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Background: Recent studies suggest differences in outcomes among patients (pts) with metastatic breast cancer (MBC) treated with abemaciclib, ribociclib, or palbociclib, but whether these differences have a genomic basis is unknown. Here, we utilize a large real-world dataset to compare the mutational landscapes of HR+/HER2- MBC samples in which CDK4/6 inhibitor (CDK4/6i) treatment was initiated ≥6 months prior to biopsy to describe variations in tumor biology associated with exposure to each CDK4/6i. We also compare mutations detected by solid tumor sequencing and liquid biopsy to better understand each assay’s ability to identify relevant alterations in this population. Methods: De-identified data from a cohort of pts with HR+/HER2- MBC (n=1172) sequenced with the Tempus xT (DNA-seq of 595-648 genes, whole exome-capture RNA-seq) solid tumor and xF (105-gene panel focused on detecting oncogenic and resistance mutations from cell-free DNA) liquid biopsy assays were retrospectively analyzed. For pts with multiple samples sequenced, the most recent sample was analyzed. Pts were selected based on receipt of CDK4/6i between metastatic diagnosis date and biopsy collection and excluded if < 6 months elapsed between CDK4/6i initiation and biopsy collection. Demographics, clinical characteristics, and NGS findings were compared between groups by Chi-squared/Fisher’s Exact tests or Kruskal-Wallis tests, as applicable. The prevalence of individual gene alterations (consisting of pathogenic/likely pathogenic SNVs/indels and copy number alterations) were compared similarly with adjustment for false-discovery. Results: We compared the immune biomarker and DNA mutational landscapes of 1172 samples collected after a period of treatment with abemaciclib, ribociclib, or palbociclib. Across all pts, the most commonly altered genes were TP53, PIK3CA, ESR1, CDH1, and GATA3. Abemaciclib-treated pts had the highest median TMB and MSI-high frequency (Table). Palbociclib-treated pts were less likely to have a high TMB (≥10 mutations/megabase) or RB1 mutations, a known biomarker of resistance to CDK4/6i (Table). We note that the total N for pts positive for TMB high or MSI-high was very low across all groups. We also compared DNA mutational landscapes between pts tested with solid tumor sequencing and liquid biopsy; the lower prevalence of RB1 mutations in palbociclib-treated pts trended towards significance in both groups (Table). Conclusions: Results from our real-world dataset suggest that treatment with the different CDK4/6i drugs results in unique immune biomarkers and DNA mutational profiles. Detection of relevant alterations such as RB1 by both tissue testing and liquid biopsy supports a role for either assay in identifying mutations associated with CDK4/6i. Our findings raise the possibility that unique targeted treatment strategies and combination therapies may be warranted after progression on the different CDK4/6i drugs. Additional investigation into the differences in genomic alterations and outcomes among CDK4/6i drugs is necessary to further explore the hypotheses generated by this real-world study. Prevalence of immune biomarkers and DNA mutations in pts treated with each CDK4/6i drug 1Pearson’s Chi-squared test; Fisher’s exact test; Kruskal-Wallis rank sum test 2False discovery rate correction for multiple testing 3,4N=464; 708 pts with missing data 5N=1163; 9 pts with missing data Citation Format: Ami N. Shah, Bora Lim, Monica M. Mita, Elizabeth Mauer, Kayla V. Layng, Calvin Chao, Adam M. Brufsky. The Mutational Landscape of 1172 Patients with Hormone Receptor-Positive, HER2-negative Metastatic Breast Cancer Treated with CDK4/6 Inhibitors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-23-12.

