bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence of unexpected actionable germline pathogenic variants identified on broad-based multi-gene panel testing in a cohort of cancer patients.
Authors: Landry Kara K. , DeSarno Michael , Kipnis Lindsay , Barquet Ramos Farid , Breen Katelyn , Patton Kaleigh , Morrissette Audrey , Buehler Ryan , Ukaegbu Chinedu , Rohanizadegan Mersedeh , Yurgelun Matthew B. , Syngal Sapna , Rana Huma Q. , Garber Judy Ellen
Published: June 2023

10523

Background: Broad-based germline multi-gene panel testing (MGPT) for inherited predisposition has become increasingly common for cancer patients. Both indications for germline testing and the spectrum of genes on MGPT have expanded. We sought to examine the frequency of an unexpected pathogenic/likely pathogenic variant (P/LPV) in patients with a variety of solid and hematologic malignancies undergoing MGPT. Methods: A retrospective review of patients with a history of cancer who underwent MGPT at a single institution from 2015 to 2021 with MGPT of > 20 cancer predisposition genes. Low penetrance genes and genes with a recessive inheritance pattern were excluded. Deidentified pedigrees were analyzed by genetic counselors for clinical diagnostic criteria and gene-specific national testing guidelines to determine whether clinical suspicion of the P/LPV was present. Results: 10,975 cancer patients underwent MGPT. 1,180 (10.9%) patients were found to have > 1 P/LPV in a moderate or highly penetrant cancer susceptibility gene. 357 (3.3%) of the P/LPV were unexpected based on patient’s personal cancer history alone. 208 (1.9%) of the P/LPV remained unexpected after patient and family cancer histories were considered. Most common cancer subtypes with an unexpected P/LPV were breast [1.5% (83/5691)], prostate [2.1% (28/1300)], colorectal [2.2% (18/823)], ovarian/fallopian [1.7% (13/781)] and uterine [ 2.8% (10/352)] cancer. Most frequent unexpected P/LPV were PMS2 (n = 19), MITF (n = 18), ATM (n = 18), BRIP1 (n = 17), CHEK2 (n = 14), HOXB13 (n = 13), SDHA (n = 12), BRCA2 (n = 7), MSH6 (n = 7), SDHC (n = 7), TP53 (n = 7), and PALB2 (n = 6). No predictor of having an unexpected P/LPV was identified in multivariable logistic regression analysis. Low penetrance or recessive variants were found in 521 (4.8%) patients. Variants of uncertain significance (VUS) were found in 3,774 (35.0%) patients. Conclusions: This large retrospective analysis of cancer patients undergoing MGPT identified an overall rate of 1.9% of P/LPV in actionable cancer predisposition genes. Findings were more often unexpected (3.3%) when considering only the patient cancer history, endorsing the importance of family cancer history for consideration of more targeted genetic testing. Identification of moderate or highly penetrant P/LPV in cancer patients is increasingly important in guiding treatment decisions, cancer screening in survivors and testing of at-risk family members. These findings may justify consideration of broader MGPT panels especially when family cancer history is uncertain or unavailable. MGPT also detected a high rate of VUS, reinforcing the importance of physician education to ensure appropriate interpretation and management.
Cardiorespiratory fitness and BMI in youth and site-specific cancer mortality in men: A population-based cohort study with register linkage.
Authors: Onerup Aron , Mehlig Kirsten , af Geijerstam Agnes , Ekblom Bak Elin , Kuhn Hans-Georg , Lissner Lauren , Åberg Maria , Börjesson Mats
Published: June 2023

10534

Background: There is insufficient evidence on the associations between cardiorespiratory fitness (CRF), body mass index (BMI), and site-specific cancer mortality. Methods: We collected data on all men who underwent military conscription 1968-2005 in Sweden at ages 16-25. CRF was assessed as maximal aerobic workload on a cycle ergometer test and classified as low, moderate, or high. BMI (kg/m2) was classified as underweight ( < 18.5), normal weight (18.5-24.9), overweight (25-29.9), or obesity (≥30). Data was cross-linked on individual level through the Swedish identification number with national registers with high validity for information on cancer mortality. Follow-up was from conscription until death, emigration, or end of follow-up (12/31/2019). Cox regression analyses included CRF and BMI as well as age, year, and site of conscription, parental education, and muscle strength. Primary analyses tested linear trends for CRF and BMI, with effect sizes for categorical comparisons for interpretation. Results: 1,083,738 men were included in the analyses and were followed for a mean of 33 years, during which 8,912 cancer-specific deaths occurred. Lower CRF and higher BMI were linearly associated with any cancer mortality as well as with several site-specific cancer mortalities (table). However, death in some major cancer sites (prostate, CNS) were not associated with CRF or BMI and higher CRF was associated with higher mortality from malignant skin cancer. Conclusions: Higher CRF and lower BMI was associated with lower cancer mortality for some, but not all cancer sites. These results could be used as a further incentive for working with modifiable risk factors in public health. [Table: see text]
Obesity and breast cancer in women under age 40.
Authors: Cattie Rabia , Chung Victoria , Henry Marcia , Alberti Matthew , Peeples James , Yuan Helen , Saxena Raina , Olet Susan , Taylor Caitlin , Sheen Melanie Anne
Published: June 2023

