Unraveling the genetic landscape of susceptibility to multiple primary cancers.

With advances in cancer screening and treatment, there is a growing population of cancer survivors who may develop subsequent primary cancers. While hereditary cancer syndromes account for only a portion of multiple cancer cases, we sought to explore the role of common genetic variation in susceptibility to multiple primary tumors. We conducted a cross-ancestry genome-wide association study (GWAS) and transcriptome-wide association study (TWAS) of 10,983 individuals with multiple primary cancers, 84,475 individuals with single cancer, and 420,944 cancer-free controls from two large-scale studies.

PTEN pathogenic variants are associated with poor prognosis in patients with advanced soft tissue sarcoma.

Background: We aimed to examine whether PTEN pathogenic variants (mutPTEN) were associated with overall survival (OS) in patients with advanced soft tissue sarcoma (STS) with the presence of one or more of the most common genomic alterations including p53, CDKN2A, RB1, and ATRX pathogenic variants.

Methods: This study included patients from Kaiser Permanente Northern California and Stanford Cancer Center with grade 2 or higher locally advanced and metastatic STS.

Results: A total of 174 patients had leiomyosarcoma (LMS), 136 had undifferentiated pleomorphic sarcoma (UPS), 78 had Liposarcoma (LPS), and 214 had other histology subtypes (Others).

Mainstream Germline Genetic Testing with Expanded Eligibility for Early Breast Cancer Patients in a Large Integrated Health System.

Background: This study evaluated a new mainstream genetic testing pathway for hereditary cancer, with expanded eligibility for early-stage breast cancer patients.

Methods: The study compared multigene panel (62 genes) germline testing uptake and results for breast cancer patients at 4 pilot sites (n = 502 patients) and 10 non-pilot sites (n = 1792 patients) within Kaiser Permanente Northern California from December 2020, to June 2021. At the pilot sites, breast care coordinators (BCCs) offered and consented patients for testing, with eligibility expanded to include all patients age 65 years or younger.

Relative contribution of COVID-19 vaccination and SARS-CoV-2 infection to population-level seroprevalence of SARS-CoV-2 spike antibodies in a large integrated health system.

Background: Understanding the relative contributions of SARS-CoV-2 infection-induced and vaccine-induced seroprevalence is key to measuring overall population-level seroprevalence and help guide policy decisions.

Methods: Using a series of six population-based cross-sectional surveys conducted among persons aged ≥7 years in a large health system with over 4.5 million members between May 2021 and April 2022, we combined data from the electronic health record (EHR), an electronic survey and SARS-CoV-2 spike antibody binding assay, to assess the relative contributions of infection and vaccination to population-level SARS-CoV-2 seroprevalence.

Mammographic density mediates the protective effect of early-life body size on breast cancer risk.

The unexplained protective effect of childhood adiposity on breast cancer risk may be mediated via mammographic density (MD). Here, we investigate a complex relationship between adiposity in childhood and adulthood, puberty onset, MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)), and their effects on breast cancer. We use Mendelian randomization (MR) and multivariable MR to estimate the total and direct effects of adiposity and age at menarche on MD phenotypes.

Relative contribution of COVID-19 vaccination and SARS-CoV-2 infection to population-level seroprevalence of SARS-CoV-2 spike antibodies in a large integrated health system.

Background: Understanding the relative contributions of SARS-CoV-2 infection-induced and vaccine- induced seroprevalence is key to measuring overall population-level seroprevalence and help guide policy decisions.

Methods: Using a series of six population-based cross-sectional surveys conducted among persons aged ≥7 years in a large health system with over 4.5 million members between May 2021 and April 2022, we combined data from the electronic health record (EHR), an electronic survey and SARS-CoV-2 spike antibody binding assay, to assess the relative contributions of infection and vaccination to population- level SARS-CoV-2 seroprevalence.

Longitudinal Changes in Sex Hormone Binding Globulin (SHBG) and Risk of Incident Diabetes: The Study of Women's Health Across the Nation (SWAN).

