transcripts in order to identify patterns, consistencies, and differences. Narrative review of existing literature related to women living with hereditary breast and ovarian cancer (HBOC) risk was completed to explore similarities and differences between published findings and our current findings. RESULTS: Nineteen individuals (9 male, 10 female) participated. Major themes addressed participants' family experiences with PancCa and PancCa death and the associated grief from the experiences. Family experiences impacted how participants interpreted and approached their own cancer risk and participated in the cancer screening program. Participants wanted to control their cancer risk and sought information and resources to prevent PancCa or PancCa related death. Distress related to risk was not described as constant but occurred around salient time points. CONCLUSION & FUTURE IMPLICATIONS: Study results begin to describe the lived experience of individuals with PancCa risk. Through this research we have uncovered important variables to further understand, measure, and intervene upon in future research. Distress related to risk was not described as ongoing, but occurred around specific and salient time points that brought risk to the forefront. Individuals with familial PancCa risk may have a unique experience compared to other hereditary cancer syndromes due to the high mortality of the disease and uncertainty related to prevention and early detection outcomes.