10536

Background: Obesity is a well-established risk factor for postmenopausal hormone-receptor positive breast cancer (BC). The role of obesity in premenopausal BC, especially in women under the age of 40, is not well understood. Multiple studies have shown a decreased rate of premenopausal BC with increasing body mass index (BMI), notably for estrogen receptor positive tumors. Even though there is an inverse association between obesity and premenopausal BC, it has been suggested that obesity has a negative prognostic role in premenopausal BC. This may be explained if premenopausal obese women develop more aggressive tumors. Obesity is associated with triple negative and Luminal B cancers in premenopausal women. We sought to evaluate the relationship between premenopausal breast cancer and obesity in a diverse patient population. Methods: We assembled a 10-year database of women diagnosed with breast cancer before age 40 in a single health system. Data collected included age at diagnosis, self-identified race, breast cancer subtype, BMI, and stage at diagnosis. The control group was all women under the age of 40 presenting to our health system in the same time period. Stratification analysis was performed using Mantel-Haenszel Risk Estimation. Results: The risk ratio between the standardized estimates of BC patients under 40 with BMI ≤ 30 to BMI > 30 is 0.7924, 95% CI (0.683 – 0.920), P = 0.0022. This implies that young BC patients are more likely to be obese than all young women presenting to our health system. There are more obese Black patients compared to White patients. The effect of obesity on BC diagnosis was more pronounced in Black patients, with a risk ratio of 0.59 compared to 0.96. Conclusions: The data presented here challenge previous research which had shown that obesity seemed to be protective against breast cancer in premenopausal women. Here, we see a statistically significant increase in obesity among young women < 40 years presenting with breast cancer. The increased risk of breast cancer diagnosis was particularly pronounced in obese Black women. Previous studies have had a very low proportion of Black women represented, which may cause underestimation of risk in this patient population. These data suggest that obesity is a risk factor for breast cancer in young women, especially in Black patients. [Table: see text]
The impact of high body mass index on hepatocellular carcinoma in viral hepatitis and cirrhosis.
Authors: Kim Moonho , Jun Baek Gyu , Shin Hwang Sik , Yi Sang-Wook
Published: June 2023

10537

Background: The impact of a high body mass index (BMI) on hepatocellular carcinoma (HCC) has been unclear in patients with viral hepatitis and liver cirrhosis (LC). Our aim is to investigate the association between BMI and HCC in patients with viral hepatitis and LC. Methods: We conducted a population-based cohort study. In total, 156,143 Korean adults who underwent routine health examinations during 2003-2006 were followed up until December 2019 via linkage to the national hospital discharge records. Multivariable-adjusted hazard ratios (HRs) per each 5 kg/m2 increase in BMI for HCC risk were calculated using Cox proportional hazard models. Results: BMI was positively associated with HCC in hepatitis B virus (HBV) patients with BMI range of 27.5~29.9 kg/m² and BMI ≥30 kg/m² and LC patients with a BMI range of 27.5~29.9 kg/m². Assuming linear associations, HRs were 1.17 for HBV, 1.08 for hepatitis C virus (HCV), and 1.11 for LC. In the subgroup analysis for the LC, the HR were 1.19 in the HBV-LC, 1.38 in the HCV-LC, 1.36 in the alcoholic LC, and 1.59 in the fatty liver LC. Women showed stronger positive associations between BMI and HCC than men in the HBV (HR, 1.45 vs 1.06) and LC (1.27 vs. 1.02). The positive association seemed to be stronger in younger age ( < 65 years) in HBV (1.17 vs 1.05) and HCV (1.33 vs 0.77) patients compared to older age ( > 65 years). Conclusions: In the BMI range of ≥25 kg/m2, a higher BMI was associated with an increased risk of HCC in LC and HBV. The associations between BMI and HCC risk are different according to liver disease, sex and age.
Barriers to cervical cancer screening in a developing Middle Eastern country: A nationwide survey.
Authors: Abdulelah Ahmed A , Abdulelah Zaid A , AlSamhori Jehad , AlQirem Lina , Al-Qirem Ahmad , AlSamhori Abdel Rahman
Published: June 2023