Background: Circulating tumor cells (CTCs) in breast cancer (BC) are commonly defined as epithelial cells (EPCAM and cytokeratin (CK) positive), lacking the universal blood cell marker CD45. Nonetheless, CTCs expressing both CK and CD45 (= dual-positive, DP cells) can be observed in the blood of cancer patients. Early evidence suggests that DP cells might derive from the fusion of tumor cells and macrophages, and we have previously demonstrated that they present aberrant genomes and are associated with worse prognosis in BC [1,2]. Here, to further investigate the mechanisms/pathways underlying their presence, we analyzed the association between DP cells and circulating tumor DNA (ctDNA) alterations. Methods: Blood samples were collected from patients with advanced BC (aBC), before starting a new line of therapy. All patients were enrolled in a prospective clinical trial. For CTC and DP cells analysis, 7.5 ml of blood collected in CellSave® tubes was processed with the FDA-approved CellSearch® platform (positivity cutoffs were ≥1 cell for DPcells and ≥5 cells for CTCs). For ctDNA analysis, plasma was collected from Streck stabilizing tubes and analyzed with the Guardant360™ NGS platform for the detection of somatic single nucleotide variants (SNVs), insertions/deletions (indels), gene fusions/rearrangements and copy number variations (CNVs), which were then classified into pathways based on previously defined profiles generated on the Cancer Genome Atlas database (RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Associations between ctDNA-detected gene alterations and circulating cell types were analyzed through chi square test, while mutant allele frequency (MAF) and number of detected alterations (NDA) were tested by Mann Whitney test. Results: We analyzed blood samples from 169 patients with luminal-like (n=80), HER2+ (n=34) and triple-negative (n=52) aBC. DPcells were detected in 85 patients (50.3 %, range 0-53), of which 40 (47 %) were CTC-positive and 45 (53%) CTC-negative. Somatic ctDNA alterations were detected in all analyzed samples. In the overall population, the presence of ≥1 DPcell was associated with SNVs in the cell cycle pathway (p = 0.043), a numerically higher incidence was also observed for CNVs in this pathway. SNVs and CNVs in the cell cycle pathway were associated with CTCs ≥ 5 as well (p = 0.005 and p = 0.003, respectively). Moreover, associations with CTCs ≥ 5 were observed for RTK SNVs and CNVs (p = 0.041 and p = 0.046, respectively), PI3K SNVs and CNVs (p = 0.006 and p = 0.007, respectively), MYC SNVs and CNVs (p = 0.042). No associations were observed in terms of MAF and NDA. In the luminal-like subgroup an association was highlighted for CNVs in the cell cycle pathway, p = 0.038. CTCs ≥ 5 were associated with PI3K SNVs (p = 0.031). In the triple-negative subgroup DPcells were associated with SNVs in the RAF pathway (p = 0.041), whereas CTCs ≥ 5 were associated with PI3K SNVs and CNVs (p = 0.044 and p = 0.024, respectively) and RTK SNVs (p = 0.008). In the HER2 positive subgroup, a higher MAF and number of detected SNVs was observed for samples with ≥1 DPcell (p = 0.0286 and p = 0.0099, respectively). Conclusions: The study analyzed ctDNA features associated with canonical and CK+/CD45+ CTCs, showing differential gene alteration profiles. Cell cycle pathway SNVs were common in both CTC populations, while other pathways (RTK, PI3K, MYC and RAF) were significantly altered in a mutually exclusive pattern. These results suggest that DPcells might have a different biological meaning compared to canonical CTCs. More studies need to be conducted to better characterize this understudied CTC subpopulation and understand their specific contribution to cancer progression. References: 1) Reduzzi C. et al., Semin Cancer Biol. 2020;60:344-350. DOI:10.1016/j.semcancer.2019.10.008 2) Reduzzi C. et al., Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) 1093-1093. DOI: 10.1200/JCO.2022.40.16_suppl.1093 Citation Format: Carolina REDUZZI, Lorenzo Gerratana, Youbin Zhang, Maroua MANAI, Paolo D’Amico, Andrew A. Davis, Jeannine Donahue, Ami N. Shah, Massimo Cristofanilli. Association between CK+/CD45+ circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) alterations in advanced breast cancer patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-26-06.

