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Background: Survival advantages with neoadjuvant chemotherapy (NACT) have been observed in patients (pts) with locally advanced breast cancer (BC) who achieve pathological complete response (pCR). Predicting risk of early recurrence in pts without pCR remains difficult. Circulating tumor DNA (ctDNA) may be a biomarker of neoadjuvant therapy response and recurrence. This study applied tumor genotyping of peripheral blood in pts with HER2− tumor BRCA-mutated (tBRCAm) BC treated with neoadjuvant niraparib. The relationship between ctDNA and tumor response was also characterized, with a focus on circulating TP53 mutant allelic frequency (MAF). Methods: Blood was collected from 21 pts enrolled in the study (NCT03329937) evaluating neoadjuvant niraparib in pts with localized HER2− tBRCAm BC. Pts received niraparib 200 mg once daily for two 28-day cycles. After 2 cycles, pts underwent surgery or received up to 6 cycles of niraparib and/or NACT prior to surgery. Blood samples were collected at screening, Cycle 1 Day 28 (C1D28), Cycle 2 Day 28 (C2D28), and pre-surgery. Ultrasound (USG) was done after each cycle and MRI after Cycle 2. Next-generation sequencing of cell-free plasma DNA was carried out using a proprietary target capture and analysis (Paweletz, Clin Cancer Res 2016). Results: ctDNA and TP53 mutations (TP53m) were detected at screening in 10/21 pts (47.6%). Across all 21 pts there was a correlation between TP53 MAF and baseline tumor stage (T) (mean [standard deviation], T1 0 [0], T2 0.05 [0.09], and T3 0.21 [0.12]; P=0.005). Linear regression modelling showed a positive correlation between tumor volume and baseline TP53 MAF (R2=0.206, P=0.0386). Baseline TP53 MAF also appeared to be associated with advanced disease stage (Table 1). Depletion of detectable TP53m from baseline was evident by C1D28 and persisted to pre-surgery (Table 2). This corresponded with decreases in tumor volume at C1D28 and further decreases at C2D28. Of 11 pts analyzed, 6 pts with >90% tumor volume decreases by MRI or USG at C2D28 had sustained TP53m depletion. Three pts had pCR; of these, 2 had sustained TP53m depletion (data unavailable for third pCR pt). Two pts with less robust tumor responses had increased pre-surgery TP53 MAF. Conclusions: We report the potential utility of ctDNA as a predictive biomarker for neoadjuvant niraparib response in pts with HER2− tBRCAm BC. Although sample size limited analysis of genes other than TP53, baseline ctDNA strongly correlated with tumor volume, and TP53 MAF was associated with tumor volume and trended towards association with disease stage. Longitudinal analysis of TP53 MAF suggested a correlation with niraparib response. Further study of ctDNA dynamics during NACT and correlation with pCR and long-term clinical outcomes is warranted. Funding: GlaxoSmithKline (GSK) study 213355; NCT03329937. Medical writing support was provided by Fishawack Indicia, part of Fishawack Health, funded by GSK. Table 1.Baseline TP53 MAF association with disease stage and subtypeTP53 MAFDisease Stage (I–III)Disease SubtypeStage IStage IIStage IIIHR+TNBC(n=8)(n=10)(n=3)(n=6)(n=15)Mean (SD)0.01 (0.02)0.07 (0.12)0.10 (0.05)0.02 (0.02)0.06 (0.10)HR, hormone receptor; MAF, mutant allelic frequency; SD, standard deviation; TNBC, triple-negative breast cancer. Table 2.TP53 MAF correlation with tumor volume decrease by ultrasound and MRIOutcomeScreeningCycle 1 Day 28 Cycle 2 Day 28 Pre-Surgeryn11997TP53 MAF, mean, (SD)0.09 (0.11)000.01 (0.02)n11112Percent change in tumor volume from baseline by MRI, mean (SD)-N/A*−72.6 (22.5)N/A*Percent change in tumor volume from baseline by ultrasound, mean (SD)-−60.8 (24.0)−80.6 (21.8)−95.9 (4.3)*MRI was only performed at Cycle 2 Day 28. MAF, mutant allelic frequency; MRI, magnetic resonance imaging; N/A, not applicable; SD, standard deviation. Citation Format: Ming Shan, Laura Spring, Minetta C Liu, Erika Hamilton, Hanna Irie, Cesar A Santa-Maria, Steven J Isakoff, James Reeves, Leif W Ellisen, Lee P Lim, Kavita Garg, Caterina Bertucci, Bin Feng, Hailei Zhang, Kaiming Sun, Julie R Graham, Erin Hofstatter, Hyo Han. Relationship between circulating tumor DNA and response to neoadjuvant niraparib in HER2-negative, BRCA-mutated breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-21.

Background: There is an incomplete understanding of why some women develop breast cancer 20-25 years earlier than the majority of women. Only 30-40% of women with high risk family history are found to have known cancer predisposing mutations. This phenomenon is referred to as “missing heredity”. We hypothesize that women with high-risk cancer family history but no known high penetrance cancer predisposing mutations who develop breast cancer at a young age have a higher deleterious load of germline high functional impact (gHFI) single nucleotide variants in cancer relevant genes. Methods: 94 women diagnosed with breast cancer age 65 with no cancer family history were identified from Yale Generations project. Whole-exome sequencing (WES) was performed on peripheral blood from 94 cases, 149 controls, and 42 matched tumors. WES data was analyzed from 1,112 female breast cancer cases with first-degree breast cancer family history and 50,887 healthy women without breast cancer family history from UKBiobank. Rare gHFI variants were defined as nonsynonymous variants predicted as deleterious in MetaSVM, or loss-of-function in gnormAD, or pathogenic in ClinVar database with mutation frequency 5% of cases using Fisher’s exact test. FDRs were calculated using Benjamini & Hochberg. Results: The majority of YCPC patients were Caucasian (78.7%), median age (43.5), with invasive ductal carcinoma (85.1%), ER+PR+HER2- (67.0%). YCPC patients had a higher average burden of rare gHFI variants in cancer hallmark genes (excluding CPGs) compared to controls (p=0.0075, adjusted for race), but did not show a higher germline burden in CPGs. Similarly, UKBiobank breast cancer patients with a family history had a higher germline variant burden in hallmark genes (excluding CPGs) compared to controls (p=0.0368). The main pathways affected by gHFI in the YCPC cohort were adaptive immunity (p=1.61 x 10-8) and extracellular matrix (p=0.0034). Thirty six (87.8%) YCPC matched tumors carried somatic mutations in known cancer related genes. Compared to TCGA, YCPC samples had fewer TP53 mutations (5% vs 17%, FDR = 0.27), but more mutations in CHEK2, GNAQ, APC, and SDHA (FDR CohortRace (%)AgeCases (N)Control (N)GenesetAverage Case BurdenAverage Case BurdenSKAT testYaleCaucasian (78.7)439414983 CPGs0.27660.30200.56921508 Hallmark4.23404.18790.0075UK BiobankBritish (100)5611125088783 CPGs0.37410.28064.19x10-51508 Hallmark3.36423.33990.0368 Citation Format: Mariya Rozenblit, Tao Qing, Yixuan Ye, Hongyu Zhao, Erin Hofstatter, Vinit Singh, Emily Reisenbichler, Michael Murray, Lajos Pusztai. Young women with breast cancer and high risk family history but no high penetrance germline mutations have a higher load of rare high functional impact germline variants in cancer relevant genes [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-01.