10545

Background: In addition to being ranked as the 4th leading malignancy worldwide, cervical cancer is associated with considerable morbidity and mortality resulting in significant burden. However, cervical cancer screening is available and has been proven to significantly minimize the associated morbidity and mortality through early detection. The identification of the barriers towards cervical cancer screening in Jordan, a developing middle eastern country, is of outstanding significance towards effective intervention and minimizing the collective health and socioeconomic burden imposed. Methods: The first consecutive 695 females aged 25 years and above with no prior history of cervical cancer and residing in Jordan across the different regions were enrolled via random probability sampling through a self-reporting survey that comprises of extensive questions regarding the participant’s demographics, medical history, awareness about cervical cancer and its screening methods. Single females were not included in the study due to culture unacceptability of performing pap smears on unmarried females. Statistical analysis was performed to identify the key barriers towards cervical cancer screening in Jordan. Results: The mean age of the enrolled participants was 42 ± 9 years with the majority of the participants having a higher level of education (84.5%), are medically insured (72.4%), and are non-smokers (74.7%). The majority of the participants, 77.7%, did not report a family history of cervical cancer. 472 participants (67.9%) were aware of the availability of a screening modality for cervical cancer, with the majority being informed through awareness campaigns (64.7%). Nonetheless, only 30.1% of the participants previously underwent pap smear for screening purposes. When the participants who did not undergo previous cervical cancer screening were compared with those who did, the participants who did not undergo any prior screening were more likely to identify the lack of information and knowledge towards screening (49.0% vs 9.6%) (p-value < 0.001), fear of the results (81.5% vs 7.2%) (p-value = 0.016), lack of belief in screening and its efficacy (2.1% vs 0.0%) (p-value = 0.037) as crucial and leading barriers. Additionally, the presence of a positive family history for cervical cancer was identified as a statistically significant promoter for screening uptake (p-value = 0.004). Nonetheless, there was no statistically significant difference between the two groups when evaluating the financial aspects of screening or embarrassment from the test as potential barriers, p-value = 0.159 and 0.738, respectively. Conclusions: Lack of knowledge towards screening and belief in its efficacy, and fear of the results were identified as driving barriers towards screening. Effective formulation of comprehensive awareness campaigns is pivotal towards successful intervention to the reported barriers.
Characterizing medical mistrust (MM) in a socio-demographically diverse sample of patients with cancer.
Authors: Park Cindy , Bass Sarah B , Ruth Karen J , Chertock Yana , Singley Katie J , Luck Caseem C , Abuhillo Malak , Khan Aleeha , Gowda Shreya , Holland Erin M , Knight Elizabeth , Verma Shreya , Rotaru Alexandru-Mircea , Hussain-Kasim Abeeda , Waisfeld Agostina , Hall Michael J.
Published: June 2023

10551

Background: Genetic and genomic testing are increasingly recognized as essential to high quality cancer care. Despite expanded eligibility for testing in recent years, barriers to genomic medicine persist. Notably, growing political and social mistrust risks negatively impacting views of medical institutions, medical professionals and complex technologies, and could undermine acceptance of genetic/genomic testing to guide treatment and identify risk in families. Prior studies have documented disparities and increased MM of genetic counseling and testing among underserved minorities which have been associated with delays or avoidance to care. We sought to identify individual characteristics associated with MM among cancer patients. Methods: A cross-sectional survey of cancer pts from the Fox Chase Cancer Center (FCCC) Burholme Campus (n=105, mixed urban/suburban, primarily insured) and Broad street campus (n=95, primarily urban underserved population) was conducted from 6/22-12/22, using a maximum variation (purposeful) sampling approach. Surveys queried MM using the LaVeist MM Index (MMI, range 0-10, measures healthcare/institution MM) and the Thompson Group Based MM Scale (GBMMS, range 1-5, measures race/ethnic specific MM; suspicion, discrimination, and lack of support subscales). Demographic and disease factors, as well as psychosocial measures (general/genetic health literacy, social support, self-advocacy, conspiratorial thinking, relationship with doctor, and trust in information sources) were also assessed. Medical decision making preference and health literacy were assessed with single validated items. The study was approved by the FCCC IRB #22-8003. Results: Participants had a median age of 62 yrs (range 25-91); 62% were female, 47% African American (AA), 15% Hispanic, 42% married, 47% high school graduate or less, 52% had household income <$50K/yr. Breast (28%), colorectal (16%), and GYN/GU (12%) cancers were the most commonly reported, and 23% reported >1 previous cancer diagnosis. Mean GBMMS was 2.11 (SD 0.80) and mean MMI was 4.63 (SD 1.54). See the table for significant associations. Conclusions: High levels of healthcare institution and race-based MM are associated with socio-demographic vulnerabilities, putting the most vulnerable cancer patients at high risk of making poor health decisions. [Table: see text]
Melanoma literacy and predictors for skin self-examination in three western U.S. states: A population-based survey.
Authors: Nelson Jacob , Latour Emile , Detweiler-Bedell Brian , Detweiler-Bedell Jerusha B. , Zell Adrienne , Wenzel Elizabeth , Stoos Elizabeth , Wiedrick Jack , Berry Elizabeth G. , Lange Jane , Etzioni Ruth , Lapidus Jodi A , Leachman Sancy Ann
Published: June 2023