Background: PARP inhibitors are currently approved for the treatment of germline BRCA1/2 mutant metastatic breast cancer (MBC), which accounts for 5-10% of breast cancer. We hypothesize that a PARP inhibitor may also have efficacy in somatic BRCA1/2 mutant MBC, expanding the potential clinical applicability of PARP inhibitors. We previously demonstrated that somatic BRCA1/2 mutations can be identified by both cell-free DNA and tumor tissue genotyping in a subset of patients with MBC who are not germline BRCA1/2 carriers. Furthermore, a PARP inhibitor was demonstrated to induce cell growth inhibition in a circulating tumor cell culture model generated from a patient with pathogenic somatic BRCA1 mutant MBC (Vidula, Dubash, CCR, 2020). In this trial, we are evaluating the efficacy of a PARP inhibitor in somatic BRCA1/2 mutant MBC. Trial Design: This phase II investigator-initiated clinical trial is enrolling 30 patients with somatic BRCA1/2 mutant MBC identified via cell-free DNA or tumor tissue genotyping. Patients are treated with talazoparib, a PARP inhibitor, until disease progression. At baseline and every 3 months, patients undergo CT chest, abdomen, and pelvis, and a bone scan for disease assessment. Patients undergo blood collection at baseline for the Cancer Risk B (CR-B) assay, a novel flow variant assay to assess double-strand break repair mutations in circulating blood cells (Syeda, 2017) and monthly blood collection for cell-free DNA analysis to evaluate changes in the genomic environment. Eligibility Criteria: Patients with MBC with a pathogenic somatic BRCA1/2 mutation identified by cell-free DNA or tumor tissue genotyping are eligible. Both patients with triple-negative breast cancer (≥ 1 prior chemotherapy) or hormone receptor positive/HER2- MBC (≥ 1 prior hormone therapy) are eligible. Patients should not be known germline BRCA1/2 carriers. There is no limit on prior therapies including receipt of a prior platinum (in the absence of disease progression on prior platinum). A prior PARP inhibitor is not allowed. Adequate performance status and organ function are needed. Specific Aims: Primary aim is progression-free survival (PFS) assessed by RECIST 1.1. Secondary aims include objective response rate and toxicity assessed by NCI CTCAE v 5.0. Exploratory aims include assessing impact of BRCA1/2 reversion mutations in cell-free DNA, studying serial changes in BRCA1/2 mutant allelic frequency in cell-free DNA, comparing pre- and post-treatment cell-free DNA results to identify changes in the genomic environment, assessing the CR-B assay positivity rate, and correlating these biomarker analyses with patient response. Statistical Methods: This study uses a two-stage design with 80% power to demonstrate that talazoparib is associated with “success” (PFS > 12 weeks) in 53% patients (4% alpha). Accrual: This study (NCT03990896) is open at Massachusetts General Hospital, MD Anderson, University of California San Francisco, and Emory, with pending activation at Northwestern, Cornell, and Vanderbilt. Five patients are enrolled as of 7/2022. Funding: This study is supported by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Senthil Damodaran, Erica L. Blouch, Nora Horick, Nathan Royce Ruffle-Deignan, Manali Bhave, Ami N. Shah, Leticia Varella, Vandana Abramson, Joseph Sparano, Leif Ellisen, Ishraq Alim, Harry Ostrer, Hope Rugo, Aditya Bardia. Phase II study of talazoparib, a PARP inhibitor, in somatic BRCA1/2 mutant metastatic breast cancer identified by cell-free DNA or tumor tissue genotyping [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-11-01.

Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes. In 2014, the Primary Immune Deficiency Treatment Consortium published criteria for diagnosing SCID, which are now revised to incorporate contemporary approaches. Patients with typical SCID must have less than 0.05 × 10

The incidence of secondary cardiac tumouris 2.3% in previous autopsies studies. Common metastasizing tumours to the heart are lung, esophagus, breast, stomach, pancreas, melanoma, and colon. The oral sqaumous cell carcinoma metastasizing to the heart are r eported in few cases. we are presenting three cases, Out of which two cases of a 51yearold and 59yearold deceased male previously diagnosed with upper esophagus and Larynx squamous cell carcinoma, found having multiple metastatic lesions of lung, liver as well as metastatic foci to the heart in histopathological examination of tissues received after conducting autopsy. Another single case of 28 yearold female of adenocarcinoma of unknown origin,possibility of ovarian origin, which shows metastasis to all major organs including heart. The involvement was limited to the myocardium with a normal pericardium and endocardium, which is not common. The case details and relevant clinical discussion of all three cases are described to highlight asymptomatic, me tastatic foci of oral as well as laryngeal squamous cell carcinoma to myocardium and one case of adenocarcinoma of unknown origin. Keywords: Cardiac metastasis, secondary cardiac tumors 140 /pISSN:22316140, eISSN:23957859 Case Series

