Cancer screening with multicancer detection tests: A translational science review.

Multicancer detection (MCD) tests use a single, easily obtainable biospecimen, such as blood, to screen for more than one cancer concurrently. MCD tests can potentially be used to improve early cancer detection, including cancers that currently lack effective screening methods. However, these tests have unknown and unquantified benefits and harms. MCD tests differ from conventional cancer screening tests in that the organ responsible for a positive test is unknown, and a broad diagnostic workup may be necessary to confirm the location and type of underlying cancer. Among two prospective studies involving greater than 16,000 individuals, MCD tests identified those who had some cancers without currently recommended screening tests, including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies, at early stages. Reported MCD test sensitivities range from 27% to 95% but differ by organ and are lower for early stage cancers, for which treatment toxicity would be lowest and the potential for cure might be highest. False reassurance from a negative MCD result may reduce screening adherence, risking a loss in proven public health benefits from standard-of-care screening. Prospective clinical trials are needed to address uncertainties about MCD accuracy to detect different cancers in asymptomatic individuals, whether these tests can detect cancer sufficiently early for effective treatment and mortality reduction, the degree to which these tests may contribute to cancer overdiagnosis and overtreatment, whether MCD tests work equally well across all populations, and the appropriate diagnostic evaluation and follow-up for patients with a positive test.

Challenges to Using Big Data in Cancer.

Big data in healthcare can enable unprecedented understanding of diseases and their treatment, particularly in oncology. These data may include electronic health records, medical imaging, genomic sequencing, payor records, and data from pharmaceutical research, wearables, and medical devices. The ability to combine datasets and use data across many analyses is critical to the successful use of big data and is a concern for those who generate and use the data. Interoperability and data quality continue to be major challenges when working with different healthcare datasets. Mapping terminology across datasets, missing and incorrect data, and varying data structures make combining data an onerous and largely manual undertaking. Data privacy is another concern addressed by the Health Insurance Portability and Accountability Act, the Common Rule, and the General Data Protection Regulation. The use of big data is now included in the planning and activities of the FDA and the European Medicines Agency. The willingness of organizations to share data in a precompetitive fashion, agreements on data quality standards, and institution of universal and practical tenets on data privacy will be crucial to fully realizing the potential for big data in medicine.

Case Studies for Overcoming Challenges in Using Big Data in Cancer.

The analysis of big healthcare data has enormous potential as a tool for advancing oncology drug development and patient treatment, particularly in the context of precision medicine. However, there are challenges in organizing, sharing, integrating, and making these data readily accessible to the research community. This review presents five case studies illustrating various successful approaches to addressing such challenges. These efforts are CancerLinQ, the American Association for Cancer Research Project GENIE, Project Data Sphere, the National Cancer Institute Genomic Data Commons, and the Veterans Health Administration Clinical Data Initiative. Critical factors in the development of these systems include attention to the use of robust pipelines for data aggregation, common data models, data deidentification to enable multiple uses, integration of data collection into physician workflows, terminology standardization and attention to interoperability, extensive quality assurance and quality control activity, incorporation of multiple data types, and understanding how data resources can be best applied. By describing some of the emerging resources, we hope to inspire consideration of the secondary use of such data at the earliest possible step to ensure the proper sharing of data in order to generate insights that advance the understanding and the treatment of cancer.

Quantitating and assessing interoperability between electronic health records.

OBJECTIVES: Electronic health records (EHRs) contain a large quantity of machine-readable data. However, institutions choose different EHR vendors, and the same product may be implemented differently at different sites. Our goal was to quantify the interoperability of real-world EHR implementations with respect to clinically relevant structured data. MATERIALS AND METHODS: We analyzed de-identified and aggregated data from 68 oncology sites that implemented 1 of 5 EHR vendor products. Using 6 medications and 6 laboratory tests for which well-accepted standards exist, we calculated inter- and intra-EHR vendor interoperability scores. RESULTS: The mean intra-EHR vendor interoperability score was 0.68 as compared to a mean of 0.22 for inter-system interoperability, when weighted by number of systems of each type, and 0.57 and 0.20 when not weighting by number of systems of each type. DISCUSSION: In contrast to data elements required for successful billing, clinically relevant data elements are rarely standardized, even though applicable standards exist. We chose a representative sample of laboratory tests and medications for oncology practices, but our set of data elements should be seen as an example, rather than a definitive list. CONCLUSIONS: We defined and demonstrated a quantitative measure of interoperability between site EHR systems and within/between implemented vendor systems. Two sites that share the same vendor are, on average, more interoperable. However, even for implementation of the same EHR product, interoperability is not guaranteed. Our results can inform institutional EHR selection, analysis, and optimization for interoperability.

