Personal History Of Cancer Research Articles

Prevalence of germline variants in Brazilian pancreatic carcinoma patients

We evaluated the prevalence of pathogenic/likely pathogenic germline variants (PGV) in Brazilian pancreatic adenocarcinoma (PC) patients, that represent a multiethnic population, in a cross-sectional study. We included 192 PC patients unselected for family history of cancer. We evaluated a panel of 113 cancer genes, through genomic DNA sequencing and 46 ancestry-informative markers, through multiplex PCR. The median age was 61 years; 63.5% of the patients presented disease clinical stages III or IV; 8.3% reported personal history of cancer; 4.7% and 16.1% reported first-degree relatives with PC or breast and/or prostate cancer, respectively. Although the main ancestry was European, there was considerable genetic composition admixture. Twelve patients (6.25%) were PGV carriers in PC predisposition genes (ATM, BRCA1, BRCA2, CDKN2A, MSH2, PALB2) and another 25 (13.0%) were PGV carriers in genes with a limited association or not previously associated with PC (ACD, BLM, BRIP1, CHEK2, ERCC4, FANCA, FANCE, FANCM, GALNT12, MITF, MRE11, MUTYH, POLE, RAD51B, RAD51C, RECQL4, SDHA, TERF2IP). The most frequently affected genes were CHEK2, ATM and FANC. In tumor samples from PGV carriers in ACD, BRIP1, MRE11, POLE, SDHA, TERF2IP, which were examined through exome sequencing, the main single base substitutions (SBS) mutational signature was SBS1+5+18, probably associated with age, tobacco smoking and reactive oxygen species. SBS3 associated with homologous repair deficiency was also represented, but on a lower scale. There was no difference in the frequency of PGV carriers between: (a) patients with or without first-degree relatives with cancer; and (b) patients with admixed ancestry versus those with predominantly European ancestry. Furthermore, there was no difference in overall survival between PGV carriers and non-carriers. Therefore, genetic testing should be offered to all Brazilian pancreatic cancer patients, regardless of their ancestry. Genes with limited or previously unrecognized associations with pancreatic cancer should be further investigated to clarify their role in cancer risk.

Strategies for Identifying and Recruiting Women at High Risk for Breast Cancer for Research Outside of Clinical Settings: Observational Study.

Research is needed to understand and address barriers to risk management for women at high (≥20% lifetime) risk for breast cancer, but recruiting this population for research studies is challenging. This paper compares a variety of recruitment strategies used for a cross-sectional, observational study of high-risk women. Eligible participants were assigned female at birth, aged 25-85 years, English-speaking, living in the United States, and at high risk for breast cancer as defined by the American College of Radiology. Individuals were excluded if they had a personal history of breast cancer, prior bilateral mastectomy, medical contraindications for magnetic resonance imaging, or were not up-to-date on screening mammography per American College of Radiology guidelines. Participants were recruited from August 2020 to January 2021 using the following mechanisms: targeted Facebook advertisements, Twitter posts, ResearchMatch (a web-based research recruitment database), community partner promotions, paper flyers, and community outreach events. Interested individuals were directed to a secure website with eligibility screening questions. Participants self-reported method of recruitment during the eligibility screening. For each recruitment strategy, we calculated the rate of eligible respondents and completed surveys, costs per eligible participant, and participant demographics. We received 1566 unique responses to the eligibility screener. Participants most often reported recruitment via Facebook advertisements (724/1566, 46%) and ResearchMatch (646/1566, 41%). Community partner promotions resulted in the highest proportion of eligible respondents (24/46, 52%), while ResearchMatch had the lowest proportion of eligible respondents (73/646, 11%). Word of mouth was the most cost-effective recruitment strategy (US $4.66 per completed survey response) and paper flyers were the least cost-effective (US $1448.13 per completed survey response). The demographic characteristics of eligible respondents varied by recruitment strategy: Twitter posts and community outreach events resulted in the highest proportion of Hispanic or Latina women (1/4, 25% and 2/6, 33%, respectively), and community partner promotions resulted in the highest proportion of non-Hispanic Black women (4/24, 17%). Although recruitment strategies varied in their yield of study participants, results overall support the feasibility of identifying and recruiting women at high risk for breast cancer outside of clinical settings. Researchers must balance the associated costs and participant yield of various recruitment strategies in planning future studies focused on high-risk women.

"I Just Assumed This Was Already Being Done": Canadian Patient Preferences for Enhanced Data Sharing for Precision Oncology.