Recurrent primary spontaneous pneumothorax (PSP) is often managed with a wedge resection (or blebectomy) and either pleurectomy or pleurodesis. There is a conflicting data regarding which approach is superior to reduce recurrence. Our objective is to evaluate the long-term recurrence rates following pleurectomy versus mechanical pleurodesis for recurrent PSP.The PearlDiver Mariner Patient Claims Database was queried for patients aged 10-25 who were presented with PSP and underwent either pleurectomy or mechanical pleurodesis between 2010 and 2020. The primary outcome was recurrence and secondary outcomes included 30-day opioid prescriptions, pain diagnoses, and reimbursement. Kaplan-Meier analysis and Cox proportional hazards regression models were used with adjustment for age and sex.Of 18,955 patients presenting with PSP, 5.1% (n = 968) were managed operatively with either pleurectomy (18.3%, n = 177) or mechanical pleurodesis (81.7%, n = 791). There was no difference in the rate of recurrence between pleurectomy and mechanical pleurodesis (5-year risk of recurrence: 25.8% versus 26.5%, adjusted hazard ratio (HR) = 1.12 [95% confidence interval (CI): 0.79, 1.58]). Furthermore, there was no difference in rate of outpatient opioid prescription (49.2% versus 52.8%, P = 0.58) or pain diagnoses (22.0% versus 22.8%, P = 0.46) between pleurectomy and mechanical pleurodesis, respectively. The median reimbursement was higher following pleurectomy as compared to mechanical pleurodesis ($14,040 versus $5,811, P = 0.02).There is no significant difference in recurrence based on type of procedure performed for recurrent primary spontaneous pneumothorax. However, reimbursement is higher following pleurectomy. Given the similar outcomes but higher cost, we recommend mechanical pleurodesis over pleurectomy for recurrent PSP.

Telehealth is the use of electronic information and telecommunication technologies to provide care when the patient and the provider are not in the same room at the same time. Telehealth accounted for less than 1% of all Medicare Fee-for-Service outpatient visits in the United States in 2019 but grew to account for 46% of all visits in April 2020. Changes in reimbursement and licensure policies during the COVID-19 pandemic appeared to greatly facilitate this increased use. Telehealth will continue to account for a substantial portion of care provided in the United States and globally. A better understanding of telehealth approaches and their evidence base by public health practitioners may help improve their ability to collaborate with health care organizations to improve population health. The article summarizes the Centers for Disease Control and Prevention's (CDC's) approach to understanding the evidence base for telehealth in public health practice, possible applications for telehealth in public health practice, and CDC's use of telehealth to improve population health.

This cross-sectional study characterizes the use of International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) Z codes for social determinants of health among surgical vs nonsurgical practitioners at 3 academic hospitals.

PURPOSE As the continuation beyond progression (BP) of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is becoming increasingly attractive for the treatment of patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer (MBC), the definition of resistance factors is crucial. The aim of the study was to investigate the impact of CDK 4/6i BP and to explore potential genomic stratification factors. MATERIALS AND METHODS We retrospectively analyzed a multi-institutional cohort of patients with HR-positive HER2-negative MBC characterized for circulating tumor DNA through next-generation sequencing before treatment start. Differences across subgroups were analyzed by chi-square test, and survival was tested by univariable and multivariable Cox regression. Further correction was applied by propensity score matching. RESULTS Among the 214 patients previously exposed to CDK4/6i, 172 were treated with non–CDK4/6i-based treatment (non-CDK) and 42 with CDK4/6i BP. Multivariable analysis showed a significant impact of CDK4/6i BP, TP53 single-nucleotide variants, liver involvement, and treatment line on both progression-free survival (PFS) and overall survival (OS). Propensity score matching confirmed the prognostic role of CDK4/6i BP both for PFS and OS. The favorable impact of CDK4/6i BP was consistent across all subgroups, and a differential benefit was suggested for ESR1-mutated patients. ESR1 and RB1 mutations were more represented in the CDK4/6i BP subgroup with respect to CDK4/6i upfront. CONCLUSION The study highlighted a significant prognostic impact of the CDK4/6i BP strategy with a potential added benefit in patients with ESR1 mutations suggesting the need for an extensive biomarker characterization.