Background: Following definitive treatment, there is no standard-of-care for patients (pts) with HR+HER2− breast cancer (BC) or TNBC beyond clinical monitoring for metastasis. Recurrence rates remain high for pts with a greater burden of residual disease after neoadjuvant chemotherapy. Detectable circulating tumor DNA (ctDNA) is also associated with a high risk of clinical relapse. However, there is no standard therapy for pts with detectable ctDNA who have not yet developed clinical metastasis. Niraparib, a poly(ADP-ribose) polymerase inhibitor (PARPi), inhibits repair of DNA damage and stalled replication forks. PARPi showed clinical activity in pts with TNBC, with increased responses in homologous recombination deficient (HRd) tumors. HRd is common in TNBC, including in pts with wild-type or mutated tumor BRCA (tBRCAwt and tBRCAm). Neoadjuvant niraparib showed clinical activity in tBRCAm HER2− BC. This study will assess niraparib in pts with tBRCAm HER2− BC or tBRCAwt TNBC who have detectable ctDNA after completion of definitive therapy. Trial Design: ZEST (NCT04915755) is a multicenter, multicohort, Phase 3, double-blind, placebo-controlled study in pts with tBRCAm HER2− BC (HR+ with concomitant endocrine therapy and TNBC; Cohort 1) or tBRCAwt TNBC (Cohort 2) with detectable ctDNA following surgery or completion of adjuvant chemotherapy and radiotherapy. Pts who previously completed definitive therapy at any time are eligible for ctDNA monitoring and potential enrollment in the trial following detection of ctDNA. HR+/HER2− pts must have known tBRCAm to qualify for ctDNA screening. For all other pts, tBRCA status will be confirmed in those with detectable ctDNA. HRd status will be assessed at prescreening; pts with tBRCAwt TNBC and HRd will be allocated to Cohort 2. Pts with detectable ctDNA and no recurrence on staging scans will be randomized 1:1 to receive niraparib or placebo. Niraparib will be given orally once daily at a dose of 300 mg; pts with body weight Funding: GlaxoSmithKline (GSK) study 213831; NCT04915755. Medical writing support was provided by Fishawack Indicia, part of Fishawack Health, funded by GSK. Table 1.Key eligibility criteriaInclusion criteriaExclusion criteria• Age ≥18 years• Prior treatment with a poly(ADP-ribose) polymerase inhibitor. • Current treatment with a cyclin-dependent kinase 4 and 6 inhibitor or endocrine therapy other than anastrozole, letrozole, exemestane, and tamoxifen. • Any sign of local recurrence or metastasis. • Lack of definitive response to preoperative chemotherapy by pathologic or radiographic evaluation, in cases where preoperative chemotherapy was administered. • Live vaccine therapy within 30 days of planned start of study randomization. • A second primary malignancy, except (a) adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ of the breast, Stage I Grade 1 endometrial carcinoma; (b) other solid tumors and lymphomas (without bone marrow involvement) diagnosed ≥5 years prior to randomization and treated with no evidence of disease recurrence, and for whom no more than 1 line of chemotherapy was applied. • Pregnancy, breastfeeding, or expecting to conceive children while receiving study treatment and/or for up to 180 days after the last dose of study treatment • History of human immunodeficiency virus • Known history of myelodysplastic syndrome or acute myeloid leukemia• Stage I-III breast cancer, with surgical resection of the primary tumor, that is confirmed as either: o triple-negative breast cancer, irrespective of tumor breast cancer gene (tBRCA) status, or o Hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- with a documented tBRCA mutation. • Completed prior standard therapy for curative intent including all of the following, if indicated: neoadjuvant treatment, surgery, adjuvant radiotherapy, and adjuvant chemotherapy. • Stable regimen of endocrine therapy, if indicated, for ≥3 months prior to enrollment (HR+ only) • Detectable circulating tumor DNA by central Signatera testing. • An archival tumor tissue specimen of the primary tumor sufficient in quality and quantity for ctDNA assay design and tBRCA and homologous recombination deficiency (HRD) testing Citation Format: Nicholas C Turner, David W Cescon, Sibylle Loibl, Wolfgang Janni, Hope Rugo, Judith Balmaña, Cheynna Crowley, Jon Chung, Giulia Fucli, Erin Hofstatter, Tara Frenkl, Melinda L Telli. ZEST: Randomized phase III study evaluating efficacy and safety of niraparib in patients with HER2-negative BRCA-mutated or triple-negative breast cancer with detectable circulating tumor DNA after definitive therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-24-02.

BRCA1 and BRCA2 pathogenic variant carriers have a high lifetime risk of developing breast and ovarian malignancies. Given the risks and significant ramifications of undergoing risk-reducing surgeries, many pathogenic variant carriers unaffected by cancer (previvors) struggle with family planning and reproductive decision making. The objective of this study was to determine the attitudes and practices of BRCA1 and BRCA2 pathogenic variant carriers with respect to family planning decision making. A cross-sectional survey was conducted of BRCA1 and BRCA2 previvors at four Northeastern medical centers. The survey was administered electronically via email using REDCap. The survey included demographic information as well as questions about genetic testing, prophylactic surgeries, family planning, and partnering. Data were analyzed with Fisher's exact tests and t tests. The survey was completed by 139 of 422 BRCA1 and BRCA2 pathogenic variant carriers (response rate 33%). Thirteen were excluded from analysis due to self-reported cancer history. Of the remaining 126, 21 (16.7%) were male and 105 (83.3%) were female. Female participants

Breast cancer remains the most common cancer in women in the United States. For certain women at high risk for breast cancer, endocrine therapy (ET) can greatly decrease the risk. Tools such as the Breast Cancer Risk Assessment Tool (or Gail Model) and the International Breast Cancer Intervention Study risk calculator are available to help identify women at increased risk for breast cancer. Physician awareness of family history, reproductive and lifestyle factors, dense breast tissue, and history of benign proliferative breast disease are important when identifying high-risk women. The updated US Preventive Services Task Force and American Society of Clinical Oncology guidelines encourage primary care providers to identify at-risk women and offer risk-reducing medications. Among the various ETs, which include tamoxifen, raloxifene, anastrozole, and exemestane, tamoxifen is the only one available for premenopausal women aged 35 years and older. A shared decision-making process should be used to increase the usage of ET and must be individualized. This individualized approach must account for each woman's medical history and weigh the benefits and risks of ET in combination with the personal values of the patient.

Aging is the leading risk factor for cancer. While it’s been proposed that the age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. Here, we show that both aging and cancer share a common epigenetic replication signature, which we modeled from DNA methylation data in extensively passaged immortalized human cells in vitro and tested on clinical tissues. This epigenetic signature of replication – termed CellDRIFT – increased with age across multiple tissues, distinguished tumor from normal tissue, and was escalated in normal breast tissue from cancer patients. Additionally, within-person tissue differences were correlated with both predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Overall, our findings suggest that age-related replication drives epigenetic changes in cells, pushing them towards a more tumorigenic state.One sentence summaryCellular replication leaves an epigenetic fingerprint that may partially underly the age-associated increase in cancer risk.

In recent years, the number of patients choosing to have direct-to-consumer (DTC) genetic testing without involving their clinicians has increased substantially. For example, the number of subscribers to a commonly used testing site has grown to more than 10 million. These services have been heavily marketed in the United States and often include information about ancestry; genetic traits; and, increasingly, disease risk. In clinical care, genetic testing by a physician is accompanied by both pre- and posttest counseling by a trained genetic counselor. However, there are not enough genetic counselors to meet the needs of all persons contemplating DTC genetic testing. Formal genetic counseling includes preparation of a family pedigree; a discussion about potential benefits, the possibility that some information might be stressful to receive or difficult to understand, and the potential for disclosure of genetic information; and a detailed informed consent process. Some DTC tests for genetic susceptibilities look for only a few known mutations in a particular gene (such as BRCA1); a negative test result does not exclude the possibility of a clinically important mutation. A positive DTC genetic test result that might change clinical management should be followed by a confirmatory test through a genetics laboratory. Here, 2 expert physicians-a general internist and a medical oncologist with genetics experience-discuss an approach to counseling a patient who is considering DTC testing to learn more about his ancestry and his risk for metabolic syndrome.

Background: Circulating tumor DNA (ctDNA) has been increasingly used in the clinical care of patients with cancer. This systematic review summarizes current data on the utility of ctDNA in breast cancer clinical research and practice and provides insights for integrating ctDNA into drug development and patient treatment. Methods: The Embase database was used to identify original clinical research articles of ctDNA in breast cancer published from 2015 to 2020. ctDNA clinical utilities were reviewed and summarized, focusing on 3 areas: early diagnosis, prognostication, and monitoring disease progression/treatment response. Associations of ctDNA with disease-free survival (DFS) and overall survival (OS) were estimated in the embedded meta-analysis. Pooled estimates were calculated using fixed-effect or random-effect models depending on study heterogeneity. Results: After screening and review, 72 articles were included. ctDNA studies have increased in recent years, with 59.7% of included articles published in 2019 or 2020. Overall, 61.1% of the studies were in patients with advanced stage/metastatic cancer; 45.8% were restricted to patients with specific cancer subtypes. ctDNA was minimally used in diagnosis; it was predominantly used in clinical outcome prediction with differences by stage. In patients with early-stage disease, the meta-analyses found that overall ctDNA detection/positivity was associated with shorter DFS (n=697; HR, 5.37; 95% CI, 2.94-9.80) and OS (n=238; HR, 4.60; 95% CI, 2.56-8.26). Specific gene mutations in ctDNA were mainly assessed in patients with advanced/metastatic disease, with mutations of ERBB, ESR1, and TP53 linked to shorter DFS in the meta-analyses (P Conclusions: Recent studies demonstrate ctDNA application in breast cancer prognostication/monitoring, suggesting an important role in patient stratification, molecular relapse identification, and personalized treatment. Large, multicenter clinical trials and real-world longitudinal data sets are needed to validate findings and to address challenges related to ctDNA to improve clinical utility and to integrate ctDNA testing into clinical practice and drug development. Citation Format: Xuezheng Sun, Nicholas Ballew, Linda Kalilani, Kelesitse Phiri, Kelly Bell, Alexander Slowly, Magdalena Zajac, Erin Hofstatter, Angela Silvestro, Zebin Wang, Jeanne Schilder. Utility of circulating tumor DNA in breast cancer clinical research and practice: systematic review and meta-analysis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6695.