In Canada, health data are siloed, slowing bioinnovation and evidence generation for personalized cancer care. Secured data-sharing platforms (SDSPs) can enable data analysis across silos through rapid concatenation across trial and real-world settings and timely researcher access. To motivate patient participation and trust in research, it is critical to ensure that SDSP design and oversight align with patients' values and address their concerns. We sought to qualitatively characterize patient preferences for the design of a pan-Canadian SDSP. Between January 2022 and July 2023, we conducted pan-Canadian virtual focus groups with individuals who had a personal history of cancer. Following each focus group, participants were invited to provide feedback on early-phase analysis results via a member-checking survey. Three trained qualitative researchers analyzed data using thematic analysis. Twenty-eight individuals participated across five focus groups. Four focus groups were conducted in English and one in French. Thematic analysis generated two major and five minor themes. Analytic themes spanned personal and population implications of data sharing and willingness to manage perceived risks. Participants were supportive of increasing access to health data for precision oncology research, while voicing concerns about unintended data use, reidentification, and inequitable access to costly therapeutics. To mitigate perceived risks, participants highlighted the value of data access oversight and governance and informational transparency. Strategies for secured data sharing should anticipate and mitigate the risks that patients perceive. Participants supported enhancing timely research capability while ensuring safeguards to protect patient autonomy and privacy. Our study informs the development of data-governance and data-sharing frameworks that integrate real-world and trial data, informed by evidence from direct patient input.

Germline pathogenic variants of cancer predisposition genes in a multicentre Italian cohort of pancreatic cancer patients.

Background and aimGermline BRCA1–2 test is routinely recommended in Pancreatic Cancer (PC) patients, due to its clinical-epidemiological relevance. Data on the prevalence of germline pathogenic variants (gPV) in other cancer predisposition and DNA Damage Repair (DDR) system-related genes in unselected PC cases are sparce in Italy. We assessed this prevalence in a multicentre cohort, to derive recommendations for PC patients. MethodsClinical data of 1200 consecutive PC patients, of any age and stage, tested with a multigene germline panel were collected. A descriptive analysis of gPV frequency and clinical variables was performed both in 1092 patients tested for an 18 genes core-panel (CP-18 cohort) and in 869 patients screened only for CDKN2A. Results11.5 % (126/1092) of CP-18 cohort patients harbored a gPV in ≥ 1 gene. Highest gPV frequencies were detected in ATM (3.1 %), BRCA2 (2.9 %), BRCA1 (1.6 %), CHEK2 (1.1 %). Patients harboring any CP-18 gene and BRCA1–2 gPV were younger and with a higher rate of personal (PH) or family history (FH) of cancer when compared to no gPV patients. The risk of having a gPV was ≥ 7 % in all subgroups of patients, including those aged > 73, with tumor stage I-III and negative FH/PH. CDKN2A gPV were detected in 2.6 % (23/869) of patients. ConclusionsA remarkable prevalence of gPV in cancer predisposition and DDR genes is reported in this large multicentre cohort of consecutive and unselected PC patients. Therefore, we recommend multigene germline testing (at least including BRCA1–2, ATM, CDKN2A, PALB2) for all PC patients, irrespective of age, stage, PH/FH.

Test-takers' perspectives on consumer genetic testing for hereditary cancer risk.

With few exceptions, research on consumer genetic testing for hereditary cancer risk has focused on tests with limited predictive value and clinical utility. Our study advances the existing literature by exploring the experiences and behaviors of individuals who have taken modern consumer genetic tests for cancer susceptibility that, unlike earlier tests, screen for medically significant variants. We interviewed 30 individuals who had undergone consumer genetic testing for hereditary cancer risk between 2014 and 2019. We explored participants' pre-test sentiments (7 items), experiences receiving results (5 items), behavioral and health-related changes (6 items), and attitudes and beliefs (3 items). Data were analyzed for thematic content. Most participants reported a personal (n = 6) and/or family history (n = 24) of cancer, which influenced their choice to pursue testing. Before testing, most participants did not consult with a physician (n = 25) or receive genetic counseling (n = 23). Nevertheless, the majority felt that they understood test-related information (n = 20) and their results (n = 20), though a considerable number reported experiencing negative emotions related to their results. Most also shared their results with family members (n = 27). Overall, participants' attitudes towards consumer genetic testing for cancer risk were predominantly positive (n = 23). This study offers new insights into how individuals use and perceive modern consumer genetic tests for hereditary cancer risk, focusing on their perceptions of the risks, benefits, and limitations of these services. Understanding test-takers' perspectives can potentially inform improvements aimed at ensuring that tests meet users' needs and deliver clinically valuable genetic risk assessments.

Characteristics associated with early vs. late adoption of lung cancer screening

BackgroundAlthough lung cancer screening (LCS) reduces lung cancer mortality among high-risk individuals, uptake overall remains low. With all cancer screening modalities, a period of diffusion among medical providers and the public is expected, with screening uptake exhibiting a distribution among early vs. late adoption. We aimed to characterize individuals undergoing LCS based upon the timeframe of screening adoption. MethodsThis retrospective study examined patients who underwent LCS between January 2015 – December 2022 in a centralized LCS program. Based on United States Preventive Services Task Force (USPSTF) criteria for LCS, early and late adopters of LCS – defined by time from eligibility to screening completion – were compared. A multivariable regression model was constructed to identify factors associated with early adoption of LCS. ResultsAmong patients screened during the study period, 90.4% were eligible based on USPSTF 2013 criteria, and 9.6% were eligible based on USPSTF 2021 criteria. Of the USPSTF 2013 eligible persons, multivariable analysis demonstrated Black/African-American individuals and current smokers had significantly greater odds of early adoption (aOR 1.428 and 1.514, respectively). Those without a family history of lung cancer or without a personal history of cancer had significantly lower odds of early adoption of LCS. ConclusionsEarly adopters were more likely to report Black/African-American race or current smoking status after adjustment for covariates. Future research should examine how screening diffuses across the overall LCS-eligible population, as well as identify factors that drive and inhibit diffusion to create programs and policies with the ultimate goal of increasing timely LCS uptake.

Contrast-enhanced mammography for surveillance in women with a personal history of breast cancer

PurposeWomen with a personal history of breast cancer have an increased risk of subsequent breast malignancy and may benefit from more sensitive surveillance than conventional mammography (MG). We previously reported outcomes for first surveillance episode using contrast-enhanced mammography (CEM), demonstrating higher sensitivity and comparable specificity to MG. We now report CEM performance for subsequent surveillance.MethodsA retrospective study of 1,190 women in an Australian hospital setting undergoing annual surveillance following initial surveillance CEM between June 2016 and December 2022. Outcome measures were recall rate, cancer detection rate, contribution of contrast to recalls, false positive rate, interval cancer rate and characteristics of surveillance detected and interval cancers.Results2,592 incident surveillance episodes were analysed, of which 93% involved contrast-based imaging. Of 116 (4.5%) recall episodes, 40/116 (34%) recalls were malignant (27 invasive; 13 ductal carcinoma in situ), totalling 15.4 cancers per 1000 surveillance episodes. 55/116 (47%) recalls were contrast-directed including 17/40 (43%) true positive recalls. Tumour features were similar for contrast-directed recalls and other diagnoses. 8/9 (89%) of contrast-directed invasive recalls were Grade 2–3, and 5/9 (56%) were triple negative breast cancers. There were two symptomatic interval cancers (0.8 per 1000 surveillance episodes, program sensitivity 96%).ConclusionRoutine use of CEM in surveillance of women with PHBC led to an increase in the detection of clinically significant malignant lesions, with a low interval cancer rate compared to previous published series. Compared to mammographic surveillance, contrast-enhanced mammography increases the sensitivity of surveillance programs for women with PHBC.

Racial discrimination and health-care system trust among American adults with and without cancer.

Racial and ethnic minoritized groups report disproportionately lower trust in the health-care system. Lower health-care system trust is potentially related to increased exposure to racial discrimination in medical settings, but this association is not fully understood. We examined the association between racial discrimination in medical care and trust in the health-care system among people with and without a personal cancer history. We examined racial discrimination and trust in a nationally representative American adult sample from the Health Information National Trends Survey 6. Racial discrimination was defined as any unfair treatment in health care on the basis of race or ethnicity. Trust in the health-care system (eg, hospitals and pharmacies) was grouped into low, moderate, and high trust. Multinomial logistic regression models were used to compare low and moderate trust relative to high trust in the health-care system and estimate odds ratios (ORs) and 95% confidence intervals (CIs). A total of 5813 respondents (15% with a personal cancer history) were included; 92% (n = 5355) reported no prior racial discrimination experience during medical treatment. Prior experiences of racial discrimination were positively associated with low (OR = 6.12, 95% CI = 4.22 to 8.86) and moderate (OR = 2.70, 95% CI = 1.96 to 3.72) trust in the health-care system relative to high trust. Similar associations were observed when stratifying by personal cancer history. Respondents who reported racial discrimination during medical encounters had lower trust in the health-care system, especially respondents with a personal cancer history. Our findings highlight the need to address racial discrimination experiences during medical care to build patient trust and promote health-care access.

The Manchester Scoring System for predicting BRCA1/2 mutations underperforms in Arabic Omani breast cancer patients.

Risk assessment models that are applied to assess the lifetime risk of cancer and pathogenic variant risk are more commonly used in Western populations. Using these models, without validation, for non-Western populations has been questioned. This study aimed to evaluate the use and consistency of the Manchester Scoring System as a risk assessment model for the Omani population. A retrospective, file-based analysis was performed on breast cancer patients seen in a genomics department over a two-year period. Personal cancer history and family history were used to analyze the Manchester scores of 409 breast and/or cancer patients. The results show that, overall, the Manchester scores were low. If this risk assessment model had been used to determine eligibility for a priori service and genetic testing decisions, 12 BRCA pathogenic cases would have been missed. At this time, the Manchester Scoring System does not seem to be the best risk assessment model for use in the Omani population, unless the eligibility threshold of ≥6 is used, which could provide a better sensitivity for the Omani population. We propose using concepts of the Manchester Scoring model to create a scoring system that is more suitable for the Omani and Arabic population.

Hereditary Cancer Clinics Improve Adherence to NCCN Germline Testing Guidelines for Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC). We conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses. A total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the post-NCCN era. After the implementation of the HCC, 77.4% were referred to GC (P<.0001). The odds ratio (OR) for referral to GC among patients with a positive family history of cancer progressively decreased following the change (pre-NCCN era: OR, 11.90 [95% CI, 3.00-80.14]; post-NCCN era: OR, 3.39 [95% CI, 1.13-10.76]; HCC era: OR, 3.11 [95% CI, 0.95-10.16]). The 2018 updates to the NCCN Guidelines for PDAC recommending germline testing for all patients with PDAC significantly increased GC referral rates at our academic medical center. Implementation of an HCC further boosted compliance with guidelines.

The Development and Evaluation of Novel Patient Educational Material for a Variant of Uncertain Significance (VUS) Result in Hereditary Cancer Genes.

A Variant of Uncertain Significance (VUS) is a difference in the DNA sequence with uncertain consequences for gene function. A VUS in a hereditary cancer gene should not change medical care, yet some patients undergo medical procedures based on their VUS result, highlighting the unmet educational needs among patients and healthcare providers. To address this need, we developed, evaluated, and refined novel educational materials to explain that while VUS results do not change medical care, it remains important to share any personal or family history of cancer with family members given that their personal and family medical history can guide their cancer risk management. We began by reviewing the prior literature and transcripts from interviews with six individuals with a VUS result to identify content and design considerations to incorporate into educational materials. We then gathered feedback to improve materials via a focus group of multidisciplinary experts and multiple rounds of semi-structured interviews with individuals with a VUS result. Themes for how to improve content, visuals, and usefulness were used to refine the materials. In the final round of interviews with an additional 10 individuals with a VUS result, materials were described as relatable, useful, factual, and easy to navigate, and also increased their understanding of cancer gene VUS results.

Recommendations of Health Care Professionals on the Issue of Breastfeeding in BRCA Carriers.

Purpose: Breastfeeding is associated with numerous short- and long-term neonatal and maternal health benefits. Specifically, in BRCA1/2 female carriers, breastfeeding has been shown to reduce the considerably increased risks of breast and ovarian cancer. Nevertheless, there is paucity of data referring to the recommended postpartum surveillance of BRCA1/2 carriers. The purpose of this study was to evaluate the recommendations of health professionals regarding breastfeeding in BRCA carriers. Methods: This cross-sectional survey was conducted using an anonymous questionnaire distributed through the "Good BRCA Genes-a support and information group for BRCA carriers" association. The questionnaire included Likert scale and open-ended questions, aimed to evaluate the performance of health professionals at various aspects of the recommended follow-up. Results: Of the 388 participants, 233 (60.0%) expressed dissatisfaction with explanations provided by health professionals regarding pregnancy and breastfeeding. Women reporting dissatisfaction with explanations were younger (36.8 ± 7.0 years) compared to those satisfied with the explanations (38.8 ± 7.6 years, p = 0.0081). No significant differences were noted between women satisfied and those dissatisfied with the explanations in terms of age of genetic diagnosis, origin, religion, geographic location, and the rates of personal or familial cancer history. Of the 175 responses to an open question "please describe the reasons for unsatisfactory explanation," 76.6% stated they received no explanation on the subject, whereas 5.4% described minimal explanation or conflicting recommendations. Surprisingly, 4.7% recalled being advised to avoid, stop, or limit breastfeeding. Discussion: The results of this survey emphasize the lack of knowledge of health professionals on the issue of breastfeeding in BRCA carriers. As genetic variants in these genes involve significant proportion of the population (up to 2.5% in Ashkenazi Jewish population), raising the awareness of health care personnel to the benefits of breastfeeding in these women seems prudent.