In critically ill, mechanically ventilated adults, diaphragmatic atrophy and reduced diaphragmatic thickening fraction (DTF) has been associated with poor extubation outcomes. Diaphragmatic ultrasound assessment in critically ill pediatric patients shows similar results, though studies are on-going. We sought to explore the feasibility and utility of using DTF, obtained during a spontaneous breathing trial (SBT) in predicting weaning outcomes.We conducted a prospective, observational study in a single-center tertiary noncardiac pediatric intensive care unit (PICU) in a children's hospital. Mechanically ventilated pediatric patients were included except for those with preexisting conditions of neuromuscular weakness, diaphragm paresis, or chronic respiratory failure requiring non-invasive or invasive mechanical ventilation at baseline. A convenience sample of 38 patients were included in the study.Weaning failure occurred in 10/38 (26%) instances with 9/38 (24%) occurring due to failed SBT and 1/38 (2%) due to failed extubation requiring reintubation. Median DTF was 24% (IQR: 12-33). DTF was significantly lower in instances of failed SBT, 12% compared to 27% (P .01). The odds ratio (OR) of SBT failure utilizing: TF 25% is 12 (CI: 1.33-108.0, Z-score: 2.22, P = .027), TV 5 mL/kg was 10.4 (CI: 1.76-61.67, Z-score: 2.58, P = .01), and combined TV 5 mL/kg and TF 25% is 17.6 (CI: 1.19-259.61, Z-score: 2.09, P = .04).Our preliminary study suggests that ultrasound measurements of diaphragm thickening fraction during spontaneous breaths in mechanically ventilated pediatric patients may be a useful addition in predicting weaning readiness.

Introduction : General surgery residents often feel unprepared to perform pediatric surgery procedures since case volume and experience may be low. Previously, we successfully implemented a simulation-based training (SBT) module for placement of a silastic silo for gastroschisis. Therefore, we designed a single institution pilot study to assess whether SBT for placement of a percutaneous peritoneal drain for perforated necrotizing enterocolitis (NEC) was feasible and lead to skill acquisition and increased confidence. Methods : Our newly created NEC module within our pediatric surgery SBT curriculum for general surgery residents was used. Residents completed two simulation sessions three months apart with confidence testing before and after each session. Skill acquisition and performance were assessed using a standardized case scenario and procedure checklist. Changes in residents’ confidence and performance were determined using Wilcoxon Signed-Rank Tests. Results : Nine post-graduate-year three general surgery residents completed this curriculum. Following completion, residents reported improved confidence completing each step of the procedure initially (p = 0.005) and at 3 months (p = 0.008) with improved technical scores (p = 0.011). The number of residents deemed proficient significantly improved (p = 0.031). Conclusion : Implementation of SBT module for perforated NEC was feasible and improved residents’ confidence and proficiency completing the procedure.

Gastrostomy tube (GT) placement is a common pediatric procedure with high postoperative resource utilization. We aimed to determine if standardized discharge instructions (SDI) reduced healthcare utilization rates.We performed a retrospective cohort study comparing postoperative hospital utilization of patients who underwent initial GT placement pre- and post-SDI protocol implementation from 2014-2019. Statistical analyses included Chi-square tests, multivariable adjusted logistic regression, adjusted Cox proportion hazard regression, and adjusted Poisson regression models when appropriate.197 patients were included, 102 (51.8%) before and 95 (48.2%) after protocol implementation. On primary analysis, SDI patients did not have significantly different total postoperative hospital utilization events at 30-days (48.0% vs. 38.9%, p = 0.25). On secondary analysis, SDI patients had lower rates of ED (8.4% vs. 19.6%, p = 0.026) and office visits (11.6% vs. 25.5%, p = 0.017) at 30-days. Non-SDIs patients had greater odds of ED visits (OR2.7, 95%CI 1.3-5.9, p = 0.01), office visits (OR3.7, 95%CI 1.7-8.1, p = 0.001) and phone calls (OR2.6, 95%CI 1.2-5.7, p = 0.016) at 1-year. The adjusted hazard ratio was 2.0 (95%CI 1.4-3.0, p 0.001). Incident rate ratio were 1.8 (95%CI 1.2-2.5, p = 0.002) at 30-days and 1.9 (95%CI 1.5-2.4, p 0.001) at 1-year post-discharge.SDIs post-GT placement may reduce multiple aspects of postoperative hospital utilization.