10558

Background: Melanoma is a leading cause of skin cancer deaths, despite being easily treated when detected early. The objective of this study is to investigate the relationship between melanoma knowledge and beliefs, and the performance of skin self-examination (SSE) in three US states with high incidence rates of melanoma. Understanding the barriers to behaviors such as SSE can aid in the development of interventions aimed at increasing the frequency of early detection and reducing melanoma-related deaths. Methods: A total of 15,000 surveys were distributed to households in the states of Oregon, Washington, and Utah using a stratified two-stage sampling design. The survey responses were weighted to resemble the gender and age distributions of the US census. Rural areas were oversampled to ensure sufficient representation. The first objective of this study was to assess melanoma literacy, including knowledge about melanoma risks, attitudes, and preventive behaviors. Our second objective was to investigate the relationship between self-reported SSE and melanoma literacy, self-efficacy, and belief in the benefits of performing SSE. Results: Among 2,326 respondents, characteristics were similar across states (weighted by census-based population percentages), including demographics, baseline knowledge, performance of SSE, and self-efficacy in performing SSE. Rural respondents had a higher frequency of personal history of melanoma (16.2%) compared to urban respondents (9.9%). Only 21.2% of the respondents demonstrated high knowledge of melanoma. 62.8% of respondents reported having performed a SSE at some point in their lives, with only 24.6% of respondents having done so in the past 2 months. Most respondents (84.8%) believed in the effectiveness of SSE in detecting skin cancer, but only 38.3% and 7.3% reported being "fairly" or "very" confident in performing SSE, respectively. The performance of SSE was most strongly correlated with higher melanoma knowledge, higher self-efficacy, and a personal history of melanoma. Conclusions: The results of the survey indicate that melanoma literacy among respondents in 3 high-risk Western states is limited. A higher level of literacy was associated with a higher likelihood of reported early detection behaviors. This study provides a baseline assessment and serves as a foundation for the development of public health campaigns aimed at promoting prevention and early detection of this deadly cancer.
Patient navigation for lung cancer screening in an urban safety-net system: A pragmatic randomized clinical trial.
Authors: Bhalla Sheena , Natchimuthu Vijaya Subbu , Lee Jessica L. , Wahid Urooj , Zhu Hong , Santini Noel O. , Browning Travis , Hamann Heidi A , Johnson David H. , Chiu Hsienchang , Lee Simon Craddock , Gerber David E
Published: June 2023

10577

Background: Although low-dose computed tomography (LDCT)-based lung cancer screening (LCS) can decrease lung cancer mortality in high-risk individuals, it may be a complex and time-intensive process that poses challenges to patients, particularly those from minority, under- and uninsured populations. We conducted a pragmatic randomized controlled trial of telephone-based navigation for LCS within an integrated, urban safety-net healthcare system (Parkland Health, Dallas, Texas). Methods: Patients eligible for LCS based on United States Preventive Services Task Force 2013 Guidelines were randomized (1:1) to usual care with or without phone-based navigation. Following a structured protocol, navigators made systemic contact with patients to provide appointment reminders, share information and resources, assess barriers to LCS, and address smoking cessation. The primary endpoint was completion of the first three consecutive steps (eg, 3 annual LDCTs or LDCT, other imaging, biopsy) in a patient’s LCS process. We also explored differences in completion of LCS steps in navigation and usual care groups according to patient characteristics using chi-square test. Results: Patients (n=447) were randomized to phone-based navigation (n=225) or usual care (n=222) between February 2017 and February 2019. Mean patient age was 62 years, 46% were female, and 69% were racial-ethnic minorities. There was no significant difference in completion of the first three steps of the LCS algorithm (12 vs. 9%; P=0.3) between arms. Completion of LCS steps was not impacted by navigation among different subgroups, including age (<65 vs. ≥65 years), gender (male vs. female), race/ethnicity (non-hispanic white vs. racial minorities), and comorbidity status (Charlson Comorbidity Index <5 vs. ≥5). A key reason for step non-completion was lack of order placement. In the navigation arm, 368 of expected 675 steps (55%) were ordered, and in the usual care arm, 344 of expected 666 steps (52%) were ordered. Despite low three-step completion rates overall, the majority (>75%) of LCS algorithm steps were completed when ordered by their clinical team(Table). In exploratory univariable analysis, completion rates for ordered steps were 86% for navigation and 79% for usual care ( P=0.03). Conclusions: In this study, lack of order placement was a key reason for incomplete LCS steps. When orders were placed, navigated patients had higher rates of completion. Clinical team education and enhanced EHR processes to simplify order placement, coupled with patient navigation, may increase LCS uptake and completion in safety-net healthcare systems. Clinical trial information: NCT02758054 . [Table: see text]
Women with pathogenic variants in moderate penetrance breast cancer genes: How frequently do they meet high penetrance genetic testing criteria?
Authors: Casasanta Nicole , Soper Emily R. , Abul-Husn Noura S.
Published: June 2023

10584

Background: 5-10% of breast cancers are associated with germline pathogenic variants in breast cancer predisposition genes. 2-5% of these variants are in moderate penetrance (MP) genes, conferring a relative risk to develop breast cancer of 2-5. Various personal history (PH) and family history (FH)-based criteria for testing high penetrance genes, such as BRCA1 and BRCA2, have been proposed, but it is unknown to what extent women with pathogenic variants in MP genes may meet such criteria. We evaluated PH and FH of cancer among women with pathogenic variants in MP genes in a diverse and unselected patient cohort in New York City to determine how often they met well-established genetic testing criteria from the National Comprehensive Cancer Network (NCCN). Methods: Exome sequence data from ~16,000 female Bio Me Biobank participants were evaluated for expected pathogenic (per ClinVar, or predicted loss-of-function) variants in ATM, BARD1, BRIP1, CHEK2, NF1, PALB2, RAD51C, and RAD51D. We extracted demographic information, PH and FH of breast, ovarian, and/or pancreatic cancer, and PH and FH of genetic testing from participant questionnaires and electronic medical record review. We then determined which participants met current NCCN criteria (version 1.2023) for high penetrance breast, ovarian, and pancreatic cancer genetic testing. Results: We identified 252 women with expected pathogenic variants in MP genes: 105 CHEK2, 58 ATM, 35 BRIP1, 24 PALB2, 9 BARD1, 8 NF1, 8 RAD51D, and 5 RAD51C. 30% met NCCN criteria, including 30% of those with CHEK2 variants, 36% ATM, 14% BRIP1, 33% PALB2, and 30% with variants in BARD1, NF1, RAD51D, or RAD51C. 36% of those who met NCCN criteria had previously undergone clinical genetic testing. 29 of 33 (88%) women with a PH of breast cancer and 52 of 81 (64%) women with a FH of breast cancer met criteria. Conclusions: Current genetic testing criteria focus on identifying individuals harboring pathogenic variants in high penetrance cancer genes. However, in our study, a substantial portion of women with a pathogenic variant in a MP breast cancer gene also met such criteria, particularly when PH or FH of breast cancer were present. Only a third of those who met NCCN criteria had undergone clinical genetic testing. These findings suggest that the majority of women with genetic risk for breast cancer may be missed in clinical practice. Studies have shown that most physicians would change management strategies for patients with pathogenic variants, including variants in MP genes. As our understanding of genetic risk for breast cancer continues to evolve, we must explore strategies to improve identification and management of individuals with variants in MP breast cancer genes.
Twenty-one gene recurrence scores in individuals with breast cancer associated with CHEK2 and ATM germline pathogenic variants.
Authors: Shah Payal Deepak , Brower Jamie , Cuff Lauren , Richardville Robert , Hamilton Jada G. , Garber Judy Ellen , Yadav Siddhartha , Couch Fergus , Offit Kenneth , Domchek Susan M. , Robson Mark E.
Published: June 2023

10585

Background: The 21-gene recurrence score assay (Oncotype DX, Genomic Health Inc., CA) is prognostic, quantifies predicted benefit of adjuvant chemotherapy, and informs clinical decisions for patients with early-stage, hormone receptor-positive (HR+) breast cancer (BC). Differences in Oncotype recurrence scores (RS) in individuals with and without BRCA1 and BRCA2 pathogenic variants (PV) have been demonstrated, but the results of this assay in patients with BC and germline CHEK2 or ATM PV have not previously been described. This is of particular relevance as CHEK2 BC have been associated with a worse prognosis. Methods: Prospective Registry of MultiPlex Testing (PROMPT) is an online research registry for individuals who have had multigene panel testing for inherited cancer susceptibility. We retrospectively evaluated Oncotype DX recurrence scores from PROMPT participants (pts) with PV or likely PV in CHEK2 or ATM. Mood’s median tests were used to compare median RS, and Yates corrected Chi-square tests were used to compare RS distributions between carriers and a genetically unselected reference population. Results: Oncotype DX reports were reviewed for 75 pts with 77 BC (n = 50 pts with CHEK2 PV with 51 BC; n = 24 with ATM PV; n = 1 with CHEK2 and ATM PV with 2 BC). Among CHEK2 carriers, median RS was 17 (range 2-43) overall, 17 (2-36) for pts < age 50, and 18.5 (8-43) for pts ≥age 50 (p-value 0.47), with distributions not significantly different than reference ( < 50, p = 0.70; ≥50, p = 0.93). Ten pts had low penetrance CHEK2 alleles (p.S428F or p.I157T) with median RS 16 (9-28) compared to 18 (2-43) in those with other CHEK2 alleles (p = 0.35). Among ATM carriers, median RS was 17 (1-35) overall, 17 (1-35) for pts < age 50, and 16 (11-32) for pts ≥age 50 (p = 0.51), with distributions also not significantly different ( < 50, p = 0.78; ≥50, p = 0.79). Conclusions: Unlike data seen in BC associated with BRCA1 and BRCA2, Oncotype DX RS in individuals with CHEK2 and ATM-associated BC are similar to the published genetically unselected commercial database median RS of 16, with no clear difference based on penetrance of CHEK2 allele. Proportions of patients < 50 and ≥50 with CHEK2 and ATM PV with RS within the range for chemoendocrine therapy consideration are also similar to the historical reference. The inferior prognosis that has been suggested in CHEK2 BC is not reflected in Oncotype DX RS. [Table: see text]
Evaluating interventions to increase the uptake of NCCN genetic counseling recommendations.
Authors: Stempel Sophie , Paul Shirlene , McPeek Chelsea , Levy Mia Alyce , Alvarado Rosalinda
Published: June 2023

10599

Background: Genetic counseling for hereditary breast cancer remains underutilized despite increased access. The lack of identification and/or referral of high-risk women for genetic counseling is the major contributor to the poor uptake. A cancer risk assessment program (CRA) utilizing NCCN guidelines was implemented in our breast imaging department to identify women at increased risk for breast cancer. We analyzed the impact of informing all women who get a screening mammogram of their genetic mutation risk and the effect of nurse navigation on increasing the subsequent uptake of genetic counseling. Methods: To assess the effectiveness of these interventions, data from July 2021 to January 2022 was extracted from the EMR and grouped into cohorts based on nurse navigation contact and the completion of genetic counseling. A chi-squared analysis was performed to determine the significance of the results. Results: A total of 22,915 patients participated in the CRA program during the study period. 2,671 (11.7%) patients qualified for genetic counseling based on NCCN guidelines. 414 (15.5%) of these patients completed a genetic counseling appointment. 298 of these patients received genetic testing (72%) and 18 (4.3%) had a pathogenic mutation found. The nurse navigator was able to reach 1,288 (48%) of the 2,671 patients (Cohort A). Of these patients, 324 (25.2%) completed genetic counseling appointments compared to 90 of the 1,383 (6.5%) patients who were not contacted by the nurse navigator (Cohort B). Statistical analysis determined there was a significant difference in uptake of genetic counseling between Cohort A and Cohort B (p<.0001). Conclusions: The implementation of the CRA program at the breast imaging center uncovered many patients who qualified for genetic counseling and testing based on NCCN guidelines. Genetic counseling uptake is significantly increased in patients who are reached by a Nurse Navigator. These interventions allowed for the discovery of unsuspected deleterious genetic mutations which require more aggressive screening to allow for the early detection of breast cancer and better overall prognosis. [Table: see text]
Digital cancer genetic risk assessment in a gynecologic oncology clinic.
Authors: Webster Emily M. , Ahsan Muhammad Danyal , Perez Luiza , Bull Leslie , Keenahan Laura , Levi Sarah R. , Kieran Shannon M. , Cantillo Evelyn , Chapman-Davis Eloise , Holcomb Kevin , Sharaf Ravi N. , Frey Melissa Kristen
Published: June 2023

10612

Background: Population-based screening for hereditary cancer syndromes and referral of those who screen positive for genetic testing is a cost effective, evidence-based national health priority. However, under-recognition of hereditary cancer syndromes remains a critical concern, with fewer than 20% of individuals with Hereditary Breast and Ovarian Cancer Syndrome and Lynch Syndrome identified. Here, we evaluate the Ambry Genetics Comprehensive, Assessment, Risk, and Education (CARE) Program, a risk-stratification tool to assess eligibility for National Comprehensive Cancer Network (NCCN) genetic testing criteria and lifetime risk for breast cancer based on the Tyrer-Cuzick (version 8.0) risk algorithm. Methods: Between November 2022 and February 2023, new patients in a gynecologic oncology clinic were prompted by text message to complete CARE prior to their appointment. Those using CARE then completed a System Usability Scale (SUS), a validated 10-item questionnaire for the assessment of perceived usability. Results: Sixty patients presented for a new patient gynecologic oncology appointment and were prompted to complete CARE. The median patient age was 55 years (interquartile range, 40-68). The patients self-identified as Non-Hispanic White (44, 73%), Non-Hispanic Black (5, 8%), Asian (5, 8%), Hispanic (3, 5%), other (2, 3%), and unknown (1, 2%). All identified as female. Forty-three patients (72%) completed CARE. Among CARE users, 11 (26%) were identified as meeting criteria for genetic testing; of these, 9 (82%) proceeded with point-of-care same day genetic testing. Nine (21%) patients were eligible for enhanced breast cancer screening based on an estimated lifetime breast cancer risk of 20% or greater; of these, 100% were referred for high-risk breast screening. There were no patient demographics associated with completion of CARE. Forty-one patients (72%) completed the SUS survey; the median SUS score was 80 (interquartile range, 60-92.5), which corresponded to 85-89th percentile and a letter grade of A-. Conclusions: Implementation of a digital tool for cancer genetic risk assessment identified a quarter of patients to be eligible for genetic testing, among whom 82% completed same-day genetic testing. Additionally, the tool was reviewed favorably by patient users. Large randomized controlled trials of health information technology tools are needed to move closer to the goal of population-based hereditary cancer risk assessment.
Impact of risk-reducing mastectomy on quality of life of women with Li-Fraumeni syndrome.
Authors: Polidorio Natalia , Sandoval Renata Lazari , Bioni Pâmela , Achatz Maria Isabel Waddington
Published: June 2023

10623

Background: Risk-reducing mastectomy (RRM) is a common strategy for managing breast cancer (BC) risk in women with Li-Fraumeni syndrome (LFS). Data on uptake and health-related quality of life (HRQoL) in LFS are limited and often extrapolated from BRCA scenario, despite the lack of evidence on survival benefits in LFS. This study evaluated RRM uptake and its impact on HRQoL in women with LFS. Methods: TP53 PV female carriers from a Brazilian LFS cohort from January 2012 to December 2022 were eligible. After informed consent, 90 women reported oncological status, uptake of RRM, and completed BREAST-Q questionnaire. Scores were compared among different BC risk management strategies and minimal important difference (MID) of ≥ 4 was described. Multivariable analyses were performed to identify surgical factors related to HRQoL outcomes. Results: 71.7% (n=33) of women diagnosed with unilateral BC (n=46) underwent contralateral risk-reducing mastectomy (CRRM) at a median age of 39 years. Among unaffected BC women (n=44), 36.3% underwent bilateral risk-reducing mastectomy (BRRM) at a median age of 36 years. CRRM was associated with lower scores for psychosocial (64[±19] vs 93[±21], p=.05) and physical well-being (72[±16] vs 92[±18], p=.001). BRRM women had lower physical well-being scores (72[±19] vs 92[±13], p=.003). MID associated with worst HRQoL outcomes were seen in all four domains on CRRM women and on satisfaction with breasts and physical well-being of BRRM patients (table). Nipple-sparing mastectomy (NSM) presented better psychosocial (74[±20] vs 52[±19], p=.04) and sexual well-being (60[±20] vs 46[±20], p=.05) when compared to skin-sparing mastectomy (SSM) on CRRM patients and with higher sexual well-being (60[±20] vs 46[±20], p=.05) on BRRM patients. Women with BRRM > 2 years had better physical well-being (83[±14] vs 56 [±12], p<.001). There were no significant differences in scores of women with age £35 years at the time of BRRM, although MID ≥ 4 was observed on psychosocial and sexual well-being and satisfaction with breasts: -23.0, -14.4, and -20.0, respectively. Conclusions: We observed high rates of RRM in LFS women and those were associated with worse outcomes on breast HRQoL in comparison to surveillance. The potential benefits and harms of RRM should be carefully discussed with patients before performing it, especially in LFS women where the survival benefits of these interventions remain uncertain. [Table: see text]
Validation of a breast cancer polygenic risk score in 15,490 Brazilians using exome sequencing.
Authors: Eichemberger Rius Flavia , Guindalini Rodrigo Santa Cruz , Viana Danilo , Salomão Júlia , Gallo Laila , Bertolacini Claudia , Mendes de Freitas Renata , Taniguti Lucas , Imparato Danilo , Zheng Yonglan , Huo Dezheng , Olopade Olufunmilayo I. , Schlesinger David
Published: June 2023