Aging is the leading risk factor for cancer. While some have proposed that the age-related accumulation of somatic mutations drives this relationship, it is likely not the full story. Here, we show that both aging and cancer share a common epigenetic replication signature, which we modeled from DNA methylation data in extensively passaged immortalized human cells in vitro and tested on clinical tissues. This epigenetic signature of replication – termed CellDRIFT – increased with age across multiple tissues, distinguished tumor from normal tissue, and was escalated in normal breast tissue from cancer patients. Additionally, within-person tissue differences were correlated with both predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Overall, our findings suggest that age-related replication drives epigenetic changes in cells, potentially pushing them towards a more tumorigenic state. Citation Format: Christopher J. Minteer, Kyra Thrush, Peter Niimi, Joel Rozowsky, Jason Liu, Mor Frank, Thomas McCabe, Erin Hofstatter, Mariya Rozenblit, Lajos Pusztai, Kenneth Beckman, Mark Gerstein, Morgan E. Levine. Revisiting the bad luck hypothesis: Cancer risk and aging are linked to replication-driven changes to the epigenome [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR009.

Purpose Age is one of the strongest risk factors for the development of breast cancer, however, the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression. Methods Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls). Results The Levine (p = 0.0037) and Yang clocks (p = 0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb-related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb-related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p = 0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration. Conclusions Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb-related genes can be used to assess the risk of developing breast cancer among unaffected individuals.

Background: Age is the largest risk factor for breast cancer development. Faster biological aging, particularly in breast tissue, may predispose women to higher risk of developing breast cancer. Recently, a set of promising biomarkers of aging, called “epigenetic clocks” (also referred to as “epigenetic age”) have been developed to estimate aging rates in tissues and cells. Using one of the original epigenetic clocks based on DNA methylation patterns, we previously demonstrated that normal breast tissue from luminal breast cancer patients exhibited accelerated aging compared to patients without breast cancer. Here we test whether incorporation of nearly a dozen epigenetic clocks, each capturing slightly different biological aging phenomena, can consistently distinguish normal breast tissue from cancer patients versus healthy controls. We also examined concordance between epigenetic age assessment from paired breast tissue and peripheral blood mononuclear cells. Methods: We examined 282 specimens including DNA from 94 normal breast tissues (41 from patients with breast cancer, and 53 from non-cancer controls) and 188 blood samples (97 from breast cancer, and 91 from controls). DNA methylation was assessed via the Illumina HumanMethylation450k and HumanMethylationEPIC BeadChip for both tissue and blood samples, and 11 epigenetic clocks were calculated following published methods. Associations of these clocks with breast cancer were examined using logistic regression models and Receiver Operating Characteristics (ROC) curves to determine predictive power in distinguishing samples from cancer patients versus healthy controls. Results: After accounting for chronological age, we observed increases in most epigenetic clocks for cancer patients compared to normal samples from controls, which indicates accelerated epigenetic aging (e.g., Zhang clock in tissue, 0.55 vs. -0.42; in blood, 0.10 vs. -0.20, all P Conclusions: Epigenetic aging-based biomarkers distinguish non-tumor breast tissues of patients with breast cancer from breast tissues of healthy controls. These findings raise the possibility that epigenetic markers assessed on needle biopsies of the breast might identify individuals at risk for developing breast cancer. Citation Format: Erin Hofstatter, Morgan Levine, Zuyun Liu, Tess O'Meara, Disha Dalela, Lajos Pusztai. Evidence of accelerated epigenetic aging of breast tissues in patients with breast cancer compared to women without cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-09-02.

Background: Breast cancer (BC) patients (pts) with Oncotype Dx recurrence scores (RS) ≤ 25 represent a large fraction of BC cases. The TAILORx study demonstrated that these pts did not receive significant benefit from adjuvant chemotherapy. Despite their low to moderate risk and sensitivity to endocrine therapy, a number of BC pts may benefit from neoadjuvant therapy. The goal of this study is to assess tumor response, utilizing the preoperative endocrine prognostic index (PEPI), to a combination of the mTOR inhibitor everolimus and an aromatase inhibitor (AI) in this pt population. Methods: This is a phase II study evaluating the efficacy and safety of neoadjuvant AI and everolimus in postmenopausal pts with hormone receptor positive (HR+)/HER2 negative clinical stage II-III BC with low risk RS (≤ 25). Patient enrollment initiated in November 2014 at the Yale Cancer Center/Smilow Cancer Hospital and Care Centers. Key inclusion criteria are ECOG 0-2, adequate organ function, a fasting cholesterol ≤ 300 mg/dl and triglycerides ≤ 2.5 x IULN. Eligible pts received daily AI therapy (anastrozole 1 mg, letrozole 2.5 mg, or exemestane 25 mg) and everolimus 10 mg daily for up to a total of 26 weeks. The primary objective of the study was to determine the percent of postmenopausal pts with clinical stage II-III HR+/HER2- BC and a RS ≤ 25 who achieve a PEPI score of 0 following neoadjuvant AI and everolimus. The secondary objectives are to assess the tolerability and side effect profile, and to identify biologic markers predictive of a PEPI 0. Simon’s optimal two-stage design was utilized with a planned sample size of 27 eligible pts. First, 15 pts will be enrolled, if 5 or more of 15 eligible patients achieve a PEPI 0, the plan is to enroll another 12 pts. If 10 or more of the 27 eligible patients achieve a PEPI 0, we will conclude that the regimen warrants further study. This design has a power of 80% and a one-sided significance level of 0.1. Results: Of the 17 pts initially enrolled, 15 were evaluable for response; 4 of 15 (26%) had a PEPI scores of 0 which did not meet the primary endpoint; 4 (26%) had a path CR and 6 (40%) had PR. Grade 3 toxicities determined to be possibly/probably study related included anemia, anorexia, hypertension, maculopapular rash and hyperglycemia. One pt developed grade 3 atrial flutter and grade 4 QT prolongation which required a dose delay. One pt required hospitalization for pneumonia. Gene expression analysis by RNA seq was performed on 9 baseline (6 pts with CR/PR vs 3 non-responders); 13 post treatment (8 pts with CR/PR vs 5 non-responders) samples with 8 matched pairs (5 pts with CR/PR vs 3 non-responders). Baseline samples from pts who had CR/PR have significantly lower expression of MYC targets and oxidative phosphorylation genes, and significantly higher expression of genes associated with epithelial mesenchymal transition and interferon signaling, in comparison to non-responders. The expression of CYP19A1 gene, that codes aromatase, is significantly increased after therapy in samples from pts with CR/PR (logFC=1.33), but not in other pts. Expression of mTORC1 signaling pathway genes is increased after therapy only in samples from pts with CR/PR. Conclusion: Although this trial did not meet the set primary endpoint, 26% of pts achieved a PEPI 0. The combination of an AI and everolimus was overall well tolerated. Our study suggested that baseline expression levels of key pathways were associated with response to neoadjuvant AI plus everolimus. Citation Format: Maysa M Abu-Khalaf, Kimberly Aderhold, Michal Marczyk, Gina Chung, Erin Hofstatter, Tara Sanft, Andrea Silber, Michael DiGiovanna, Daniel Zelterman, Lajos Puzstai, Christos Hatzis. Neoadjuvant aromatase inhibitor therapy plus the mTOR inhibitor everolimus in postmenopausal women with hormone receptor positive/HER2 negative breast cancer and an oncotype Dx recurrence score (≤25) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-13-02.

Purpose: Age is one of the strongest risk factors for the development of breast cancer, however the underlying etiology linking age and breast cancer remains unclear. We have previously observed links between epigenetic aging signatures in breast/tumor tissue and breast cancer risk/prevalence. However, these DNA methylation-based aging biomarkers capture diverse epigenetic phenomena and it is not known to what degree they relate to breast cancer risk, and/or progression. Methods: Using six epigenetic clocks, we analyzed whether they distinguish normal breast tissue adjacent to tumor (cases) vs normal breast tissue from healthy controls (controls). Results: The Levine (p=0.0037) and Yang clocks (p=0.023) showed significant epigenetic age acceleration in cases vs controls in breast tissue. We observed that much of the difference between cases and controls is driven by CpGs associated with polycomb related genes. Thus, we developed a new score utilizing only CpGs associated with polycomb related genes and demonstrated that it robustly captured epigenetic age acceleration in cases vs controls (p=0.00012). Finally, we tested whether this same signal could be seen in peripheral blood. We observed no difference in cases vs. controls and no correlation between matched tissue/blood samples, suggesting that peripheral blood is not a good surrogate marker for epigenetic age acceleration. Conclusions: Moving forward, it will be critical for studies to elucidate whether epigenetic age acceleration in breast tissue precedes breast cancer diagnosis and whether methylation changes at CpGs associated with polycomb related genes can be used to assess the risk of developing breast cancer among unaffected individuals.