Objective: To investigate the associations of longitudinal changes in sex hormone binding globulin (SHBG) and testosterone (T) over the menopause transition with the risk of diabetes.

Research Design And Methods: We followed 2,952 participants in the Study of Women's Health Across the Nation (SWAN) who were premenopausal or early perimenopausal and diabetes-free at baseline. SHBG,T, and estradiol (E2) levels were measured at up to 13 follow-up visits (over up to 17 years).

Mode of Detection of Second Breast Cancers in Patients Undergoing Surveillance After Treatment of Ductal Carcinoma in Situ.

Background: For patients undergoing posttreatment surveillance after ductal carcinoma in situ (DCIS), the NCCN Guidelines for Breast Cancer recommend annual breast imaging and physical examination every 6 to 12 months for 5 years, and then annually. The aim of our study was to evaluate the modes of detection (imaging, patient reported, or physical examination) of second cancers in a cohort of patients undergoing surveillance after primary DCIS treatment to better inform surveillance recommendations.

Methods: We performed a retrospective cohort study of patients with DCIS treated between January 1, 2008, and December 31, 2011, within a large integrated health care system.

Evaluation of the international Ki67 working group cut point recommendations for early breast cancer: comparison with 21-gene assay results in a large integrated health care system.

Purpose: The International Ki67 Working Group (IKWG) has developed training for immunohistochemistry (IHC) scoring reproducibility and recommends cut points of ≤ 5% and ≥ 30% for prognosis in ER+, HER2-, stage I/II breast cancer. We examined scoring reproducibility following IKWG training and evaluated these cut points for selecting patients for further testing with the 21-gene Recurrence Score (RS) assay.

Methods: We included 307 women aged 50+ years with node-negative, ER+PR+HER2- breast cancer and with available RS results.

Sex-dependent Prognosis of Patients with Advanced Soft Tissue Sarcoma.

Purpose: To examine whether overall survival (OS) differs for male and female patients with advanced soft-tissue sarcoma (STS).

Experimental Design: The study included patients from Kaiser Permanente Northern California and Stanford Cancer Center with grade 2 and 3 locally advanced or metastatic STS whose tumor underwent next-generation sequencing. We used Cox regression modeling to examine association of sex and OS adjusting for other important factors.

The mediating role of mammographic density in the protective effect of early-life adiposity on breast cancer risk: a multivariable Mendelian randomization study.

Observational studies suggest that mammographic density (MD) may have a role in the unexplained protective effect of childhood adiposity on breast cancer risk. Here, we investigated a complex and interlinked relationship between puberty onset, adiposity, MD, and their effects on breast cancer using Mendelian randomization (MR). We estimated the effects of childhood and adulthood adiposity, and age at menarche on MD phenotypes (dense area (DA), non-dense area (NDA), percent density (PD)) using MR and multivariable MR (MVMR), allowing us to disentangle their total and direct effects.

Examination of fully automated mammographic density measures using LIBRA and breast cancer risk in a cohort of 21,000 non-Hispanic white women.

Background: Breast density is strongly associated with breast cancer risk. Fully automated quantitative density assessment methods have recently been developed that could facilitate large-scale studies, although data on associations with long-term breast cancer risk are limited. We examined LIBRA assessments and breast cancer risk and compared results to prior assessments using Cumulus, an established computer-assisted method requiring manual thresholding.

Germline Genetic Testing Among Women ≤ 45 Years of Age with Ductal Carcinoma In Situ Versus Invasive Breast Cancer in a Large Integrated Health Care System.

Background: We compared the results of hereditary cancer multigene panel testing among patients ≤ 45 years of age diagnosed with ductal carcinoma in situ (DCIS) versus invasive breast cancer (IBC) in a large integrated health care system.

Methods: A retrospective cohort study of hereditary cancer gene testing among women ≤ 45 years of age diagnosed with DCIS or IBC at Kaiser Permanente Northern California between September 2019 and August 2020 was performed. During the study period, institutional guidelines recommended the above population be referred to genetic counselors for pretesting counseling and testing.

Sex- and Co-Mutation-Dependent Prognosis in Patients with SMARCA4-Mutated Malignancies.

Background: Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear.

Methods: This cohort included patients from Northern California Kaiser Permanente with next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and , , , , and co-mutations.

Comparison of Mammography AI Algorithms with a Clinical Risk Model for 5-year Breast Cancer Risk Prediction: An Observational Study.

Background Although several clinical breast cancer risk models are used to guide screening and prevention, they have only moderate discrimination. Purpose To compare selected existing mammography artificial intelligence (AI) algorithms and the Breast Cancer Surveillance Consortium (BCSC) risk model for prediction of 5-year risk. Materials and Methods This retrospective case-cohort study included data in women with a negative screening mammographic examination (no visible evidence of cancer) in 2016, who were followed until 2021 at Kaiser Permanente Northern California.

The application of lag times in cancer pharmacoepidemiology: a narrative review.

Purpose: With the increasing utilization of medications worldwide, coupled with the increasing availability of long-term data, there is a growing opportunity and need for robust studies evaluating drug-cancer associations. One methodology of importance in such studies is the application of lag times.

Methods: In this narrative review, we discuss the main reasons for using lag times.

Gain-of-Function and Non-Gain-of-Function Mutations Are Associated With Differential Prognosis in Advanced Pancreatic Ductal Adenocarcinoma.

Purpose: To examine the impact of gain-of-function (GOF) and non-GOF mutations on prognosis of advanced pancreatic ductal adenocarcinoma (PDAC) among patients with , , and comutations.

Methods: This cohort included patients with locally advanced, recurrent, and de novo metastatic PDAC with next-generation sequencing performed from November 2017 to May 2022. We defined R175H, R248W, R248Q, R249S, R273H, R273L, and R282W as GOF and all other p53 mutations (mutp53) as non-GOF.

Breast Cancer Recurrence by Subtype in a Diverse, Contemporary Cohort of Young Women.

Background: Young breast cancer (YBC) patients are a unique subpopulation that are often underrepresented in randomized clinical trials. Furthermore, large national cancer databases lack detailed information on recurrence, a meaningful oncologic outcome for young patients.

Study Design: A retrospective review of YBC patients (age 40 years or younger) with stage I to III breast cancer diagnosed from 2008 to 2018 was performed.

Identification of Drug-Cancer Associations: A Nationwide Screening Study.

Unlabelled: The main tool in drug safety monitoring, spontaneous reporting of adverse effects, is unlikely to detect delayed adverse drug effects including cancer. Hypothesis-free screening studies based on administrative data could improve ongoing drug safety monitoring. Using Danish health registries, we conducted a series of case-control studies by identifying individuals with incident cancer in Denmark from 2001 to 2018, matching each case with 10 population controls on age, sex, and calendar time.

Assessment of genetic susceptibility to multiple primary cancers through whole-exome sequencing in two large multi-ancestry studies.

Background: Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored.

Methods: To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls).

Telehealth for Preoperative Evaluation of Patients With Breast Cancer During the COVID-19 Pandemic.

Introduction The COVID-19 pandemic drove rapid, widespread adoption of telehealth (TH). We evaluated surgical telehealth utilization and outcomes for newly diagnosed breast cancer patients during the initial pandemic period. Methods We identified patients with breast cancer diagnosed March 17, 2020 through May 17, 2020 who underwent surgery as the initial treatment.

Anti-Müllerian hormone levels and breast cancer risk in the study of women's health across the nation.

Purpose: The relation of premenopausal anti-Müllerian hormone (AMH) levels with breast cancer risk has been evaluated in a few studies, but primarily in non-Hispanic White women.

Methods: We evaluated the association of AMH levels with breast cancer risk in Study of Women's Health Across the Nation (SWAN), a multi-ethnic cohort of women. At enrollment, participants had an intact uterus and ≥ 1 ovary, and ≥ 1 menstrual period in the last 3 months.