10631

Background: Brazil has a highly admixed population with significant Southern European, African and Native American genetic ancestries. Approximately 75% of the population has two or more continental ancestries. Therefore, breast cancer polygenic risk scores (PRS) developed in predominantly European populations requires validation in the Brazilian population. Compared with genotyping arrays and whole genome sequencing, affordable and scalable whole exome sequencing (WES) allows genotyping of both rare and common variants in the targeted regions and imputation of common variants not directly captured. In this study we validate a previously developed 3820-variant PRS using WES in 15,490 Brazilians. Methods: The cohort consisted of 6,362 women with a history of breast cancer (mean age 49.6, stddev 11.6) and 9,128 unphenotyped adults as controls (mean age 41.6, stddev 13.3). WES were performed on germline DNA and variants were called and curated. Imputation was done using the 1000 Genomes Phase 3 reference panel for variants falling outside the WES captured regions. After excluding subjects with known pathogenic or likely pathogenic variants in BRCA1, BRCA2, PALB2, PTEN, or TP53, and first or second-degree relatives of the probands, 14,577 individuals remained in the final analysis (5,730 cases and 8,847 controls). We restricted PRS calculation to 2,893 of the original 3,820 variants with an estimated global imputation accuracy of 96%. Odds ratios (OR) were adjusted using the top 10 principal components. Results: The breast cancer PRS showed a highly significant correlation with cancer risk (p-value = 7.1e-81, OR = 1.43, 95% confidence interval (CI) = 1.38-1.48 per PRS standard deviation). Compared with women in the middle deciles, those in the highest 10% had an OR of 1.93, while those in the lowest 10% had an OR of 0.52 (Table). Conclusions: In this study we show that WES can capture 76% of the variants included in a previously developed and validated breast cancer PRS, and the calculated PRS is correlated with breast cancer risk in the admixed Brazilian population. This opens the door for clinical studies into the application of PRS in Brazil, particularly in women without mutations in breast cancer high-penetrance genes. In addition, our WES-based PRS strategy can be quickly, affordably, and seamlessly adopted by labs that already offer Hereditary Breast Cancer panels that use WES as a backbone. [Table: see text]
Pre-diagnosis dietary patterns and risk of multiple myeloma in the NIH-AARP cohort.
Authors: Parikh Richa , Castro Francesca , Eustaquio Jelyn C. , Derkach Andriy , Joseph Janine , Lesokhin Alexander M. , Usmani Saad Zafar , Shah Urvi A
Published: June 2023

10635

Background: Despite patient interest in knowing whether diet is linked to multiple myeloma (MM), there is limited research on dietary patterns and MM risk (Malik et al. BCJ 2022). Two studies have assessed this risk, albeit with a small number of MM cases. The EPIC-Oxford cohort and Oxford Vegetarian study (65 MM cases) showed that fish eaters, vegetarians and vegans had significantly reduced MM risk compared to meat eaters (Key et al. AJCN 2014). The Nurses’ Health Study and Health Professionals Follow-up Study (478 MM cases) showed a significantly increased MM risk in men with Empirical Dietary Inflammatory Pattern (Lee et al. JNCI Can Spectr 2019). To our knowledge, this is the largest epidemiologic study to date assessing pre-diagnosis dietary patterns and MM risk. Methods: The NIH-AARP Diet and Health study is a prospective cohort of 567,169 persons who completed a food frequency questionnaire in 1995-1996 and were followed until December 2011. Healthy Eating Index-2015 (HEI-2015), Healthy Diet Score (HDS), alternate Mediterranean Diet (aMED) and healthful Plant-based Diet Index (hPDI) scores were calculated using a priori defined methods and grouped into quartiles, with higher scores reflecting healthier eating patterns. We prospectively evaluated the association between pre-diagnosis dietary patterns and MM incidence in this cohort. Hazard ratios (HR) and 95% confidence intervals (95%CI) were estimated using multivariate Cox proportional hazards models adjusted for age at study entry, sex, race, body mass index, education, and total energy intake (by residual method). Sensitivity analysis was conducted to assess reverse causality by excluding MM cases diagnosed within one year of follow-up. Results: Among 392,589 participants (after exclusions), a total of 1,366 MM cases (59% males; 92% non-Hispanic whites) were identified during the follow-up period. Analysis revealed a significant association between hPDI scores and reduced MM risk (highest vs lowest quartile, HR 0.85; 95%CI 0.73-1.0; p=0.043) (Table). In sensitivity analysis (1,302 MM cases), the association was no longer significant (HR 0.87; 95%CI 0.74-1.03; p 0.09) but trended in the same direction. This may be due to small sample size, given MM is a rare disease. HEI-2015, HDS and aMED scores were not associated with MM risk. Conclusions: A healthful plant-based diet was associated with reduced MM risk in the NIH-AARP cohort. These results will help oncologists and patients make informed choices about their diet. [Table: see text]
Indirect treatment comparison of first-line CDK4/6-inhibitors in post-menopausal patients with HR+/HER2- metastatic breast cancer.
Authors: Zhao Joseph J , Fong Khi Yung , Chan Yiong Huak , Tey Jeremy Chee Seong , Dawood Shaheenah S. , Lee Soo-Chin , Finn Richard S. , Sundar Raghav , Lim Joline SJ
Published: June 2023