The FDA Oncology Center of Excellence Scientific Collaborative: Charting a Course for Applied Regulatory Science Research in Oncology.

The FDA Oncology Center of Excellence (OCE) is a leader within the agency in scientific outreach activities and regulatory science research. On the basis of analysis of scientific workshops, internal meetings, and publications, the OCE identified nine scientific priority areas and one cross-cutting area of high interest for collaboration with external researchers. This article describes the process for identifying these scientific interest areas and highlights funded and unfunded opportunities for external researchers to work with FDA staff on critical regulatory science challenges.

Impact of Broadening Trial Eligibility Criteria for Patients with Advanced Non-Small Cell Lung Cancer: Real-World Analysis of Select ASCO-Friends Recommendations.

PURPOSE: Cancer clinical trials often accrue slowly or miss enrollment targets. Strict eligibility criteria are a major reason. Restrictive criteria also limit opportunities for patient participation while compromising external validity of trial results. We examined the impact of broadening select eligibility criteria on characteristics and number of patients eligible for trials, using recommendations of the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research. EXPERIMENTAL DESIGN: A retrospective, observational analysis used electronic health record data from ASCO's CancerLinQ Discovery database. Study cohort included patients with advanced non-small cell lung cancer treated from 2011 to 2018. Patients were grouped by traditional criteria [no brain metastases, no other malignancies, and creatinine clearance (CrCl) ≥ 60 mL/minute] and broadened criteria (including brain metastases, other malignancies, and CrCl ≥ 30 mL/minute). RESULTS: The analysis cohort included 10,500 patients. Median age was 68 years, and 73% of patients were White. Most patients had stage IV disease (65%). A total of 5,005 patients (48%) would be excluded from trial participation using the traditional criteria. The broadened criteria, however, would allow 98% of patients (10,346) to be potential participants. Examination of patients included by traditional criteria (5,495) versus those added (4,851) by broadened criteria showed that the number of women, patients aged 75+ years, and those with stage IV cancer was significantly greater using broadened criteria. CONCLUSIONS: This analysis of real-world data demonstrated that broadening three common eligibility criteria has the potential to double the eligible patient population and include trial participants who are more representative of those encountered in practice.See related commentary by Giantonio, p. 2369.

Development of CancerLinQ, a Health Information Learning Platform From Multiple Electronic Health Record Systems to Support Improved Quality of Care.

PURPOSE: ASCO, through its wholly owned subsidiary, CancerLinQ LLC, developed CancerLinQ, a learning health system for oncology. A learning health system is important for oncology patients because less than 5% of patients with cancer enroll in clinical trials, leaving evidence gaps for patient populations not enrolled in trials. In addition, clinical trial populations often differ from the overall cancer population with respect to age, race, performance status, and other clinical parameters. MATERIALS AND METHODS: Working with subscribing practices, CancerLinQ accepts data from electronic health records and transforms the local representation of a patient's care into a standardized representation on the basis of the Quality Data Model from the National Quality Forum. CancerLinQ provides this information back to the subscribing practice through a series of tools that support quality improvement. CancerLinQ also creates de-identified data sets for secondary research use. RESULTS: As of March 2020, CancerLinQ includes data from 63 organizations across the United States that use nine different electronic health records. The database includes 1,426,015 patients with a primary cancer diagnosis, of which 238,680 have had additional information abstracted from unstructured content. CONCLUSION: As CancerLinQ continues to onboard subscribing practices, the breadth of potential applications for a learning health care system widen. Future practice-facing tools could include real-world data visualization, recommendations for treatment of patients with actionable genetic variations, and identification of patients who may be eligible for clinical trials. Feeding these insights back into oncology practice ensures that we learn how to treat patients with cancer not just on the basis of the selective experience of the 5% that enroll in clinical trials, but from the real-world experience of the entire spectrum of patients with cancer in the United States.

Next-Generation Sequencing and the Clinical Oncology Workflow: Data Challenges, Proposed Solutions, and a Call to Action.

PURPOSE: Next-generation sequencing (NGS) of tumor and germline DNA is foundational for precision oncology, with rapidly expanding diagnostic, prognostic, and therapeutic implications. Although few question the importance of NGS in modern oncology care, the process of gathering primary molecular data, integrating it into electronic health records, and optimally using it as part of a clinical workflow remains far from seamless. Numerous challenges persist around data standards and interoperability, and clinicians frequently face difficulties in managing the growing amount of genomic knowledge required to care for patients and keep up to date. METHODS: This review provides a descriptive analysis of genomic data workflows for NGS data in clinical oncology and issues that arise from the inconsistent use of standards for sharing data across systems. Potential solutions are described. RESULTS: NGS technology, especially for somatic genomics, is well established and widely used in routine patient care, quality measurement, and research. Available genomic knowledge bases play an evolving role in patient management but lack harmonization with one another. Questions about their provenance and timeliness of updating remain. Potentially useful standards for sharing genomic data, such as HL7 FHIR and mCODE, remain primarily in the research and/or development stage. Nonetheless, their impact will likely be seen as uptake increases across care settings and laboratories. The specific use case of ASCO CancerLinQ, as a clinicogenomic database, is discussed. CONCLUSION: Because the electronic health records of today seem ill suited for managing genomic data, other solutions are required, including universal data standards and applications that use application programming interfaces, along with a commitment on the part of sequencing laboratories to consistently provide structured genomic data for clinical use.

BRCA Challenge: BRCA Exchange as a global resource for variants in BRCA1 and BRCA2.

The BRCA Challenge is a long-term data-sharing project initiated within the Global Alliance for Genomics and Health (GA4GH) to aggregate BRCA1 and BRCA2 data to support highly collaborative research activities. Its goal is to generate an informed and current understanding of the impact of genetic variation on cancer risk across the iconic cancer predisposition genes, BRCA1 and BRCA2. Initially, reported variants in BRCA1 and BRCA2 available from public databases were integrated into a single, newly created site, www.brcaexchange.org. The purpose of the BRCA Exchange is to provide the community with a reliable and easily accessible record of variants interpreted for a high-penetrance phenotype. More than 20,000 variants have been aggregated, three times the number found in the next-largest public database at the project's outset, of which approximately 7,250 have expert classifications. The data set is based on shared information from existing clinical databases-Breast Cancer Information Core (BIC), ClinVar, and the Leiden Open Variation Database (LOVD)-as well as population databases, all linked to a single point of access. The BRCA Challenge has brought together the existing international Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium expert panel, along with expert clinicians, diagnosticians, researchers, and database providers, all with a common goal of advancing our understanding of BRCA1 and BRCA2 variation. Ongoing work includes direct contact with national centers with access to BRCA1 and BRCA2 diagnostic data to encourage data sharing, development of methods suitable for extraction of genetic variation at the level of individual laboratory reports, and engagement with participant communities to enable a more comprehensive understanding of the clinical significance of genetic variation in BRCA1 and BRCA2.

Evidence synthesis and guideline development in genomic medicine: current status and future prospects.

PURPOSE: With the accelerated implementation of genomic medicine, health-care providers will depend heavily on professional guidelines and recommendations. Because genomics affects many diseases across the life span, no single professional group covers the entirety of this rapidly developing field. METHODS: To pursue a discussion of the minimal elements needed to develop evidence-based guidelines in genomics, the Centers for Disease Control and Prevention and the National Cancer Institute jointly held a workshop to engage representatives from 35 organizations with interest in genomics (13 of which make recommendations). The workshop explored methods used in evidence synthesis and guideline development and initiated a dialogue to compare these methods and to assess whether they are consistent with the Institute of Medicine report "Clinical Practice Guidelines We Can Trust." RESULTS: The participating organizations that develop guidelines or recommendations all had policies to manage guideline development and group membership, and processes to address conflicts of interests. However, there was wide variation in the reliance on external reviews, regular updating of recommendations, and use of systematic reviews to assess the strength of scientific evidence. CONCLUSION: Ongoing efforts are required to establish criteria for guideline development in genomic medicine as proposed by the Institute of Medicine.

Family history assessment: impact on disease risk perceptions.

BACKGROUND: Family Healthware™, a tool developed by the CDC, is a self-administered web-based family history tool that assesses familial risk for six diseases (coronary heart disease; stroke; diabetes; and colon, breast, and ovarian cancers) and provides personalized prevention messages based on risk. The Family Healthware Impact Trial (FHITr) set out to examine the clinical utility of presenting personalized preventive messages tailored to family history risk for improving health behaviors. PURPOSE: The purpose of this study was to examine the impact of Family Healthware on modifying disease risk perceptions, particularly among those who initially underestimated their risk for certain diseases. DESIGN: A total of 3786 patients were enrolled in a cluster-randomized trial to evaluate the clinical utility of Family Healthware. SETTING/PARTICIPANTS: Participants were recruited from 41 primary care practices among 13 states between 2005 and 2007. MAIN OUTCOME MEASURES: Perceived risk for each disease was assessed at baseline and 6-month follow-up using a single-item comparative risk question. Analyses were completed in March 2012. RESULTS: Compared to controls, Family Healthware increased risk perceptions among those who underestimated their risk for heart disease (15% vs 9%, p<0.005); stroke (11% vs 8%, p<0.05); diabetes (18% vs 11%, p<0.05); and colon cancer (17% vs 10%, p=0.05) but not breast or ovarian cancers. The majority of underestimators did not shift in their disease risk perceptions. CONCLUSIONS: Family Healthware was effective at increasing disease risk perceptions, particularly for metabolic conditions, among those who underestimated their risk. Results from this study also demonstrate the relatively resistant nature of risk perceptions. TRIAL REGISTRATION: This study is registered at clinicaltrials.govNCT00164658.

Alcohol and tobacco lower the age of presentation in sporadic pancreatic cancer in a dose-dependent manner: a multicenter study.

OBJECTIVES: The objective of this study was to examine the association between tobacco and alcohol dose and type and the age of onset of pancreatic adenocarcinoma (PancCa). METHODS: Prospective data from the Pancreatic Cancer Collaborative Registry were used to examine the association between age of onset and variables of interest including: gender, race, birth country, educational status, family history of PancCa, diabetes status, and tobacco and alcohol use. Statistical analysis included logistic and linear regression, Cox proportional hazard regression, and time-to-event analysis. RESULTS: The median age to diagnosis for PancCa was 66.3 years (95% confidence intervals (CIs), 64.5-68.0). Males were more likely than females to be smokers (77% vs. 69%, P=0.0002) and heavy alcohol and beer consumers (19% vs. 6%, 34% vs. 19%, P<0.0001). In univariate analysis for effects on PancCa presentation age, the following were significant: gender, alcohol and tobacco use (amount, status and type), family history of PancCa, and body mass index. Both alcohol and tobacco had dose-dependent effects. In multivariate analysis, alcohol status and dose were independently associated with increased risk for earlier PancCa onset with greatest risk occurring in heavy drinkers (HR 1.62, 95% CI 1.04-2.54). Smoking status had the highest risk for earlier onset pancreatic cancer with a HR of 2.69 (95% CI, 1.97-3.68) for active smokers and independent effects for dose (P=0.019). The deleterious effects for alcohol and tobacco appear to resolve after 10 years of abstinence. CONCLUSIONS: Alcohol and tobacco use are associated with a dose-related increased risk for earlier age of onset of PancCa. Although beer drinkers develop pancreatic cancer at an earlier age than nondrinkers, alcohol type did not have a significant effect after controlling for alcohol dose.

Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.

Genome- and exome-sequencing costs are continuing to fall, and many individuals are undergoing these assessments as research participants and patients. The issue of secondary (so-called incidental) findings in exome analysis is controversial, and data are needed on methods of detection and their frequency. We piloted secondary variant detection by analyzing exomes for mutations in cancer-susceptibility syndromes in subjects ascertained for atherosclerosis phenotypes. We performed exome sequencing on 572 ClinSeq participants, and in 37 genes, we interpreted variants that cause high-penetrance cancer syndromes by using an algorithm that filtered results on the basis of mutation type, quality, and frequency and that filtered mutation-database entries on the basis of defined categories of causation. We identified 454 sequence variants that differed from the human reference. Exclusions were made on the basis of sequence quality (26 variants) and high frequency in the cohort (77 variants) or dbSNP (17 variants), leaving 334 variants of potential clinical importance. These were further filtered on the basis of curation of literature reports. Seven participants, four of whom were of Ashkenazi Jewish descent and three of whom did not meet family-history-based referral criteria, had deleterious BRCA1 or BRCA2 mutations. One participant had a deleterious SDHC mutation, which causes paragangliomas. Exome sequencing, coupled with multidisciplinary interpretation, detected clinically important mutations in cancer-susceptibility genes; four of such mutations were in individuals without a significant family history of disease. We conclude that secondary variants of high clinical importance will be detected at an appreciable frequency in exomes, and we suggest that priority be given to the development of more efficient modes of interpretation with trials in larger patient groups.

Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers.

PURPOSE: Mutations in BRCA1/2 dramatically increase the risk of both breast and ovarian cancers. Three mutations in these genes (185delAG, 5382insC, and 6174delT) occur at high frequency in Ashkenazi Jews. We evaluated how these common Jewish mutations (CJMs) affect cancer risks and risk reduction. METHODS: Our cohort comprised 4,649 women with disease-associated BRCA1/2 mutations from 22 centers in the Prevention and Observation of Surgical End Points Consortium. Of these women, 969 were self-identified Jewish women. Cox proportional hazards models were used to estimate breast and ovarian cancer risks, as well as risk reduction from risk-reducing salpingo-oophorectomy (RRSO), by CJM and self-identified Jewish status. RESULTS: Ninety-one percent of Jewish BRCA1/2-positive women carried a CJM. Jewish women were significantly more likely to undergo RRSO than non-Jewish women (54% v 41%, respectively; odds ratio, 1.87; 95% CI, 1.44 to 2.42). Relative risks of cancer varied by CJM, with the relative risk of breast cancer being significantly lower in 6174delT mutation carriers than in non-CJM BRCA2 carriers (hazard ratio, 0.35; 95% CI, 0.18 to 0.69). No significant difference was seen in cancer risk reduction after RRSO among subgroups. CONCLUSION: Consistent with previous results, risks for breast and ovarian cancer varied by CJM in BRCA1/2 carriers. In particular, 6174delT carriers had a lower risk of breast cancer. This finding requires additional confirmation in larger prospective and population-based cohort studies before being integrated into clinical care.

Clinical utility of family history for cancer screening and referral in primary care: a report from the Family Healthware Impact Trial.

PURPOSE: To assess the effectiveness of computerized familial risk assessment and tailored messages for identifying individuals for targeted cancer prevention strategies and motivating behavior change. METHODS: We conducted a randomized clinical trial in primary care patients aged 35-65 years using Family Healthware, a self-administered, internet-based tool that collects family history for six common diseases including breast cancer, colon cancer, and ovarian cancer, stratifies risk into three tiers, and provides tailored prevention messages. Cancer screening adherence and consultation were measured at baseline and 6-month follow-up. RESULTS: Of 3283 participants, 34% were at strong or moderate risk of at least one of the cancers. Family Healthware identified additional participants for whom earlier screening (colon cancer, 4.4%; breast cancer, women ages: 35-39 years, 9%) or genetic assessment (colon cancer, 2.5%; breast cancer, 10%; and ovarian cancer, 4%) may be indicated. Fewer than half were already adherent with risk-based screening. Screening adherence improved for all risk categories with no difference between intervention and control groups. Consultation with specialists did not differ between groups. CONCLUSION: Family Healthware identified patients for intensified cancer prevention. Engagement of clinicians and patients, integration with clinical decision support, and inclusion of nonfamilial risk factors may be necessary to achieve the full potential of computerized risk assessment.

Modification of BRCA1-Associated Breast and Ovarian Cancer Risk by BRCA1-Interacting Genes.

Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (P(FDR)) with breast cancer were identified at ATM (P(FDR) = 0.029), BRCC45 (P(FDR) = 0.019), BRIP1 (P(FDR) = 0.008), CTIP (P(FDR) = 0.017), MERIT40 (P(FDR) = 0.019), NBS1 (P(FDR) = 0.003), RAD50 (P(FDR) = 0.014), and TOPBP1 (P(FDR) = 0.011). Haplotypes at ABRA1 (P(FDR) = 0.007), BRCC45 (P(FDR) = 0.016 and P(FDR) = 0.005 in two haplotype blocks), and RAP80 (P(FDR) < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.

Long-term outcomes, branch-specific expressivity, and disease-related mortality in von Hippel-Lindau type 2A.

Although a large kindred with familial pheochromocytoma (Pheo) and paraganglioma (PGL) was discovered in 1962 and later found to represent von Hippel-Lindau (VHL) type 2A (mutation Y112H), the phenotype lacks current characterization. Branch-specific expressivity was suspected based on oral family history. Family pedigree analysis, prospective interviews, and extensive record review were used to extend the pedigree, determine phenotype, examine branch-specific expression, and analyze mortality rates over 5 decades. In its 3 known affected branches the kindred now comprises 107 people with or at-risk for VHL, of whom 49 have been diagnosed and 35/49 (71%) are clinically affected. Phenotypic cumulative lifetime risk was 71% for Pheo/PGL, 15% for hemangioblastoma, 33% for retinal angioma, 3% for renal cell carcinoma, and 3% for pancreatic cysts. The mean ages for VHL and Pheo/PGL diagnosis were younger in successive generations. Branch II-4 predominately expressed RA, while branch II-5 predominantly expressed Pheo/PGL. Disease-specific mortality occurred early and was less frequent in successive generations. This analysis of Y112H VHL confirms a high cumulative risk for pheochromocytoma/paraganglioma. Over time, both age at diagnosis and disease-specific mortality have decreased. The observed branch-specific expressivity prompts further study of genetic and environmental disease modifiers in this large family.

Genetic variation in IGF2 and HTRA1 and breast cancer risk among BRCA1 and BRCA2 carriers.

BACKGROUND: BRCA1 and BRCA2 mutation carriers have a lifetime breast cancer risk of 40% to 80%, suggesting the presence of risk modifiers. We previously identified significant associations in genetic variants in the insulin-like growth factor (IGF) signaling pathway. Here, we investigate additional IGF signaling genes as risk modifiers for breast cancer development in BRCA carriers. METHODS: A cohort of 1,019 BRCA1 and 500 BRCA2 mutation carriers were genotyped for 99 single-nucleotide polymorphisms (SNP) in 13 genes. Proportional hazards regression was used to model time from birth to diagnosis of breast cancer for BRCA1 and BRCA2 carriers separately. For linkage disequilibrium (LD) blocks with multiple SNPs, an additive genetic model was used. For an SNP analysis, no additivity assumptions were made. RESULTS: Significant associations were found between risk of breast cancer and LD blocks in IGF2 for BRCA1 and BRCA2 mutation carriers (global P values of 0.009 for BRCA1 and 0.007 for BRCA2), HTRA1 for BRCA1 carriers (global P value of 0.005), and MMP3 for BRCA2 carriers (global P = 0.0000007 for BRCA2). CONCLUSIONS: We identified significant associations of genetic variants involved in IGF signaling. With the known interaction of BRCA1 and IGF signaling and the loss of PTEN in a majority of BRCA1 tumors, this suggests that signaling through AKT may modify breast cancer risk in BRCA1 carriers. IMPACT: These results suggest potential avenues for future research targeting the IGF signaling pathway in modifying risk in BRCA1and BRCA2 mutation carriers.