Background: Circulating tumor DNA (ctDNA) is being evaluated as a tool to monitor disease and guide therapy escalation and de-escalation in advanced breast cancer. The patient, disease, and treatment characteristics that influence whether tumor DNA is isolated and sequenced from the bloodstream are not well understood. We aimed to describe patient and disease characteristics of cases with undetectable ctDNA levels despite progressive metastatic breast cancer (MBC). Methods: We retrospectively identified patients (pts) with MBC who had ctDNA evaluation by the Guardant 360 assay (Redwood City, CA) as part of their routine care from 2015-2020. We correlated the ctDNA assay with the disease status at collection. We identified the patient cohort with no detectable ctDNA despite evaluation at the time of progressive disease but prior to the initiation of a new therapy (ND ctDNA/PD) and compared the clinical, pathologic, and molecular features of this group to those with detected ctDNA. Differences were tested by two proportion z-tests. Results: Of 1151 ctDNA samples collected among 473 pts with MBC, 87 (7.5%) samples had no detectable (ND) ctDNA. 54 of 87 samples with ND ctDNA were collected at a time of stable or responding disease or after a new line of therapy was started, leaving only 33 ctDNA evaluations (2.8%) among 30 pts with ND ctDNA despite collection at the time of PD prior to new therapy. Among this group there were 14 pts (47%) with HR+ HER-, 11 pts (37%) with HER2+, and 5 pts (17%) with TN MBC. This compared to 254 pts (60%) with HR+ HER2-, 82 pts (19%) with HER2+, and 85 pts (20%) with TN MBC and detectable ctDNA. HER2-positive MBC was more common in the ND ctDNA/PD group than detectable ctDNA group (p-0.02). In the ND ctDNA/PD group, the median time from MBC diagnosis to ctDNA evaluation was 7 months and pts had received a median of 0.5 prior lines of therapy for MBC. Four pts (13%) had lobular breast cancer, 24 pts (80%) had recurrent disease, 14 pts (47%) had visceral metastases, and 12 pts (40%) had oligometastatic disease. Sites of metastases at the time of ND ctDNA/PD were bone n=16 (53%), lung n=7 (23%), liver n=6 (20%), lymph node n=11 (37%), skin and soft tissue n=5 (17%), and CNS n=5 (17%). When compared to those with detectable ctDNA these differences in characteristics were not statistically significant, although numerically pts with ND ctDNA had more CNS disease (17% vs 10%) and less liver disease (20% vs 32%). At the time of ND ctDNA, the site of progression was bone n=14 (47%), CNS n=5 (17%), lymph node n=9 (30%), lung n=7 (23%), and liver n=5 (17%). There was a single site of progression in 20 pts (67%). 16 of 30 pts had repeat ctDNA analysis of which 9 pts had subsequent detectable ctDNA with a median VAF of 0.3%, a median of 1 alteration per sample, and oncogenic or likely oncogenic alterations in TP53 in 3 pts and BRCA1, CCNE1, CDH1, and PIK3CA in 1 pt each. Seven had tissue NGS, all of which showed multiple oncogenic alterations. The remaining 22 pts with ND ctDNA but no PD were responding to therapy based on imaging or had already started a new therapy since the last progression. This group also had a high proportion of HER2+ MBC (n=7, 32%) and low proportion with visceral disease (n=6, 27%) Conclusions: Although ctDNA is a highly sensitive tool to detect active MBC ( Citation Format: Ami N Shah, Lorenzo Gerratana, Shruti Chandra, Dhruvika Mukhija, Neelima Katam, Anthony K Kang, Andrew A Davis, Millen Srivastava, Saya Jacob, Paolo D'Amico, Qiang Zhang, Carolina Reduzzi, Michael Gurley, Firas Wehbe, William J Gradishar, Amir Behdad, Massimo Cristofanilli. Progressive metastatic breast cancer with no detectable circulating tumor DNA: Evaluating limitations of this highly sensitive tool [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 P2-08-04.

Background: Endocrine therapy with CDK 4/6 inhibitors (ET/CDK4/6i) represents the 1st line therapy for ER+/HER2- ABC. While majority of patients derive clinical benefit with combination therapy, a subset have refractory disease with progression within 6 months. However, predictive biomarkers for rapid progression are lacking. In this study, we evaluated genomic profiles associated with rapid disease progression on ET/CDK4/6i. Methods: We identified 77 patients who received 1st line ET/CDK4/6i combination therapy (AI or SERD with one of the 3 approved CDK4/6is) and had ctDNA analysis performed via plasma based genotyping utilizing the commercially available Guardant360 assay at three sites: Washington University in St. Louis, MO, Northwestern University (Chicago, IL), and Massachusetts General Hospital (Boston, MA). We aimed to look at the differences in patient characteristics and genomic profiles of the tumors assessed from baseline ctDNA specimens between the patients with rapid progression (time to progression TTP Citation Format: Marko Velimirovic, Lorenzo Gerratana, