Familial Cancer Research Articles

MECOM and the PRDM gene family in uterine endometrial cancer: bioinformatics and experimental insights into pathogenesis and therapeutic potentials

To elucidate the expression profiles, methylation states, and clinicopathological significance of the PRDM gene family, focusing on the MECOM gene's role in uterine endometrial cancer (UCEC) and its molecular interactions with the TGF-beta signaling pathway. Our methodology combined detailed bioinformatics analyses using UALCAN and GEPIA with in vitro assessments in HEC-1-A cells. Techniques included CRISPR-Cas9 for gene editing and various cellular assays (CCK-8, flow cytometry, Transwell) to evaluate the effects of MECOM on cell proliferation, migration, and apoptosis, alongside Western blot analysis for protein regulation in the TGF-beta pathway. MECOM was upregulated in UCEC tissues, influencing tumor cell behavior significantly. Knockout studies demonstrated reduced proliferation and migration and increased apoptosis, while overexpression showed reverse effects. Mechanistically, MECOM modulated critical proteins within the TGF-beta pathway, impacting cell cycle dynamics and apoptotic processes. The PRDM gene family, particularly MECOM, plays a crucial role in the pathogenesis and progression of UCEC, suggesting its utility as a target for novel therapeutic interventions. Our findings offer valuable insights for future research and potential clinical application in managing uterine endometrial cancer.

Implementation of polygenic risk scores in secondary prevention of (breast) cancer

Abstract Utilizing polygenic risk scores to inform secondary prevention of breast cancer via population screening programs is one of the pioneering applications of genomics in public health applications. Over the last decade, polygenic risk scores for breast cancer have been developed and validated in various European populations (AUC ± 0.63, OR per Z unit ± 1.6, depending on the population). In some countries, the polygenic risk score has been integrated with decision modeling tools, such as CanRisk in the Netherlands, and low-level implementation into health and care systems has started. Implementation strategies vary, but generally consider initial implementation into high-risk populations, such as breast cancer families, in specialized clinical setting, such as academic medical centres, or specialized cancer clinics, referring relatives of patients to population screening based on comprehensive risk modelling, including polygenic risk scores. This route may be followed by other disease fields as well. The presentations outlines the current evidence and considerations on breast cancer genetic risk modelling, clinical pilot studies and the outline of step-wise implementation of such models to benefit secondary prevention programs. We start from the perspective of a single hospital, to the needed steps to upscale to national populations, both in diversity of these populations, as the throughput of genetic testing and counselling, until the harmonization and recalibration of various European healthcare models. We draw from examples of the Genotyping on all patients (GOALL), building cancer health platforms (CanHeal) and Genome of Europe (GoE) consortia.

Expression of EGFRvIII and its co‑expression with wild‑type EGFR, or putative cancer stem cell biomarkers CD44 or EpCAM are associated with poorer prognosis in patients with hepatocellular carcinoma.

The aberrant expression of HER family members and cancer stem cells (CSCs) have been associated with tumour progression and resistance to therapy. At present, several HER inhibitors have been approved for the treatment of patients with a range of cancers but not for the treatment of patients with hepatocellular carcinoma (HCC). The present study investigated the co‑expression and prognostic significance of HER family members, type‑III deletion mutant EGFR (EGFRvIII), and the putative CSC biomarkers CD44 and epithelial cell adhesion molecule (EpCAM) in 43 patients with HCC. The relative expression of these biomarkers was determined using immunohistochemistry. At a cut off value of >5% of tumour cells stained for these biomarkers, 35% [wild‑type (wt)EGFR], 58% (HER‑2), 0% (HER‑3), 19% (HER‑4), 26% (EGFRvIII), 40% (CD44) and 33% (EpCAM) of patients were positive. In 23, 14 and 9% of the patients, wtEGFR expression was accompanied by co‑expression with HER‑2, EGFRvIII and HER‑2/EGFRvIII, respectively. EGFRvIII expression, membranous expression of CD44 and co‑expression of wtEGFR/EGFRvIII were associated with poor overall survival (OS). By contrast, cytoplasmic CD44 expression was associated with a longer OS time. The present study also investigated the effect of several agents targeting one or more members of the HER family, other growth factor receptors and cell signalling proteins on the proliferation of HCC cell lines. Among agents targeting one or more members of the HER family, the pan‑HER family blocker afatinib was the most effective, inhibiting the proliferation of three out of seven human liver cancer cell lines (LCCLs), while the CDK inhibitor dinacicilib was the most effective agent, inhibiting the proliferation of all human LCCLs tested. Taken together, the present results suggested that EGFRvIII expression and its co‑expression with wtEGFR or CD44 was of prognostic significance. These results also support further investigations of the therapeutic potential of drugs targeting EGFRvIII and other members of the HER family in patients with HCC.

Two founder variants account for over 90% of pathogenic BRCA alleles in theOrkney and Shetland Isles in Scotland.

For breast and ovarian cancer risk assessment in the isolated populations of the Northern Isles of Orkney and Shetland (in Scotland, UK) and their diasporas, quantifying genetically drifted BRCA1 and BRCA2 pathogenic variants is important. Two actionable variants in these genes have reached much higher frequencies than in cosmopolitan UK populations. Here, we report a BRCA2 splice acceptor variant, c.517-2A>G, found in breast and ovarian cancer families from Shetland. We investigated the frequency and origin of this variant in a population-based research cohort of people of Shetland ancestry, VIKING I. The variant segregates with female breast and ovarian cancer in diagnosed cases and is classified as pathogenic. Exome sequence data from 2108 VIKING I participants with three or more Shetlandic grandparents was used to estimate the population prevalence of c.517-2A>G in Shetlanders. Nine VIKING I research volunteers carry this variant, on a shared haplotype (carrier frequency 0.4%). This frequency is ~130-fold higher than in UK Biobank, where the small group of carriers has a different haplotype. Records of birth, marriage and death indicate genealogical linkage of VIKING I carriers to a founder from the Isle of Whalsay, Shetland, similar to our observations for the BRCA1 founder variant c.5207T>C from Westray, Orkney. In total, 93.5% of pathogenic BRCA variant carriers in Northern Isles exomes are accounted for by these two drifted variants. We thus provide the scientific evidence of an opportunity for screening people of Orcadian and Shetlandic origins for each drifted pathogenic variant, particularly women with Westray or Whalsay ancestry.

Assessment of glucose and HbA1c monitoring in a pancreatic cancer surveillance program for high-risk individuals.

Several studies suggest that new-onset diabetes mellitus (NOD) is an early manifestation of pancreatic ductal adenocarcinoma (PDAC). Therefore, the international CAncer of the Pancreas Screening (CAPS) Consortium recommends glucose and HbA1c monitoring in high-risk individuals (HRIs) undergoing surveillance. However, evidence that such monitoring improves PDAC detection is lacking. Our aim was to investigate the association between serum glucose and HbA1c values and the development of PDAC in HRIs undergoing surveillance. Participants were recruited from the Familial Pancreatic Cancer (FPC) surveillance cohort, which follows hereditary predisposed HRIs yearly by MRI and/or EUS and blood sampling. Those who underwent fasting glucose and/or HbA1c monitoring at least once were eligible candidates. 404 HRIs met the inclusion criteria. During a median follow-up of 41 months (range 14-120), nine individuals developed PDAC and four (without PDAC) were diagnosed with NOD. Glucose levels ranged from 3.4-10.7 mmol/L (mean 5.6 ± 0.7) and HbA1c levels from 25-68 mmol/mol (mean 37.7 ± 4.1). Mean values did not differ significantly between PDAC cases and controls. The percentage of individuals with at least one elevated value were comparable between PDAC cases and controls for glucose (33% and 27%, p=0.707) and HbA1c (22% and 14%, p=0.623). No consistent glucose or HbA1c trends over time suggested a correlation with PDAC development. In this HRI surveillance cohort, measuring glucose and HbA1c values did not contribute to PDAC detection. Larger and longer-term studies are needed to determine the final role of glucose and HbA1c monitoring in PDAC surveillance.

Family Resilience and Its Influencing Factors in Patients With Cancer and Their Family Members: A Systematic Review.

This review aims to explore factors influencing family resilience in families providing care for patients with cancer and to provide suggestions for future research directions. Six electronic databases were searched including Web of Science, CINAHL, EMBASE, PsycINFO, PubMed and CNKI from their inception to December 2023. The article reference lists were also manually searched. The Mixed Method Appraisal Tool was used to assess the included studies in this review. The 27-item checklist Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was followed to report this review. Twenty-one studies from six online databases reported that either individual or family factors have effects on family resilience and were described into five clusters on the basis of the Walsh model of family resilience, including demographic and clinical factors, personal strengths and resources, family stressors, family resilient coping processes and family resilient adaptation outcomes. Family resilience in cancer families plays a pivotal role in coping with family stressors and facilitating positive outcomes through domains of coping. Future researches need to explore factors related to family resilience from dyadic perspectives and to establish multidisciplinary intervention strategies for developing levels of family resilience in cancer families. PROSPERO: CRD42024535349.

Unrecognised actionability for breast cancer risk variants identified in a national-level review of Australian familial cancer centres.

Breast cancer remains a significant global health challenge. In Australia, the adoption of publicly-funded multigene panel testing for eligible cancer patients has increased accessibility to personalised care, yet has also highlighted the increasing prevalence of variants of uncertain significance (VUS), complicating clinical decision-making. This project aimed to explore the spectrum and actionability of breast cancer VUS in Australian familial cancer centers (FCCs). Leveraging data from 11 FCCs participating in the Inherited Cancer Connect database, we retrieved VUS results from 1472 patients. Through ClinVar crosschecks and application of gene-specific ACMG/AMP guidelines, we showed the potential for reclassification of 4% of unique VUS as pathogenic or likely pathogenic, and 80% as benign or likely benign. Surveys conducted with FCCs and diagnostic laboratories described current practices and challenges in variant reclassifications, highlighting resource constraints preventing periodic VUS review and notifications from the laboratories to the FCCs. Our study suggests there are benefits to routine VUS review and reclassification, particularly in publicly-funded healthcare systems. Future research should focus on assessing the clinical impact and cost-effectiveness of implementing routine variant review practices, alongside efforts to enhance communication between FCCs and laboratories.

Salivary Transmembrane Mucins of the MUC1 Family (CA 15-3, CA 27.29, MCA) in Breast Cancer: The Effect of Human Epidermal Growth Factor Receptor 2 (HER2)

The MUC1 family of transmembrane glycoproteins (CA 15-3, CA 27.29, MCA) is aberrantly expressed among patients with breast cancer. Objectives: to measure the level of degradation products of MUC1, including CA 15-3, CA 27.29, and MCA, in the saliva of breast cancer patients and to describe the biochemical processes that influence their expression and the regulation of their biological functions. Methods: The case–control study included three groups (breast cancer, fibroadenomas, and healthy controls). All study participants provided saliva samples strictly before starting treatment. The levels of MUC1, including CA 15-3, CA 27.29, and MCA, free progesterone and estradiol, cytokines (MCP-1, VEGF, TNF-α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18), and amino acids (Asp, Gln, Gly, His, Leu + Ile, Orn, Phe, Pro, Tyr) were determined. Results: It was shown that the levels of the MUC1 family in the saliva of patients with HER2-positive breast cancer were significantly lower compared to the control group. The level of pro-inflammatory cytokines and the level of free estradiol affected the expression of MUC1. We obtained a reliable relationship between the aggressive nature of tumor growth, an increased level of pro-inflammatory cytokines, a low level of free estradiol, and the suppressed expression of salivary MUC1. Conclusions: Among patients with aggressive breast cancer, a high level of pro-inflammatory cytokines, and a low level of free estradiol, there was an inhibition of the expression of pathologically unchanged glycoprotein MUC1 in saliva.

Is there a right time to die? How patients, families and assisted dying providers decide on and anticipate a date with death

Research has explored why people seek assisted dying (AD), families’ bereavement, and AD providers’ experiences, yet few studies have investigated decision-making of the time and date for AD. This article elucidates how cancer patients, families and AD providers decide on and experience living with a date and time for AD in New Zealand. We longitudinally interviewed 23 people. Using thematic analysis, we identified four decision-making phases: deciding how and when to draw a line in the sand, the final countdown, a date with death and the right time. Picking a date was an embodied, relational, situational decision that balanced time left, families’ wishes, providers’ needs, and AD regulations. Time is a silent factor in AD decision-making; choosing a date reorients time to clock, event and embodied time, and contrives the right time for death. We discuss the implications and recommend how AD providers and policymakers can support service users and providers.

Risk factors for second primary breast cancer by laterality, age, and race and ethnicity.

Epidemiologic studies of risk factors for second primary breast cancer (SBC) have been conducted primarily in non-Hispanic White (NHW) women. A racially- and ethnically-diverse population-based pooled cohort of 9,639 women with first primary stage I-III invasive breast cancer (FBC) was linked with the California Cancer Registry; 618 contralateral SBC (CSBC) and 278 ipsilateral SBC (ISBC), diagnosed >6 months after FBC, were identified. Using Fine and Gray models accounting for competing risks, we assessed associations of CSBC and ISBC risk with FBC clinical characteristics and epidemiologic factors. In younger women (FBC at age <50 years), higher CSBC risk was associated with ER/PR-negative FBC [hazard ratio (HR)=1.68], breast cancer family history (HR = 2.20), and nulliparity (HR = 1.37). In older women (FBC at age ≥50 years), higher risk was associated with breast cancer family history (HR = 1.32), premenopausal status (HR = 1.49), overweight (HR = 1.39), and higher alcohol consumption (HR = 1.34). For ISBC, higher risk was associated with married status (HR = 1.94) in younger women, and overweight (HR = 1.60) among older women. For CSBC, HR estimates were generally similar across racial and ethnic groups. Even after adjustment for these risk factors, compared with NHW women, risk remained elevated for CSBC in younger African American, Asian American, and Hispanic women, and for ISBC in older African American and Hispanic women with ER/PR-positive FBC. Our findings support genetic risk evaluation, enhanced screening, and lifestyle changes in women at higher risk of SBC. Additional risk factors must contribute to the unequal burden of SBC across racial and ethnic groups.

Germline genetic variants in a case of familial cancer: RAD51D and four other co-segregated variants

Germline genetic variants in a case of familial cancer: RAD51D and four other co-segregated variants

Plasma metabolomics profiles and breast cancer risk

BackgroundBreast cancer (BC) is the most common cancer in women and incidence rates are increasing; metabolomics may be a promising approach for identifying the drivers of the increasing trends that cannot be explained by changes in known BC risk factors.MethodsWe conducted a nested case–control study (median followup 6.3 years) within the New York site of the Breast Cancer Family Registry (BCFR) (n = 40 cases and 70 age-matched controls). We conducted a metabolome-wide association study using untargeted metabolomics coupling hydrophilic interaction liquid chromatography (HILIC) and C18 chromatography with high-resolution mass spectrometry (LC-HRMS) to identify BC-related metabolic features.ResultsWe found eight metabolic features associated with BC risk. For the four metabolites negatively associated with risk, the adjusted odds ratios (ORs) ranged from 0.31 (95% confidence interval (CI): 0.14, 0.66) (L-Histidine) to 0.65 (95% CI: 0.43, 0.98) (N-Acetylgalactosamine), and for the four metabolites positively associated with risk, ORs ranged from 1.61 (95% CI: 1.04, 2.51, (m/z: 101.5813, RT: 90.4, 1,3-dibutyl-1-nitrosourea, a potential carcinogen)) to 2.20 (95% CI: 1.15, 4.23) (11-cis-Eicosenic acid). These results were no longer statistically significant after adjusting for multiple comparisons. Adding the BC-related metabolic features to a model, including age, the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk score improved the accuracy of BC prediction from an area under the curve (AUC) of 66% to 83%.ConclusionsIf replicated in larger prospective cohorts, these findings offer promising new ways to identify exposures related to BC and improve BC risk prediction.

7161 Similar Progression-Free Survival in Familial Non-medullary Thyroid Cancer and Sporadic Differentiated Thyroid Cancer Patients

Abstract Disclosure: E. Chuki: None. N. Behairy: None. S. Auh: None. A. Makarewicz: None. N. Uttarkar Vikram: None. P. Padmasree: None. C. Cochran: None. S. Gubbi: None. J. Klubo-Gwiezdzinska: None. Background: There is conflicting data on the disease aggressiveness in patients with Familial Non-medullary Thyroid Cancer (FNMTC) as compared with sporadic differentiated thyroid cancer (sDTC). Moreover, limited evidence exists comparing FNMTC and sDTC responsiveness to treatment. Therefore, the goal of this study was to compare response to standard therapy, defined as progression-free survival (PFS), in patients with FNMTC and sDTC. Methods: This was a single-center Institutional Review Board-approved cohort study, including patients diagnosed with FNMTC or sDTC, subjected to standard therapy with a median follow-up of 4.8 years (range 2.1-10 years). Patients with FNMTC were matched to patients with sDTC in a 1:2 ratio using the Ccoptimalmatch package in R based on age, sex, and American Thyroid Association (ATA) risk stratification at presentation. PFS was defined from the date of initial thyroid surgery to the first evidence of progression, assessed by RECIST 1.1 criteria. Demographics, cancer characteristics, and treatment modalities were collected and compared. Kaplan-Meier curves and log-rank tests were employed to assess differences in PFS. SAS 9.4 software was used for analyses, with a p-value set at 0.05. Results: The study consisted of 198 subjects, with 66 patients affected by FNMTC and 132 sDTC cases, aged 43.1±14.3, 69.7% female, 47% low, 45.5% intermediate and 7.6% high ATA risk for recurrence. Within the FNMTC cohort 26 (39.4%) cancer cases were detected by screening. There were no differences in age, sex and ATA risk stratification between the study groups due to exact matching (±1 year for age). No significant differences were observed in histology type (p = 0.49), multifocality (p = 0.59), gross extrathyroidal extension (p = 0.76), or presence of distant metastases (p = 0.09). FNMTC exhibited smaller tumor size at diagnosis (mean 1.2±0.96 vs 1.8±1.5 cm, p &amp;lt; 0.01), and fewer positive lymph nodes (p = 0.02). Initial surgery extent favored more total thyroidectomies in the FNMTC group (p &amp;lt; 0.01), and there was a higher prevalence of repeat neck surgeries in the sDTC group (p = 0.045). There was no difference in utilization of RAI therapy between the groups (p = 0.68). During follow up 15.2% of FNMTC and 12.9% of sDTC patients presented with disease progression. PFS probabilities at 5, 10, 15, 20, and 25 years were similar between both groups (0.8 and 0.85 at 5 years, 0.8 and 0.78 for subsequent years) (p = 0.99). Conclusions: The initial surgical treatment for FNMTC tends to be more extensive than applied in sDTC, despite a smaller tumor size and lower number of metastatic lymph nodes at diagnosis. This strategy could lead to a lower need for repeat neck surgeries. The smaller tumor size at diagnosis of FNMTC might be a result of an active screening of affected families. The similar PFS in patients with FNMTC and sDTC suggests a comparable tumor biology and similar responsiveness to standard therapy. Presentation: 6/3/2024

Hypofractionated Radiotherapy for Breast Cancer: Experience of the Radiotherapy Department of the Mali Hospital

Aim: To evaluate the outcomes of hypofractionated radiotherapy in breast cancer. Patients and Methods: It was a retrospective study over a 3-year period, from January 2016 to December 2018, of breast cancer patients treated with hypofractionated radiotherapy at Mali Hospital. All patients with histologically confirmed breast cancer without distant metastases were included. We excluded all patients treated for breast cancer with palliative or normofractionated radiotherapy, patients with metastatic disease on admission and incomplete records. Patients were classified according to the 7th edition TNM classification. Radiotherapy was administered using an Elekta Compact 6MV linear accelerator with the 3D conformal technique, at a total dose of 42 Gy at a rate of 2.8Gy/fraction in 15 sessions, and 5 sessions/week. Data were collected from medical records and treatment sheets, entered into Excel and analysed using SPSS version 23 software. Results: Sixty-four patients out of 129 met our selection criteria (49.61%). The mean age was 44.65+/-11.11 with extremes of 25 and 88 years. Previous hormonal contraception was found in 23.43% of cases, familial breast cancer in 6.25% and nulliparity in 4.68% of cases. Ultramammography was performed in all patients. Assessment of distant extension consisted of a thoraco-abdominal CT scan in 92.18% of cases, and abdominal ultrasound combined with a chest X-ray in 7.82% of cases. Histology of the biopsy specimen showed non-specific carcinoma in 96.87% of cases, Scarf-Bloom and Richardson (SBR) grade II in 64.81% and grade III in 27.78%. Immunohistochemistry was performed in 26 patients, hormone receptor positive in 57.69% (n=15) and triple negative in 42.31% (n=11). Patients were classified as stage T3 or T4 in 82.68% of cases. 95.4% of patients underwent mastectomy and 4.6% lumpectomy; all patients underwent axillary curage. The patients were treated with hypofractionated radiotherapy on the wall and the supra- and sub-clavicular lymph

EP.01D.02 Heterogeneous Germline Variants Detected in EGFR-Mutant Familial Lung Cancer Patients and Family Members

EP.01D.02 Heterogeneous Germline Variants Detected in EGFR-Mutant Familial Lung Cancer Patients and Family Members

Building a community-academic partnership to expand services for childhood cancer survivors in a rural, low-income region in California.

360 Background: Community-engaged research is an effective approach to address health disparities that is well-established in the public health domain and has not been widely applied in childhood cancer survivorship. We present our multi-year experience building a community-academic partnership and community-engaged childhood cancer survivorship research portfolio. Methods: We have developed a partnership between Jacob’s Heart Children’s Cancer Support Services, a nonprofit community-based organization (CBO) and an academic pediatric cancer survivorship team, with the goal of improving health outcomes for childhood cancer survivors and their families in the Salinas Valley, a rural, low-income region in California with majority Hispanic/Latino/a/e residents. Our partnership process is guided by principles of community-based participatory research, prioritizing trust and involving community members as equal partners in all phases of research. Results: In year 1 (2021-2022), we held successive meetings which identified common goals and shared values, established the collaboration, and sought funding to advance our goals. In year 2 (2022-2023), with internal grant funding, we conducted a qualitative needs assessment interviewing childhood cancer survivors, parents, and CBO staff. Teamwork enriched the data analysis and allowed us to identify problems in communication as an area of need, which directly informed subsequent grant proposals. In year 3 (2023-2024), with external funding we began a multi-year study to understand and improve survivorship-related communication among Hispanic/Latino/a/e young adult childhood cancer survivors, their parents, and clinicians. Current and future projects include collaborative design and pilot testing of a novel communication intervention, formation of a dedicated community advisory board, and a CBO-driven program evaluation. Findings from our community-engaged studies have prompted new sets of research questions and illustrate opportunities for institutional change in the clinic setting. In parallel, the CBO has leveraged research findings in real-time to identify barriers to seeking support among childhood cancer survivors and families, and adapted and improved programming for families in response. Through our joint research portfolio, we have incorporated training and mentorship for staff at the CBO and medical trainees at the academic center. Conclusions: A community-academic partnership in a rural, low-income region has the potential to reduce health disparities and improve childhood cancer survivors’ health outcomes through collaborative program development and community-engaged research. Fueled by mutual investment and strong momentum, our partnership facilitates an interconnected cycle of research and practice change that is grounded in community needs.

Family history and cancer risk study (FOREST): A clinical trial assessing electronic patient-directed family history input for identifying patients at risk of hereditary cancer

BackgroundHereditary cancer syndromes cause a high lifetime risk of early, aggressive cancers. Early recognition of individuals at risk can allow risk-reducing interventions that improve morbidity and mortality. Family health history applications that gather data directly from patients could alleviate barriers to risk assessment in the clinical appointment, such as lack of provider knowledge of genetics guidelines and limited time in the clinical appointment. New approaches allow linking these applications to patient health portals and their electronic health records (EHRs), offering an end-to-end solution for patient-input family history information and risk result clinical decision support for their provider. MethodsWe describe the design of the first large-scale evaluation of an EHR-integrable, patient-facing family history software platform based on the Substitutable Medical Applications and Reusable Technologies on Fast Healthcare Interoperability Resources (SMART on FHIR) standard. In our study, we leverage an established implementation science framework to evaluate the success of our model to facilitate scalable, systematic risk assessment for hereditary cancers in diverse clinical environments in a large pragmatic study at two sites. We will also evaluate the success of the approach to improve the efficiency of downstream genetic counseling resulting from pre-counseling pedigree generation. ConclusionsOur research study will provide evidence regarding a new care delivery model that is scalable and sustainable for a variety of medical centers and clinics. Trial registrationThis study was registered on ClinicalTrials.gov under NCT05079334 on 15 October 2021.

Assessing capacity for hereditary cancer risk assessment in metro Chicago.

307 Background: Since 2005, the United States Preventive Services Task Force (USPSTF) recommends that primary care (PC) clinicians identify and refer adults with a high-risk cancer family history to cancer genetic services (CGS), yet hereditary cancer risk assessment (HCRA) continues to be underutilized in PC. A population-based approach to HCRA in PC settings can expand access to cancer prevention and early detection to vulnerable populations and reduce disparities in cancer outcomes. The Chicago Cancer Screening and Testing Access Coalition (CCSTAC) is developing strategies to integrate HCRA in PC settings. We conducted an environmental scan to assess current capacity to deliver 1) HRCA in Federally Qualified Health Centers (FQHCs) and 2) follow-up CGS for high risk patients. Methods: In 2023, we administered two surveys to assess HCRA practices in Metro Chicago. We invited 22 FQHCs to complete a 21-item survey of current practices, readiness to implement, and barriers to HCRA. We also invited 21 CGS sites to complete a 25-item survey to understand staffing, utilization, referral patterns, and barriers to access. Surveys were administered electronically via Qualtrics. We conducted a descriptive analysis of survey data. Results: Twenty FQHCs (91%) completed the survey on HCRA in PC; 85% reported familiarity with USPSTF guidelines for HCRA. The majority (75%) reported no plans to implement HCRA. Clinic workflow, paucity of follow-up resources, cost, lack of provider knowledge, and absence of HCRA as a mandatory performance measure were cited as the most significant barriers to implementation. Genetic counselors (GCs) from 19 CGS hospital-based sites (90%) completed the survey on availability of genetic services. CGS were most often located in a cancer center (47%); no CGS were located in PC. Most referrals originated from oncology, surgery, or gastroenterology, with the lowest rate of referrals from community-based PC. Nearly half of CGS clinics (47%) reported capacity for at least a small increase in patient volume. Wait-time at the majority of CGS clinics was less than a month. GCs cited patient logistics (e.g. transportation, time off work), lack of referral information from providers, and systemic racism as significant barriers in patient access to CGS. Conclusions: After almost 20 years of evidence-based guidelines, use of HCRA is still very limited in the community-based PC setting. Our findings point to a need to bridge the gap between hospital-based CGS and FQHCs to ensure patients in vulnerable communities have access to guideline-concordant cancer prevention and screening strategies. Based on these findings, CCSTAC is designing strategies to integrate HCRA in primary care at FQHCs focused on provider education, well-designed clinic workflows, connections with existing CGS, and advocacy to align UDS and HEDIS measures with USPSTF guidelines.

Clinical, histological and receptor profiles of invasive breast cancer and ductal carcinoma in situ in females with germline pathogenic variants in PTEN and implications for germline testing

PTEN hamartoma tumour syndrome (PHTS) is an autosomal dominant hereditary cancer syndrome, caused mostly by germline pathogenic variants in PTEN. Female carriers have an up to 80% lifetime risk of breast cancer. Pathologic features of breast cancer in PHTS have seldom been reported.In a collaboration between all histopathology laboratories in our state and our statewide familial cancer service, we tracked the breast biopsies of 12 females with known PTEN pathogenic or likely pathogenic variants (Jan 1990 to Jan 2018). Two further cases were added by a Victorian cancer genetics unit.Breast cancer, inclusive of invasive cancer or ductal carcinoma in situ (DCIS), was diagnosed in 12 of 14 cases (85.7%). One case had a family history of PHTS and six a family history of breast cancer. The mean age at first breast cancer diagnosis was 41.6 years (range 27-63). Six cases developed more than one breast cancer. Five (42%) developed contralateral breast cancer. Ten of the 12 invasive cancers were of no special type, two were reported as lobular carcinomas. None were grade 1. When reported, all cancers were hormone receptor positive and HER2 negative. All were associated with DCIS. The DCIS spanned all grades.The two cases without breast cancer still required surgery for exuberant benign changes, including papillomas, fibroadenomatoid change, florid ductal epithelial hyperplasia, adenosis and stromal fibrosis.We note that the morphology and receptor profiles of breast cancer in individuals with P/LP PTEN variants are not distinctive. Contrary to prevalent beliefs, these cancers do not conform to the contemporary definition of apocrine breast carcinoma. Greater familiarity of healthcare professionals with the overall clinical and pathologic findings in PHTS and the validated Cleveland Clinic PTEN calculator (http://www.lerner.ccf.org/gmi/ccscore) would improve the recognition of female PHTS individuals with breast cancer. Earlier identification of their cancer predisposition syndrome would benefit these patients and their families who are at high risk of a range of cancers.

A role for germline variants in multiple myeloma?

In Blood Cancer Discovery, Thibaud and colleagues report the incidence of pathogenic germline variants (PGVs) in multiple myeloma patients and that these are associated with DNA repair pathway genes including BRCA1 and BRCA2. They find an association of patients with PGVs and previous family or personal history of cancer and that these patients are diagnosed slightly earlier than those without PGVs. Patients with PGVs had a longer progression free survival than those without PGVs when they received high dose melphalan and autologous stem cell transplant, providing a therapeutic rationale for diagnostic germline testing in myeloma.