POT1 tumour predisposition: a broader spectrum of associated malignancies and proposal for additional screening program

Protection of Telomeres Protein 1 (POT1) protein is an essential subunit of the shelterin telomere binding complex, regulating telomere length. Some POT1 gene pathogenic variants (PV) lead to telomere elongation, genomic instability and higher risk of cancer. POT1 tumour predisposition syndrome (POT1-TPD) has autosomal dominant inheritance and unknown penetrance. It is associated with increased risk of cutaneous melanoma, chronic lymphocytic leukaemia, angiosarcoma and gliomas. In this work, we aim to describe a broader cancer phenotype related to POT1-TPD, in three families (two with a four generation pedigree, one with a five generation pedigree). The three index cases were referred to our oncogenetic centre for genetic counselling due to their personal history of cancer. Two underwent clinical exome sequencing of 4,867 genes associated with Mendelian genetic diseases, and another underwent gene panel sequencing including POT1, which identified three different POT1 PV: NC_000007.14(NM_015450.2):c.349C>T; NC_000007.14(NM_015450.2):c.233T>C and NC_000007.14(NM_015450.2):c.818G>A; already described in the literature. Referenced relatives, did a target genetic test (according to the POT1 PV identified in the family). In total, 37 individuals were tested (51.4% females), median age of 46 (22–81) years, with POT1 PV detected in 22. POT1-TPD was observed, but also a higher incidence of other cancers (other sarcomas, papillary thyroid cancer, early onset prostate cancer and leukaemia). These findings contribute to an increase in our knowledge about POT1 PV, and it can play a role in the definition of future POT1 PV screening criteria, POT1 carrier surveillance protocols (possibly considering screening for all types of sarcomas) and in genetic counselling.

Population-Level Identification of Patients With Lynch Syndrome for Clinical Care, Quality Improvement, and Research.

Identification of those at risk of hereditary cancer syndromes using electronic health record (EHR) data sources is important for clinical care, quality improvement, and research. We describe diagnostic processes, previously seldom reported, for a common hereditary cancer syndrome, Lynch syndrome (LS), using EHR data within a community-based, multicenter, demographically diverse health system. Within a retrospective cohort enrolled between 2015 and 2020 at Kaiser Permanente Northern California, we assessed electronic diagnostic domains for LS including (1) family history of LS-associated cancer; (2) personal history of LS-associated cancer; (3) LS screening via mismatch repair deficiency (MMRD) testing of newly diagnosed malignancy; (4) germline genetic test results; and (5) clinician-entered diagnostic codes for LS. We calculated proportions and overlap for each diagnostic domain descriptively. Among 5.8 million individuals, (1) 28,492 (0.49%) had a family history of LS-associated cancer of whom 3,635 (13%) underwent genetic testing; (2) 100,046 (1.7%) had a personal history of a LS-associated cancer; and (3) 8,711 (0.1%) were diagnosed with colorectal cancer of whom 7,533 (86%) underwent MMRD screening and of the positive screens (486), 130 (27%) underwent germline testing. One thousand seven hundred and fifty-seven (0.03%) were diagnosed with endometrial cancer of whom 1,613 (92%) underwent MMRD screening and of the 195 who screened positive, 55 (28%) underwent genetic testing. (4) 30,790 (0.05%) had LS germline genetic testing with 707 (0.01%) testing positive; and (5) 1,273 (0.02%) had a clinician-entered diagnosis of LS. It is feasible to electronically characterize the diagnostic processes of LS. No single data source comprehensively identifies all LS carriers. There is underutilization of LS genetic testing for those eligible and underdiagnosis of LS. Our work informs similar efforts in other settings for hereditary cancer syndromes.