A significant proportion of prostate cancer diagnoses may be associated with a strong hereditary component. Men who have multiple single-gene polymorphisms and a family history of prostate cancer have a significantly greater risk of developing prostate cancer. Numerous single-gene alterations have been confirmed to increase the risk of prostate cancer. These include breast cancer genes 1 and 2 (BRCA1 and BRCA2, respectively), mutL homolog 1 (MLH1), mutS homologs 2 and 6 (MSH2 and MSH6, respectively), postmeiotic segregation increased 2 (PMS2), homeobox B13 (HOXB13), checkpoint kinase 2 (CHEK2), nibrin (NBN), BRCA1-interacting protein C-terminal helicase 1 (BRIP1), and ataxia telangiectasia mutated (ATM). Currently, there are no uniform guidelines on the definition of hereditary prostate cancer and genetic testing. With the advent of next-generation sequencing, which is capable of testing multiple genes simultaneously, and the approval of olaparib for BRCA1/BRCA2 or ATM-mutated, metastatic, castrate-resistant prostate cancer, it is being recognized that the results of genetic testing have an impact on therapeutic strategies. In this review, the authors examine the role of genetic counseling and testing, the challenges of insurance coverage for testing, the available germline and somatic testing panels, and the complexity of each testing method and its implications. Cancer 2018. © 2018 American Cancer Society.

Introduction Up to 40% of patients with breast cancer may not adhere to adjuvant endocrine therapy. Therapy-related adverse effects (AEs) are important contributors to nonadherence. We developed a bidirectional text-message application, BETA-Text, that simultaneously tracks adherence, records symptoms, and alerts the clinical team. Patients and Methods We piloted our intervention in 100 patients. The intervention consisted of text messages to which patients responded for 3 months: daily, evaluating adherence; weekly, evaluating medication-related AEs; and monthly, regarding barriers to adherence. Concerning responses prompted a telephone call from a clinic nurse. The primary objective was to assess patient acceptance of this intervention using self-reported surveys. To compare participants with the general population at our institution, we assessed 100 consecutively treated patients as historical controls using medical record review. Results We approached 141 consecutive patients, 100 (71%) of whom agreed to participate and 89 of whom completed the intervention. A majority of patients reported that the intervention was easy to use (98%) and helpful in taking their medication (96%). Four patients discontinued therapy before 3 months, and 93% of patients who continued therapy took ≥ 80% of their medication. The frequency of AEs reported by participants via text was higher than that reported in clinical trials: hot flashes (72%), arthralgias (53%), and vaginal symptoms (35%). Approximately 39% of patients reported one or more severe AE that prompted an alert to the provider team to call the patient. Conclusion A daily bidirectional text-messaging system can monitor adherence and identify AEs and other barriers to adherence in real time without inconveniencing patients. AEs of endocrine therapy, as detected using this texting approach, are more prevalent than reported in clinical trials.

BACKGROUND: Age is the biggest risk factor for developing breast cancer, which suggests that the biological aging process is a direct driver of cancer etiology. In all normal tissues, DNA methylation status changes systematically with age and is believed to mediate the biological consequences of aging. DNA methylation patterns, commonly referred to as 'Epigenetic Clocks', can be used as measures of aging. However, the chronologic and epigenetic ages can have subtle differences in different individuals. We hypothesize that accelerated epigenetic aging (i.e. DNA methylation indicating an older age than the chronologic age of the individual) is a risk factor for breast cancer development. METHODS: We used DNA methylation data from blood samples and clinical data from n=2,107 participants in the Women's Health Initiative (WHI) and tested the association between breast cancer risk and two of the most commonly used epigenetic clocks by Horvath (based on 353 CpGs) and Hannum et al. (based on 71 CpGs). DNA methylation in whole blood was measured using the Illumina HumanMethylation450 BeadChip. We used Cox proportional hazard models to assess the association between two epigenetic age predictors (calculated using the algorithms by Horvath and Hannum et al.) and subsequent risk of breast cancer. The model was adjusted for several breast cancer risk factors including: chronologic age at the time of blood sampling, observational vs. clinical trial, clinical trial arm, race/ethnicity, education, BMI, waist-hip ratio, smoking, alcohol, age at menopause, age at menarche, number of pregnancies, age at first birth, previous mastectomy, months breastfed, and cell count estimates. Family history data and BRCA mutation status was incomplete in the WHI and therefore could not be included in our analysis. RESULTS: Increased epigenetic age determined by the Horvath clock relative to chronological age was associated with increased future incidence of invasive breast cancer, even after adjusting for known risk factors (HR=1.04, P=0.03). Utilizing the Hannum clock, we found no significant association between epigenetic age and breast cancer risk (HR=1.01, P=0.568). When we included both age predictors as independent variables in a single model, the strength of the association between the Horvath epigenetic age and breast cancer risk increased (Horvath HR=1.09, P=6.3e-5; Hannum HR=0.95, p=0.077), such that every one year increase in epigenetic age relative to chronological age was associated with a 9% increased risk of future breast cancer. These results suggest that the aging signal in the Horvath clock that is unique from that captured by Hannum is what drives the specific association with breast cancer. CONCLUSIONS: Our results support the hypothesis that “accelerated” epigenetic aging measured in the blood increases breast cancer risk. We also demonstrate that the two epigenetic clocks capture different aspects of aging, only some of which have implications for breast cancer risk. Epigenetic clocks may assist in targeting breast cancer screening to higher risk populations in the future, and understanding the biological mechanisms that are altered by the epigenetic changes may lead to new risk reduction strategies. Citation Format: Hofstatter EW, Levine M, Hatzis C, Pusztai L. Age-related methylation signals of breast cancer risk in blood [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-05-01.

10531 Background: Genomic assays, such as RS, are used to determine chemotherapy benefit in early-stage, estrogen receptor (ER)- and/or progesterone receptor (PR)-positive, HER2 negative BC patients (pts). Currently, guidelines to use pts’ germline genetic testing results to guide adjuvant therapy are lacking. Several reports have indicated worse outcomes for BC pts with g CHEK2 pathogenic variants (PV). We investigated whether PV in CHEK2 were associated with increased RS. Methods: Patient-level clinical data and RS were derived from electronic medical records of seven medical centers between years 2013-17. Confirmation of RS using the Genomic Health provider portal was performed. 38 pts with germline PV in CHEK2 (15 pts/39.5% with c.1100delC mutation) and RS score (cases) were matched with BC pts whose genetic testing did not identify PV (controls) using a 1:2 matching schema. Pts were matched based on age at diagnosis and lymph node (LN) status. LN negative pts were further matched based on T-stage. A multivariate random intercept linear mixed model of CHEK2 mutation status on RS was performed, adjusting for PR. A secondary ordinal univariate analysis was conducted that categorized RS into low, intermediate and high risk ( < 18, 18-30, and > 30, respectively). P-values were reported based on a null hypothesis of no effect against a two-sided alternative. Results: The median RS for cases was 19.5 (interquartile range [IQR]: 15 to 25) and the median RS for controls was 18 (IQR: 12 to 22). A greater proportion of cases were categorized as high risk (10.5%) compared to controls (5.6%), and a smaller proportion of cases were categorized as low risk (36.8%) compared to controls (49.3%). Cases had higher grade and increased proportion of PR-negative BC as compared with controls (grade 1: 12.1% of cases versus 32.4% of controls; PR-negative: 7.9% of cases versus 5.6% of controls). The variables used to match cases and controls (age, lymph node status, and T-stage) had similar summary statistics. The RS was 1.97-point higher in pts with g CHEK2 PV compared to controls, after adjusting for PR (95% confidence interval [CI]: 1.02-point lower to 4.96-point higher; p = 0.194). The secondary analysis of CHEK2 mutation status on an ordinal RS risk group yielded comparable results; on average, the odds of being high risk compared to the combined intermediate/low risk groups was 1.72 times higher in cases compared to controls (95% CI: 0.77 to 3.80; p = 0.181), but these differences were not significant. Conclusions: Our case-control study did not show a statistically higher RS for BC that develops in pts with g CHEK2 PV. Further studies are warranted to evaluate the association between type of CHEK2 PV (frameshift versus missense) and other modifying genetic variables and RS.

Background: Trinidad and Tobago (T&T) is a southern Caribbean island with a population of approx. 1.3 million. According to WHO/PAHO, T&T has the 2nd highest breast cancer mortality rate in the region, and breast cancer continues to lead in incidence and mortality in cancers among female citizens. Notably, a large proportion of breast cancer cases in T&T appear to occur at a young age; with nearly 36% of breast cancers diagnosed under the age of 50. It is known that a younger age at diagnosis can be associated with Hereditary Breast and Ovarian Cancer syndrome (HBOC), characterized by germline mutations in tumor suppressor genes such as BRCA, PTEN and TP53. Yet, the prevalence of HBOC mutations remains unknown in T&T, as local health services for genetic counseling and testing in T&T currently do not exist. As such, our study aimed to determine the prevalence rate of HBOC mutations among women with breast cancer in T&T who met NCCN criteria for evaluation for HBOC syndrome; thus investigating whether there is a need to include genetic testing and counseling in local oncology management in T&T. Methods: At the National Radiotherapy Center, the main oncology unit in T&T, female breast cancer patients, who met the NCCN criteria for further genetic counseling/testing, were recruited either through doctor referrals or chart reviews. We conducted interviews inquiring about their personal breast cancer diagnosis, risk factors for breast cancer, as well as any relevant family history. This was followed by the collection of saliva samples using Oragene kits, which were then analyzed by Color Genomics Inc. for 30 genes associated with hereditary cancers; including 19 HBOC associated genes such as BRCA1, BRCA2, TP53 and PTEN. Finalized results were returned to patients by genetic counselors from Color Genomics. Results: 165 patients who met NCCN guidelines for HBOC counseling/testing were approached, of whom 150 agreed to participate. Due to funding and resource limitations, 60 samples were collected thus far; ages ranged from 19-56. The majority of women met NCCN criteria based on age of personal breast cancer diagnosis (40%), and/or family history of breast and/or ovarian cancer (60%). Preliminary results show that of 49 samples, 10 patients tested positive for deleterious HBOC germline mutations: 7 - BRCA1, 2 - BRCA2 and 1 - PTEN; thus far giving a prevalence rate of 20%. Discussion: Therefore, our results found a strikingly high HBOC germline mutation prevalence rate of 20% among a cohort of female breast cancer patients meeting NCCN criteria in T&T. As we continue to finalize the incoming data on these patients, we hope to draw associations between their genetic status and their respective tumor markers, family history, and personal medical history. However, these initial results demonstrate the need to include genetic counseling and testing in the local oncology management in T&T, as the identification of HBOC mutations can influence treatment options, as well as help identify family members who are at high risk for cancer predisposition. Ultimately, this integration could help alleviate the country's high incidence and mortality rates with respect to breast cancer, and save the public healthcare system significant financial resources.Background: Trinidad and Tobago (T&T) is a southern Caribbean island with a population of approx. 1.3 million. According to WHO/PAHO, T&T has the 2nd highest breast cancer mortality rate in the region, and breast cancer continues to lead in incidence and mortality in cancers among female citizens. Notably, a large proportion of breast cancer cases in T&T appear to occur at a young age; with nearly 36% of breast cancers diagnosed under the age of 50. It is known that a younger age at diagnosis can be associated with Hereditary Breast and Ovarian Cancer syndrome (HBOC), characterized by germline mutations in tumor suppressor genes such as BRCA, PTEN and TP53. Yet, the prevalence of HBOC mutations remains unknown in T&T, as local health services for genetic counseling and testing in T&T currently do not exist. As such, our study aimed to determine the prevalence rate of HBOC mutations among women with breast cancer in T&T who met NCCN criteria for evaluation for HBOC syndrome; thus investigating whether there is a need to include genetic testing and counseling in local oncology management in T&T. Methods: At the National Radiotherapy Center, the main oncology unit in T&T, female breast cancer patients, who met the NCCN criteria for further genetic counseling/testing, were recruited either through doctor referrals or chart reviews. We conducted interviews inquiring about their personal breast cancer diagnosis, risk factors for breast cancer, as well as any relevant family history. This was followed by the collection of saliva samples using Oragene kits, which were then analyzed by Color Genomics Inc. for 30 genes associated with hereditary cancers; including 19 HBOC associated genes such as BRCA1, BRCA2, TP53 and PTEN. Finalized results were returned to patients by genetic counselors from Color Genomics. Results: 165 patients who met NCCN guidelines for HBOC counseling/testing were approached, of whom 150 agreed to participate. Due to funding and resource limitations, 60 samples were collected thus far; ages ranged from 19-56. The majority of women met NCCN criteria based on age of personal breast cancer diagnosis (40%), and/or family history of breast and/or ovarian cancer (60%). Preliminary results show that of 49 samples, 10 patients tested positive for deleterious HBOC germline mutations: 7 - BRCA1, 2 - BRCA2 and 1 - PTEN; thus far giving a prevalence rate of 20%. Discussion: Therefore, our results found a strikingly high HBOC germline mutation prevalence rate of 20% among a cohort of female breast cancer patients meeting NCCN criteria in T&T. As we continue to finalize the incoming data on these patients, we hope to draw associations between their genetic status and their respective tumor markers, family history, and personal medical history. However, these initial results demonstrate the need to include genetic counseling and testing in the local oncology management in T&T, as the identification of HBOC mutations can influence treatment options, as well as help identify family members who are at high risk for cancer predisposition. Ultimately, this integration could help alleviate the country's high incidence and mortality rates with respect to breast cancer, and save the public healthcare system significant financial resources. Citation Format: Parkinson GT, Chagpar AB, Hofstatter EW, Nunez-Smith M. Investigation of HBOC germline mutations in women diagnosed with breast cancer in Trinidad and Tobago [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-10-01.

Next-generation sequencing promotes identification of mutations in non-BRCA1/2 genes in hereditary cancer families. The contribution of mutations in moderate penetrance genes to hereditary cancer risk is not well established. Here, we report a family with early onset breast and fallopian tube cancer that was identified as carrying germline mutations in BARD1 and ATM genes. Loss of heterozygosity studies suggest a causative role of the BARD1 mutation in the development of primary peritoneal cancer, but fail to confirm an association between germline ATM mutations and breast cancer development in this family. Complexities in interpreting implications of mutations in moderate-risk cancer susceptibility genes are discussed.

Purpose As a result of improved understanding of DNA repair mechanisms, poly(ADP-ribose) polymerase inhibitors (PARPi) are increasingly recognized to play an important therapeutic role in the treatment of cancer. The aim of this article is to provide a review of PARPi function in DNA damage repair and synthetic lethality and to demonstrate how these mechanisms can be exploited to provide new PARPi-based therapies to patients with solid tumors. Methods Literature from a range of sources, including PubMed and MEDLINE, were searched to identify recent reports regarding DNA damage repair and PARPi. Findings DNA damage repair is central to cellular viability. The family of poly(ADP-ribose) polymerase proteins play multiple intracellular roles in DNA repair, but function primarily in the resolution of repair of single-strand DNA breaks. Insights through the discovery of germline BRCA1/2 mutations led to the understanding of synthetic lethality and the potential therapeutic role of PARPi in the treatment of cancer. Further understanding of DNA damage repair and the concept of BRCA -like tumors have catalyzed PARPi clinical investigation in multiple oncologic settings. Implications PARPi hold great promise in the treatment of solid tumors, both as monotherapy and in combination with other cancer therapeutics. Multiple PARPi clinical trials are currently underway. Further understanding of aberrant DNA repair mechanisms in the germline and in the tumor genome will allow clinicians and researchers to apply PARPi most strategically in the era of personalized medicine.

Background Age is one of the most important risk factors for developing breast cancer. However, age-related changes in normal breast tissue that potentially lead to breast cancer are incompletely understood. Quantifying tissue-level DNA methylation can contribute to understanding these processes. We hypothesized that occurrence of breast cancer should be associated with an acceleration of epigenetic aging in normal breast tissue. Results Ninety-six normal breast tissue samples were obtained from 88 subjects (breast cancer = 35 subjects/40 samples, unaffected = 53 subjects/53 samples). Normal tissue samples from breast cancer patients were obtained from distant non-tumor sites of primary mastectomy specimens, while samples from unaffected women were obtained from the Komen Tissue Bank (n = 25) and from non-cancer-related breast surgery specimens (n = 28). Patients were further stratified into four cohorts: age

Interpretation of complex cancer genome data, generated by tumor target profiling platforms, is key for the success of personalized cancer therapy. How to draw therapeutic conclusions from tumor profiling results is not standardized and may vary among commercial and academically-affiliated recommendation tools. We performed targeted sequencing of 315 genes from 75 metastatic breast cancer biopsies using the FoundationOne assay. Results were run through 4 different web tools including the Drug-Gene Interaction Database (DGidb), My Cancer Genome (MCG), Personalized Cancer Therapy (PCT), and cBioPortal, for drug and clinical trial recommendations. These recommendations were compared amongst each other and to those provided by FoundationOne. The identification of a gene as targetable varied across the different recommendation sources. Only 33% of cases had 4 or more sources recommend the same drug for at least one of the usually several altered genes found in tumor biopsies. These results indicate further development and standardization of broadly applicable software tools that assist in our therapeutic interpretation of genomic data is needed. Existing algorithms for data acquisition, integration and interpretation will likely need to incorporate artificial intelligence tools to improve both content and real-time status.

Despite their efficacy, uptake of selective estrogen receptor modulators for breast cancer chemoprevention remains low. Exemestane, an aromatase inhibitor, has recently been identified as a potential chemopreventive option with fewer serious side effects compared with selective estrogen receptor modulators in postmenopausal women. The purpose of this study was to assess the uptake of exemestane in a breast cancer prevention clinic. A retrospective chart review was conducted to capture chemoprevention uptake by postmenopausal women presenting to the Yale Breast Cancer Prevention Clinic between November 2011 and November 2012. Descriptive statistics of the study population have been presented. Statistical analyses were carried out using SAS 9.3 (SAS Institute Inc., Cary, North Carolina, USA) between December 2012 and February 2013. Of 90 postmenopausal women, 56 were eligible for chemoprevention. Their mean age was 56.8 years. Among the women, 39% had osteopenia or osteoporosis. Thirteen women chose to start chemoprevention medication (23%). Although 31% of the chemopreventive medication administered included exemestane, only four of 56 postmenopausal women opted for exemestane (7%). Chemoprevention uptake rates of postmenopausal women in the setting of a breast cancer prevention clinic are higher than that reported in the general population; however, they remain low overall despite the inclusion of exemestane as an option. A significant proportion of postmenopausal women have decreased bone density, which is a potential barrier to exemestane uptake. The results provide practical implications suggesting that exemestane may have limited impact on breast cancer chemoprevention uptake. Further investigations should focus on understanding the factors that influence, predict, and increase chemoprevention uptake.

In recent years, the field of oncology has witnessed rapid advancements in genetic sequencing simultaneously with steeply declining costs of sequencing technology. As a result, genomics-driven cancer medicine and the use of tumor profiling are quickly becoming mainstays of cancer therapy. Oncology patients can benefit from tumor profiling by allowing the selection of targeted therapies tailored to their disease. However, it is increasingly recognized that the process of determining a tumor DNA sequence may lead to incidental discovery of underlying germline mutations which can impact other aspects of a patient’s health, and that of their family. How to handle the ‘incidentalome’ has been the subject of recent public debate, yet patient education about the potential risks of tumor profiling remains sparse. Patient perspectives and clinical implications of the tumor incidentalome must be specifically addressed by the oncology community as tumor profiling expands to become a new standard of care.

Extended adjuvant endocrine therapy (10 vs. 5 years) trials have demonstrated improved outcomes in early-stage estrogen receptor (ER)-positive breast cancer; however, the absolute benefit is modest, and toxicity and tolerability challenges remain. Predictive and prognostic information from genomic analysis may help inform this clinical decision. The purpose of this study was to assess the impact of the Breast Cancer Index (BCI) on physician recommendations for extended endocrine therapy and on patient anxiety and decision conflict. Patients with stage I–III, ER-positive breast cancer who completed at least 3.5 years of adjuvant endocrine therapy were offered participation. Genomic classification with BCI was performed on archived tumor tissues and the results were reported to the treating physician who discussed results with the patient. Patients and physicians completed pre- and post-test questionnaires regarding preferences for extended endocrine therapy. Patients also completed the validated traditional Decisional Conflict Scale (DCS) and State Trait Anxiety Inventory forms (STAI-Y1) pre- and post-test. 96 patients were enrolled at the Yale Cancer Center [median age 60.5 years (range 45–87), 79 % postmenopausal, 60 % stage I). BCI predicted a low risk of late recurrence in 59 % of patients versus intermediate/high in 24 and 17 %, respectively. Physician recommendations for extended endocrine therapy changed for 26 % of patients after considering BCI results, with a net decrease in recommendations for extended endocrine therapy from 74 to 54 %. After testing, fewer patients wanted to continue extended therapy and decision conflict and anxiety also decreased. Mean STAI and DCS scores were 31.3 versus 29.1 (p = 0.031) and 20.9 versus 10.8 (p

Introduction: Genetic testing for breast cancer risk is increasingly available, and patients’ perceptions regarding how results may affect their health insurance may affect their likelihood to opt for testing. We sought to determine the changes in patient perceptions regarding the impact of genetic testing on health insurance over a five year period from 2005 to 2010. Notably, during this time period two significant U.S. federal health care laws were enacted. First, the Genetic Information Nondiscrimination Act (GINA) passed in 2008, protecting against the use of genetic information for health insurance coverage. Second, the Patient Protection and Affordable Care Act (PPACA) passed in 2010, representing a major regulatory overhaul of the U.S. health care system, promising universal access to health care coverage. Methods: The National Health Interview Survey is a population-based face-to-face survey conducted annually by the CDC. In 2005 and in 2010, a cancer supplement was fielded which asked respondents who had undergone genetic testing whether they felt this had, or would, affect their health insurance. We evaluated the cohort of participants who had undergone genetic testing for breast cancer, and used SUDAAN statistical software to evaluate changes in the proportion who felt genetic testing would adversely affect their health insurance, and factors associated with this perception. Results: In 2005, 48 respondents had undergone genetic testing for breast cancer, representing 333,544 people in the population. Of these, 16.8% felt that genetic testing had, or would, affect their health insurance. In 2010, 16 respondents had undergone genetic testing for breast cancer, representing 93,301 people in the population. Of these, 17.4% felt that genetic testing had, or would affect their health insurance. In 2005, this perception varied based on insurance status, education, and region; but in 2010, perceptions of the impact of genetic testing on health insurance were unaffected by these factors. Patient Perception of Genetic Testing Effect on Health Insurance 20052010 %p-value%p-valueInsurance 0.006 0.276Uninsured11.8 22.8 Medicaid0 59.5 Medicare28.7 7.0 Private15.7 18.8 Other35.4 0 Education 0.031 0.463< Grade 128.7 7.9 High School/GED0 17.2 Some college0 19.0 Associates34.5 19.5 Bachelors34.2 5.6 Masters/Prof/Doctorate38.3 42.5 Region 0.077 0.122Northeast35.3 30.3 Midwest17.0 6.1 South3.2 29.1 West5.8 10.7 Age 0.449 0.4635512.2 21.1 Conclusion: More people undergoing genetic testing for breast cancer risk in 2010 were concerned that this would adversely affect their health insurance than in 2005, and there was less variation in this perception based on insurance, education and region than in the earlier period. We conclude that, despite the passage of significant U.S. legislation including GINA and PPACA, nearly 1 in 5 people undergoing genetic testing remained concerned about potential risk to their health insurance coverage. Accurate and early identification of those people carrying a cancer genetic mutation is crucial to cancer prevention and treatment efforts; our results suggest a dire need for improved education regarding federal protections for genetic testing so that any barriers to seeking genetic counseling are eliminated. Citation Format: Erin Hofstatter, Anees Chagpar. Patient perceptions of the impact of genetic testing for breast cancer risk on health insurance [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-11.

This was a feasibility study with the primary purpose to identify women with a diagnosis of breast cancer for survivorship care plan (SCP) delivery at the postoperative visit and deliver an SCP after treatment. The secondary purpose was to determine if patients' knowledge about their diagnosis, treatment, and risk for future adverse events improved with the SCP.Sixty-seven English-speaking women older than age 18 years with stage I-III breast cancer were enrolled at their postoperative appointment. The participants' treatment was tracked through the electronic medical record; SCPs were generated based on information abstracted from the records. After treatment completion, participants received an SCP during a routine follow-up appointment. Knowledge of tumor, treatments, adverse events, and screening recommendations were assessed before receiving the SCP and 2 months later. Accuracy at baseline and follow-up were compared using the McNemar test.One hundred twenty-nine visits were screened to identify 75 eligible participants. Seventy-five eligible participants (100%) agreed to enroll, and 71 (95%) were given an SCP. Participants were more accurate in reporting details about their history, screening recommendations, and potential adverse events at follow-up than they were at baseline for most measures, but the only statistically significant changes were found with stage (P = .0016) and increased risk of leukemia (P = .0348).It is feasible to identify and deliver SCPs to women with breast cancer who are approached during the postoperative visit in a surgical clinic. Additionally, SCPs seem to improve patient knowledge in several areas.

The purpose of this two-cohort Phase II trial was to estimate the pathologic complete response (pCR: ypT0/is ypN0) rate when trastuzumab plus pertuzumab are administered concurrently during both the taxane and anthracycline phases of paclitaxel and 5-fluorouracil/epirubicin/cyclophosphamide (FEC) neoadjuvant chemotherapy. The pCR rates were assessed separately in hormone receptor (HR) positive and negative cases following Simon’s two-stage design, aiming to detect a 20% absolute improvement in pCR rates from 50 to 70 and 70 to 90% in the HR-positive and HR-`negative cohorts, respectively. The HR-negative cohort completed full accrual of 26 patients; pCR rate was 80% (95% CI 60–91%). The HR+ cohort was closed early after 24 patients due to lower than expected pCR rate of 26% (95% CI 13–46%) at interim analysis. Overall, 44% of patients (n = 22/50) experienced grade 3/4 adverse events. The most common were neutropenia (n = 10) and diarrhea (n = 7). There was no symptomatic heart failure, but 28% (n = 14) had ≥ 10% asymptomatic decrease in LVEF; in one patient, LVEF decreased to

Purpose: The 21-gene recurrence score (RS) assay is used to help formulate adjuvant chemotherapy recommendations for patients with estrogen receptor–positive, early-stage breast cancer. Most frequently, medical oncologists order RS after surgery. Results take an additional 2 weeks to return, which can delay decision making. We conducted a prospective quality-improvement project to assess the impact of early guideline-directed RS ordering by surgeons before the first visit with a medical oncologist on adjuvant therapy decision making. Materials and Methods: Surgical oncologists ordered RS testing following National Comprehensive Cancer Network guidelines at time of diagnosis or at time of surgery between July 1, 2015 and December 31, 2015. We measured the testing rate of patients eligible for RS, time to chemotherapy decisions, rates of chemotherapy use, accrual to RS-based clinical trials, cost, and physician acceptance of the policy and compared the results to patients who met eligibility criteria for early guideline-directed testing during the 6 months before the project. Results: Ninety patients met eligibility criteria during the testing period. RS was ordered for 91% of patients in the early testing group compared with 76% of historical controls ( P < .001). Median time to chemotherapy decision was significantly shorter in the early testing group (20 days; 95% CI, 17 to 23 days) compared with historical controls (32 days; 95% CI, 29 to 35 days; P < .001). There were no significant differences in time to chemotherapy initiation, chemotherapy use, RS-based trial enrollment, or calculated costs between the groups. Conclusion: Early guideline-directed RS testing in selected patients is an effective way to shorten time to treatment decisions.

Some suggest that lymph node (LN) evaluation not be performed routinely in women aged ≥70 years with clinically (c) LN-negative (−), hormone receptor (HR)-positive (+) breast cancer. We sought to determine the association of omission of LN evaluation on survival. Patients who met the above criteria and were diagnosed from 2004 to 2012 were identified in the NCDB and SEER databases. Overall survival (OS) and breast cancer-specific survival (BCSS) were determined. Using the NCDB, we identified 157,584 cLN− HR+ patients aged ≥70 years in whom survival and LN evaluation data were available. A total of 126,638 patients (80.2%) had regional LN surgery. With a median follow-up of 41.6 months, there was a significant difference in OS between those who had LN evaluation and those who did not (median OS: 100.5 vs. 70.9 months, respectively, p

6574 Background: Trinidad and Tobago (T&T) is the southern-most Caribbean island, and according to the WHO/PAHO, it has the 2nd highest breast cancer mortality rate in the region. Notably, a large proportion of breast cancer cases in T&T occur at a young age; with nearly 36% of them being diagnosed under the age of 50. There is a known association between a younger age at diagnosis and Hereditary Breast and Ovarian Cancer syndrome (HBOC). Yet, the prevalence of HBOC mutations remains unknown in T&T, as genetic counseling and testing services are extremely limited in the region. Therefore, we sought to determine the prevalence and spectrum of HBOC mutations in T&T. Methods: At the National Radiotherapy Center, T&T’s main oncology unit, female breast cancer patients, who met NCCN criteria for further genetic counseling and testing were recruited through chart reviews. After pre-test counseling, enrolled subjects had a detailed interview about their personal breast cancer diagnosis and family history. A saliva sample was collected using an Oragene kit, and analyzed by Color Genomics Inc. for 30 genes associated with hereditary cancers. Finalized results were returned to patients by genetic counselors from Color Genomics. Results: A total of 118 female patients who met NCCN guidelines for HBOC testing received genetic testing. A majority were 50 years of age or younger (69/118, 59%). The cohort was ethnically diverse: 34% African, 15% Asian, 48% multiple ethnicity, and 3% other/unknown. A pathogenic or likely pathogenic variant (positive result) was identified in 21.2% of the cohort (25/118) - most commonly identified in the BRCA1 gene (13/25, 52%), followed by BRCA2 (5/25, 20%), PTEN (2/25, 8%), BRIP1 (1/25, 4%), CHEK2 (1/25, 4%), MSH6 (1/25, 4%), PALB2 (1/25, 4%), and RAD51C (1/25, 4%). Conclusions: We found a strikingly high HBOC germline mutation prevalence rate of 21.2% among a cohort of female breast cancer patients meeting NCCN criteria for HBOC testing in T&T. Given the growing implications of germline HBOC mutations for breast cancer treatment and prevention, our results demonstrate an urgent need for funding, as well as the development of robust genetic counseling and testing services in T&T.

Introduction: Tamoxifen and raloxifene have been shown to reduce the risk of breast cancer by up to 50%, yet the uptake of these agents remains poor. We sought to determine factors associated with chemoprevention uptake in a nationally representative sample. Methods: The National Health Interview Survey (NHIS) is a population-based survey conducted annually by the CDC and is designed to be representative of the non-institutionalized civilian population in the United States. We utilized data from the 2010 NHIS cancer supplement to determine factors associated with chemoprevention uptake in women ≥ 35 years of age. Statistical analyses were conducted using SUDAAN software. Results: In 2010, 10,959 women ≥ 35 years of age were surveyed, representing 83,377,082 people in the population. Of these, 0.21% reported taking chemoprevention, using either tamoxifen or raloxifene. On bivariate analyses, factors correlating with chemoprevention uptake included age, race/ethnicity, education, insurance, income and geographic region (see Table). Interestingly, MRI use, family history of premenopausal breast cancer in first degree relatives, and personal risk perception were not associated with chemoprevention use. On multivariate analysis, education and income remained independent predictors of chemoprevention use. Conclusion: Approximately 0.2% of women take chemoprevention. It is concerning that sociodemographic factors of education and income are independent predictors of the use of chemopreventive agents for breast cancer, while risk perception and family history do not seem to correlate with uptake rates. These findings are a call to action for improved education and counseling of those who are at greatest risk, and highlight potential disparities in access to appropriate chemoprevention across all sociodemographic groups. Bivariate and Multivariate Analyses of Factors Correlated with Chemoprevention UptakeFactorBivariate AnalysisMultivariate Analysis Chemoprevention (%)No Chemoprevention (%)p-valueOR (95% CI)p-valueAge 0.0481 0.1087< 40 yr3.2211.93 1.00 40-49 yr5.8726.11 0.78 (0.05-12.44) 50-59 yr11.7024.88 1.44 (0.10-21.43) 60-69 yr23.8218.54 3.15 (0.32-31.41) 70-79 yr44.4110.77 8.62 (0.78-94.75) 80+ yr10.997.77 1.53 (0.10-23.66) Race/ethnicity 0.0006 0.8372Hispanic3.9011.06 00.81 (0.11-5.85) White96.1071.63 1.00 Black011.80 - Asian04.61 - Other00.89 - Education 0.0371 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-05.

Background: Despite national guidelines for routine screening mammography at least every two years beginning at age 40 for all women, and common knowledge of the increased risk associated with a family history, many women with a family history of breast cancer do not follow these recommendations. We sought to determine (a) the reasons why these women fail to adhere to screening guidelines, and (b) how these reasons compared with the general population in a nationally representative sample. Methods: The National Health Interview Survey (NHIS), conducted annually by the Centers for Disease Control, is designed to be representative of the US population. The 2010 NHIS Cancer Supplement was used to evaluate the most common reasons women with a first degree family history of breast cancer cited for not having a mammogram in the past two years. Results: In 2010, there were 9631 women over the age of 40 (representing 73,448,042 people in the population) surveyed. Of these, 12.5% had a first degree family history of breast cancer. Overall, 21.5% of women over 40 claimed they did not have a mammogram within the past 2 years, and this rate was not significantly different between those with a first degree family history of breast cancer and those without (20.5% vs. 21.6%, respectively, p = 0.452). The reasons why women with and without a family history failed to adhere to screening guidelines, however, significantly differed, primarily driven by the fact that women with a first degree family history of breast cancer who were older than age 40 knew that they were not too young to have a mammogram (see table below, p Conclusions: While women with a first degree family history of breast cancer are known to be at increased risk, they are not more likely to adhere to screening mammography guidelines than the general population and over 20% will not have had a mammogram within the past two years. Over a third of these women at increased risk report that they didn't think about it or didn't think they needed one, and 13.8% state their doctor didn't recommend a mammogram. These data highlight a significant need to better educate women with a family history of a first degree relative with breast cancer and their physicians regarding the need for appropriate screening. Proportion (%) First Degree Family HistoryNo First Degree Family HistoryNever thought about it27.8931.36Didn't need it7.159.32Doctor didn't say I needed it13.8212.17Haven't had any problems10.899.14Put it off12.4711.14Too expensive13.3412.36Too unpleasant3.173.36Too young01.96Don't have a doctor1.701.92Other9.577.28 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-13-04.

While next-generation genome sequencing can successfully guide cancer therapy, it can also reveal significant incidental findings that patients, families, and physicians may not be prepared to handle and may not want to know.

Women ≥70 years old with clinically (c) lymph node (LN) negative (-), hormone receptor (HR) positive (+) breast cancer are recommended not to be routinely staged with a sentinel LN biopsy. We sought to determine how this affects adjuvant decision-making.Statistical analyses were performed to determine the association of LN evaluation with adjuvant chemotherapy and radiation therapy in cLN-, HR + breast cancer patients in the National Cancer Database.Between 2004 and 2013, there were 193,728 patients aged 70-90 with cLN-, HR + breast cancer; 15.0% were LN+. LN + patients were more likely to receive chemotherapy (28.3% vs. 5.5%, p 0.001), hormonal therapy (83.6% vs. 71.4%, p 0.001), post-lumpectomy radiation therapy (81.4% vs. 73.6%, p 0.001) and post-mastectomy radiation therapy (30.3% vs. 5.1%, p 0.001).15% of patients aged 70-90 will be LN+. These patients more frequently receive systemic and radiation therapy. LN status may affect treatment in these patients.

A 48-year-old female presents to the office complaining of vaginal dryness and painful intercourse. Her past medical history is significant for an estrogen receptor-positive breast cancer treated surgically 6 months ago. She is currently on tamoxifen for endocrine therapy. Her last menstrual period was 4 months ago, and over the past 4 months, she has experienced moderate hot flashes and trouble sleeping due to night sweats for which she initiated gabapentin with significant benefit. She notes that her personal life and relationship is being affected by the vaginal symptoms.

The US Preventative Services Task Force recommends providers perform a risk assessment in order to identify those patients who have a personal and/or family history of cancer that may be associated with a hereditary cancer predisposition. The collection of an accurate, cancer-focused family history is the foundation of this risk assessment. Professional organizations have created guidelines outlining when patients should be referred to a provider with expertise in hereditary cancer genetics for further risk assessment. Debate exists over which health care providers have this expertise and who should ideally provide these services, but most agree that patients and providers are best served when providers collaborate with one another as part of multidisciplinary teams with open communication. The cancer genetic counseling process has been described as a multistep communication process that includes intake, risk assessment, pretest counseling and informed consent, and result disclosure and interpretation. Though the focus of this volume is the management of individuals with BRCA mutations, any current discussion of hereditary breast and ovarian cancer would not be complete without mention of other rare high-penetrance and moderate-penetrance genes that are now included in many routine clinical genetic testing options for hereditary breast and ovarian cancer. Thus, the available data about these genes will also be summarized.

Recent developments in breast imaging technology and chemoprevention clinical trials have provided promising new options for patients at increased risk of breast cancer. Yet there remains much debate and confusion among providers, patients, and insurers regarding accurate breast cancer risk assessment, appropriate breast cancer screening, and options for breast cancer prevention. We review the most recent literature on these topics in order to provide practicing clinicians with current, practical updates on breast cancer prevention and early detection for women at increased risk of breast cancer.

Purpose: The 3-biomarker homologous recombination deficiency (HRD) assay measures the number of telomeric allelic imbalances, loss of heterozygosity, and large-scale state transitions in tumor DNA and combines these metrics into a single score that reflects DNA repair deficiency. The goal of this study is to assess the consistency of these HRD measures in different biopsies from distinct areas of the same cancer. Experimental Design: HRD scores, BRCA mutation status, and BRCA1 promoter methylation were assessed in 99 samples from 33 surgically resected, stage I–III breast cancers; each cancer was biopsied in three distinct areas. Homologous recombination repair (HR) deficiency was defined as either high HRD score (≥42) or tumor BRCA mutation. Results: Eighty-one biopsies from 32 cancers were analyzed. Tumor BRCA status was available for all samples, HRD scores for 70, and BRCA1 methylation values for 76 samples. The BRCA1/2 mutation and promoter methylation status and HR category showed perfect concordance across all biopsies from the same cancer. All tumors with BRCA1/2 mutations or promoter methylation had high HRD scores, as did 17% (4/24) of the BRCA1/2 wild-type and nonmethylated tumors. The HRD scores were also highly consistent between different biopsies from the same tumor with an intraclass correlation coefficient of 0.977, indicating that only 2.3% of the variance is attributed to within-tumor biopsy-to-biopsy variation. Conclusions: These results indicate that within-tumor spatial heterogeneity for HRD metrics and the technical noise in the assay are small and do not influence HRD scores and HR status. Clin Cancer Res; 23(5); 1193–9. ©2016 AACR.

Because of the paucity of large, randomized trials concerning the cardiac care of patients with cancer, treatment and prevention of chemotherapy-induced cardiotoxicity must rely on insights gained from small trials and case reports as well as the application of guidelines developed for the general population. In these clinical vignettes, we present patients referred by their oncologists to a cardiologist for specialized evaluation and management of cardiotoxicity with the goal of emphasizing the importance of identifying risk factors for cardiotoxicity, initiating evidence-based therapy, and establishing a close collaboration between oncologists and cardiologists.

PALB2 (Partner And Localizer of BRCA2) binds to and co-localizes with BRCA2 in DNA repair. Germline mutations in PALB2 have been identified in approximately 1–2% of familial breast cancer and 3–4% of familial pancreatic cancer cases. The goal of this study was to evaluate the prevalence of PALB2 mutations in women with breast cancer without BRCA1/2 mutations who also had a personal or family history of pancreatic cancer. PALB2 mutation analysis was performed in 94 non-BRCA1/2 breast cancer patients with a personal or family history of pancreatic cancer. Two truncating PALB2 mutations, c.3549C>CA and c.2962C>CT, were identified resulting in a mutation prevalence of 2.1%. The proband found to carry the c.3549C>CA PALB2 mutation had a mother diagnosed with both breast and pancreatic cancer; this relative was subsequently confirmed to carry the identical mutation. The proband with the c.2962C>CT mutation had a father and paternal aunt diagnosed with pancreatic cancer; neither relative was available for testing. Two novel PALB2 missense variants were also found, one of which was deemed potentially deleterious. The prevalence rate of PALB2 mutations in a non-BRCA1/2 breast cancer population specifically selected for a family history of pancreatic cancer does not appear to be significantly increased compared to that observed in other breast cancer populations studied thus far. Further evaluation is needed to determine the prevalence of PALB2 mutations and the clinical utility of such testing in those individuals affected with both breast and pancreatic cancers.

1554Background: In the United States, nearly 300,000 cancer diagnoses each year are attributed to poor diet and physical inactivity. We sought to determine whether perceived personal breast cancer ...

586Background: The goal of this Phase I/II trial is to assess the safety and efficacy of concurrent administration of durvalumab with weekly nab-paclitaxel (100 mg/m2) x 12 followed by dd AC x 4 as...

e13541Background: Recent evidence suggests that black cohosh (Cimicifuga racemosa) may prevent and treat breast cancer through anti-proliferative, pro-apoptotic, anti-estrogenic, and anti-inflammat...

We performed an analysis to determine the relative contribution of the Oncotype DX (ODX) recurrence score (RS) results in adjuvant therapy delivery compared with traditional pathologic factors.We performed a retrospective review of women with stage I-IIIA breast cancer treated at the Yale Comprehensive Cancer Center from 2006 to 2012 with available ODX results. We constructed separate logistic models with the clinicopathologic factors alone and also integrating RS and compared these models using the likelihood ratio test and c-statistic to determine whether integration of the RS will result in better prediction of chemotherapy (CTx) delivery.We identified 431 women with a median age of 58 years. The RS was low (18), intermediate (18-30), and high (30) in 56%, 37%, and 7%, respectively. CTx was delivered to 30% of the patients. Age, differentiation, lymphovascular invasion, and progesterone receptor (PR) positivity50% were associated with CTx delivery in multivariable logistic regression of clinicopathologic factors alone (P.05). In the model integrating the RS, an intermediate or a high RS was the most influential factor for CTx delivery (odds ratio, 7.87 vs. 265.35, respectively; P.0001). The PR results and grade were no longer significant (P = .74 and P = .06, respectively). The integration of the RS resulted in improved model fit and precision, indicated by the likelihood ratio test (ΔG2, 100.782; df = 2; P.0001) and an improved c-statistic (0.720 vs. 0.856).Gene expression profiling appears to account for a substantial amount of variability in CTx delivery in current practice. Further work is needed to ensure appropriate test usage and cost-effectiveness.

There is growing consensus that multigene prognostic tests provide useful complementary information to tumor size and grade in estrogen receptor (ER)-positive breast cancers. The tests primarily rely on quantification of ER and proliferation-related genes and combine these into multivariate prediction models. Since ER-negative cancers tend to have higher proliferation rates, the prognostic value of current multigene tests in these cancers is limited. First-generation prognostic signatures (Oncotype DX, MammaPrint, Genomic Grade Index) are substantially more accurate to predict recurrence within the first 5 years than in later years. This has become a limitation with the availability of effective extended adjuvant endocrine therapies. Newer tests (Prosigna, EndoPredict, Breast Cancer Index) appear to possess better prognostic value for late recurrences while also remaining predictive of early relapse. Some clinical prediction problems are more difficult to solve than others: there are no clinically useful prognostic signatures for ER-negative cancers, and drug-specific treatment response predictors also remain elusive. Emerging areas of research involve the development of immune gene signatures that carry modest but significant prognostic value independent of proliferation and ER status and represent candidate predictive markers for immune-targeted therapies. Overall metrics of tumor heterogeneity and genome integrity (for example, homologue recombination deficiency score) are emerging as potential new predictive markers for platinum agents. The recent expansion of high-throughput technology platforms including low-cost sequencing of circulating and tumor-derived DNA and RNA and rapid reliable quantification of microRNA offers new opportunities to build extended prediction models across multiplatform data.