1071

Background: In phase III studies, the CDK4/6-inhibitors palbociclib, ribociclib, and abemaciclib all have demonstrated similar clinical efficacy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC) with regards to the primary endpoint of progression-free survival (PFS). However, the lack of overall survival (OS) benefit in the PALOMA-2 study is inconsistent with the OS benefit seen with the other two CDK4/6-inhibitors. This study sought to elucidate indirect treatment survival outcomes between CDK4/6-inhibitors in this setting. Methods: Phase III randomized controlled trials comparing first-line aromatase inhibitor with or without a CDK4/6-inhibitor in post-menopausal patients with HR+/HER2- MBC. A graphical reconstructive algorithm was utilized to retrieve patient level time-to-event data from reported Kaplan-Meier OS and PFS curves. Survival analyses were conducted with Cox proportional hazards model with a shared-frailty term incorporated to account for inter-study differences. Two-stage indirect treatment comparison model was conducted as a sensitivity analysis. Results: Three randomized phase III trials – PALOMA-2, MONALEESA-2 and MONARCH-3 – comprising 1,827 patients were included. Indirect pairwise comparison of all CDK4/6-inhibitor showed no significant PFS differences across one-stage and two-stage models (all p>0.05). Likewise, indirect treatment comparison between ribociclib vs palbociclib (one-stage: HR=0.903, 95%-CI: 0.746-1.094, p=0.297), abemaciclib vs palbociclib (one-stage: HR=0.843, 95%-CI: 0.690-1.030, p=0.094) and abemaciclib vs ribociclib (one-stage: HR=0.933, 95%-CI: 0.753-1.157, p=0.528) failed to demonstrate a significant OS difference. Conclusions: Findings from this indirect treatment comparison suggest no significant PFS or OS differences between CDK4/6-inhibitor agents when combined with an aromatase inhibitor in post-menopausal patients with HR+/HER- MBC. [Table: see text]
Clinical outcomes and correlation with longitudinal circulating tumor (ct)DNA dynamics of a phase I/II study of GSK525762 combined with fulvestrant in patients with hormone receptor-positive/HER2-negative (HR+/HER2−) advanced or metastatic breast cancer.
Authors: Cescon David W. , Hilton John Frederick , Hicks Kirsty , Zhang Qu , Barbash Olena , Dhar Arindam , Oliveira Mafalda , Sparano Joseph A.
Published: June 2023

1073

Background: Endocrine therapy is the main treatment option for hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer (mBC). However, many patients experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extra-terminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Pre-clinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy (objective response rate [ORR]) of molibresib combined with fulvestrant in women with HR+/HER2− mBC. The association between early ctDNA dynamics and clinical outcomes was also assessed. Methods: In this phase I/II dose-escalation and expansion study, patients received oral molibresib 60 mg or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2− BC with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Baseline and week 4 plasma samples were collected and tested using a 74-gene ctDNA panel. Molecular response (MR) was defined as at least 50% reduction of baseline ctDNA level calculated as the average allele frequency of detected single nucleotide variants or indels. Results: The study included 123 patients. The 3 most common molibresib-related adverse events (AEs) were nausea (52%), dysgeusia (49%), and fatigue (44%). At molibresib 60 mg, >90% patients experienced treatment-related AEs, with varying incidence of Grade ≥3 AEs (17%–71%) amongst subgroups. The ORR was 13% (95% confidence interval [CI], 8–20), not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected baseline circulating tumor DNA, a strong association was observed between baseline copy number amplification (CNA) presence and poor progression-free survival (PFS) with hazard ratio (HR) of 2.89 (95% CI, 1.73–4.83; P < 0.0001). MR was significantly correlated with better PFS (HR=0.38; 95% CI, 0.19–0.75; P = 0.0037), which was further improved when MR was refined as no baseline CNA (HR=0.22; 95% CI, 0.09–0.54; P = 0.0003). Conclusions: Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study. Copy number adjusted ctDNA MR is a promising early marker for clinical benefit. Clinical trial information: NCT02964507 .