Barricades to aiding cascading: Patient-reported barriers to uptake in the context of clinician-facilitated cascade testing for hereditary cancer syndromes.

e13533 Background: Cascade testing extends genetic testing to relatives of individuals with known pathogenic variants. Cascade testing can prompt lifesaving cancer surveillance, however, up to two thirds of at-risk relatives do not complete recommended genetic testing. Previous studies suggest that a clinician-mediated approach of direct relative contact can increase testing rates. As part of an ongoing clinician-facilitated cascade testing intervention, we investigated the barriers to completion of cascade testing. Methods: All patients with a known cancer-associated germline mutation presenting to a gynecologic oncology clinic from 11/2023-2/2024 were offered clinician-facilitated cascade testing, an intervention whereby the genetics team was granted permission to contact designated at-risk relatives by telephone, review the familial mutation, and assist with accessing genetic testing. Patients that declined were asked about their decision and responses were analyzed using the socio-ecological model. Results: Ninety patients were offered clinician-facilitated cascade genetic testing and 50 (55%) declined. Of the patients that declined: median age was 45 (range 23-84), 41 (82%) self-identified as non-Hispanic, 38 (76%) as White, 23 (46%) were of Ashkenazi Jewish heritage, 23 (46%) had a personal history of cancer. There were no significant differences in any of the above variables when comparing those that declined and accepted the intervention. Twenty-nine (58%) patients declined because all family members were already tested. The most common barriers were “limited access to care” (5, 10%) at the healthcare community level, and “perceived readiness of relatives” (5, 10%) at the interpersonal relationship level. While these were the most common, most barriers were at the individual level including “perceived lack of responsibility” (3, 6%), “limited knowledge” (2, 4%), and “emotional burden” (2, 4%) (Table). Stated barriers were not associated with any demographical group. Conclusions: Although clinician-facilitated cascade testing has been shown to increase rates of relative testing uptake, several barriers persist at all levels of the socio-ecological model. While facilitated interventions should be individualized, our findings suggest that future interventions should focus efforts at all socio-ecological levels. Clinical trial information: NCT04613440 . [Table: see text]

Pathogenic germline variant discovery in plasma cell disorders: Insights from genetic counseling referrals and testing.

10619 Background: Our research has shown that 10% of multiple myeloma (MM) patients harbor pathogenic or likely-pathogenic germline variants (PGVs) in cancer predisposition genes, with a significant enrichment observed in BRCA1/2 genes. PGVs are notably more common in younger MM patients and those with a personal or familial cancer history. This study presents our experience in referring plasma cell disorder (PCD) patients at increased risk for carrying PGVs, due to either clinical history or suspicious tumor NGS findings, for genetic counseling and subsequent germline testing. Methods: This retrospective study reviewed patient records from our institution's PCD clinic, focusing on those referred for a genetic evaluation between 2020 and 2024 due to suspected cancer predisposition. We compiled demographic and clinical data for these patients, reasons for referral, and cancer history of patients and their families. The uptake of germline testing, identified mutations, and subsequent recommendations for advanced cancer surveillance and prevention, including cascade testing, were also analyzed. Germline testing utilized targeted hereditary cancer panels from five companies and was conducted on DNA samples extracted from peripheral blood, saliva/buccal swabs, or skin biopsies. Results: 52 PCD patients underwent a genetic evaluation and were included in this review, comprising 31 MM, 9 smoldering MM, and 12 MGUS cases. Median age at the time of referral was 63, and 54% of patients were female. Racial composition was 62% White, 15% Black/African-American, 12% Hispanic, 2% Asian, with 10% undisclosed. 8 patients were referred due to suspicious findings in tumor NGS, while the rest were referred due to clinical suspicion. A personal history of cancer was reported by 19 patients (37%), and 49 had a first- or second-degree relative with cancer (94%). 38 patients (73%) underwent germline testing, of which 15 (39%) harbored PGVs (11 had MM, 4 had smoldering MM). 8 PGV carriers had well-established founder variants. The remaining 7 had PGVs in genes including BRCA2 (n=3), PALB2 (n=1), BLM (n=1), SMAD4 (n=1) and NTHL1 (n=1). Of note, all 8 referred for suspicious findings in tumor NGS were confirmed to harbor PGVs. All PGV-positive patients were recommended for cascade testing and enhanced cancer screening. Conclusions: Our findings indicate a 39% PGV detection rate in PCD patients referred for genetic evaluation, underscoring the potential benefit of implementing screening guidelines in this population. PGV detection led to recommendations for intensified surveillance and cascade testing in all cases, impacting both patients and their families. The discovery of BRCA2PGVs in 20% (3/15) of cases reinforces its potential role as a predisposition gene in MM, corroborating our prior findings.

Effect of demographic and clinician factors on patients' likelihood of pursuing hereditary cancer genetic testing.

e22538 Background: Hereditary cancer genetic testing (GT) is an essential tool for cancer screening and prevention. As indications for GT expand, we may consider whether patients are sufficiently informed and motivated to undergo testing. We surveyed people meeting criteria for GT to assess their likelihood to pursue GT. Methods: Individuals who met modified NCCN guidelines for GT based on self-reported personal/family cancer history were invited to participate in a clinical trial of interventions promoting uptake of GT. Participants completed a baseline survey assessing experiences and attitudes relating to GT. Respondents were asked to rate their perceived importance of GT and their readiness to receive GT (scale of 0-10). These outputs were averaged (Cronbach’s alpha = 0.841) into an index representing their likelihood of pursuing GT. Linear regression was performed to investigate the relationship between several independent variables and the likelihood of pursuing GT. Gender, age, and race were considered, as well as self-reported circumstantial factors including 1) whether the individual had previously heard of GT, 2) whether a biologic relative had previously received GT, 3) qualifying eligibility variable(s) (family vs personal history of cancer), and 4) whether the individual had received a clinical recommendation to undergo GT. Results: 312 participants completed the baseline survey. The mean age of respondents was 61.9 ± 14.47 years, 52% identified as male, and 91% were white. 53% of respondents qualified for the trial based on family history alone and 15% had a clinician recommendation for GT. Younger age was associated with higher likelihood of pursuing GT (p = 0.004) as was receiving a prior recommendation for GT from a clinician (p = 0.01). When clinician recommendation was added to the model, the R-squared value increased from 0.44 to 0.64, indicating that recommendation accounts for a large portion of variance. Gender, race, personal/family cancer history, having previously heard of GT, and a biologic relative having received GT were not statistically significant. Conclusions: Concordant with previous literature, clinician recommendation to undergo GT is a significant contributor to the likelihood of pursuing GT. Older individuals may have lower readiness for GT compared with their younger counterparts, which could have implications for clinicians’ approaches to genetic counseling. Given that indications for GT have expanded, clinicians should remain up to date with current clinical guidelines.

Use of cell-free tumor DNA in early detection of lung cancer.

e20088 Background: USPSTF recommends annual screening for lung cancer with low-dose computed tomography (LDCT) in adults 50-80 years with 20 pack-year smoking history or current/former smoking in the past 15 years. This prospective study evaluated whether we could detect lung cancer at the time of LDCT screening from cell-free tumor DNA using Guardant Health’s LUNAR-2 assay. Methods: Kaiser Permanente Colorado (KPCO) members with upcoming LDCT screenings were invited via email/phone and recruited into two groups, (1) suspicious lung nodules or (2) no lung nodules. We limited enrollment to patients whose LDCT results were classified under the Lung-RADS (version 1.0) categories of 1-3 (recommended follow-up at 12-month intervals) or category 4 (“suspicious”; recommended follow-up at 3-month intervals). We excluded members with lung nodules &gt; 30mm, those with a history of any hematologic malignancy, history of invasive malignancy within the past 5 years, currently pregnant, or known dementia or cognitive impairment. After informed consent, Guardant Health LUNAR test collection kits were mailed to the participant with sample collection instructions provided. Participants were asked to have their blood drawn on the day of their LDCT visit, or no more than 14 days of the scan. We also collected survey and EHR data on smoking history, LDCT, and other associated factors. The KPCO tumor registry confirmed all reported cancers. Results: The study initiated in September 2020 and ended in 08/2022 with 982 individuals consented and blood samples collected. Participants were on average 68 years old, 56% female, 58% former smokers, and 85% had no personal history of cancer. A total of 15 lung cancer cases and 22 other cancer cases were diagnosed. Data analysis is ongoing and expected to be completed early 2024. Conclusions: This study will demonstrate sensitivity and specificity of the LUNAR-2 assay to detect lung cancer relative to standard of care screening modalities in high-risk populations. We will also evaluate whether factors such as comorbidities, pack year history, or medications affect assay accuracy. The impact of this research can inform blood-based early detection of lung cancer.

Information and prevention needs among germline TP53(gTP53m)pathogenic variants carriers.

10551 Background: Li-Fraumeni syndrome (LFS) and more generally g TP53m situations increase the risk of many malignancies. A modifier role of several attributable factors has been recently suggested on LFS-carcinogenesis, including reproductive and lifestyle factors, obesity, physical activity (PA) and diet. However, among g TP53m carriers, prevention approaches have yet primarily focused on intensive cancer screening, with very little emphasis put on primary prevention measures. Methods: As part of the construction of a multicenter, national, multidisciplinary intervention delivering multimodal cancer prevention to g TP53m carriers, we designed a specific patient survey that aimed to analyze potential participants’ needs and wishes. The online questionnaire was sent to g TP53m adult carriers already followed in two national reference centers (n=120). Participants were asked to rate their personal perception of importance and need for each item from 0 to 100 (0=not interested, 100=very interested). The questionnaire contained no identifying data and was approved by the local ethics and data protection committee. Results: The response rate was 61%. 18% were aged &lt; 30, 71% between 30 and 60. g TP53m had been diagnosed in the past 10 years in 29% of patients, and 11% for &lt; 2 years. 58% had a personal history of cancer, and 18% were still receiving a treatment. The median perceived risk of new cancer was 79% for all, and 65% for those w/o a previous history of cancer. 19% did not feel comfortable to participate in information workshops with people they do not know. The median score of the main question on devoting a day to cancer risk information and primary and secondary prevention measures was 88 (95%CI 78 -96). The main desired topics (median score 69-92) were information on research programs, personal cancer risk, well-being measures, psychological aspects, and other cancer risk factors (diet, PA, etc). Wished supports were individual consultation for nutrition (score 81.5 (95%CI 59 -87.5), group workshop for risk factors (score 76 (95%CI 64 -86) and individual coaching for PA (score 76 (95%CI 71 -88.5). Demand for addictologist was low. Conclusions: This study could identify major unmet needs and very strong information-seeking behaviors among g TP53m carriers. It enables us to co-construct a coordinated multi-professional intervention focused on proactive shared cancer prevention. In a second phase, we will assess the effectiveness and feasibility of this new personalized cancer prevention intervention.

Improving feasibility and timeliness of hereditary cancer risk assessment with a brief patient-administered digital tool and rapidly available telehealth genetic counseling.

10614 Background: Multiple guidelines recommend hereditary cancer risk assessment for all adults, yet it rarely is performed. This is largely due to the time-consuming nature of such assessments and difficulty with access to genetic counseling for those at high risk. We designed a care model to address these issues that is suitable for both oncology and non-oncology settings. It includes a brief patient-administered and clinically validated digital hereditary cancer risk assessment tool, followed by immediate online self-scheduling features for telehealth genetic counseling, with appointments available within 48 hours. The digital tool uses a guideline-based algorithm to assess whether genetic testing for hereditary cancer risk is indicated. Here we aim to evaluate the effectiveness and timeliness of this model. Methods: We conducted a retrospective chart review of consecutive patients that engaged with this model from May 2021 to August 2023 at 32 obstetrics and gynecology clinics. We also used nationwide data from the National Society of Genetic Counselor's (NSGC) Professional Status Survey. To assess timeliness of genetic counseling appointments in this care model, we compared the time from scheduling the appointment to the start of the appointment to wait times at health systems for comparable non-urgent cancer genetic counseling appointments, from the NSGC data. Effectiveness was assessed via rates of completion of the tool and scheduling of genetic counseling. Results: 2538 patients (98% female, mean age 37 years, 3.9% with a personal history of cancer) initiated the care model and 95% (2415/2538) completed the risk assessment tool. A quarter (26% (628/2415)) met criteria for germline genetic testing. The median time to complete the tool was 2.7 minutes (IQR 2.9). At the end of the tool, patients could click a button to schedule an appointment with a genetic counselor to discuss hereditary cancer risk and genetic testing. 44% (274/628) booked an appointment. The median time from scheduling to genetic counseling appointment was 2.8 days (IQR 4.9 days), which is shorter than the median wait time for comparable genetic counseling appointments at health systems in the nationwide NSGC dataset (21 days (IQR 53 days); p&lt;&lt; 0.01). Conclusions: The tool completion rate, rate of patients meeting criteria, and uptake of genetic counseling indicate the model is effective. Timeliness was improved by this model, with the digital tool assessing risk in ~3 minutes, compared to previous reports of ~30 minutes for manual hereditary cancer risk assessment. In addition, the timeliness of genetic counseling appointments was markedly better than the current standard of care. These findings suggest that this care model can support physicians in providing timely guideline-recommended hereditary cancer risk assessment to their patients.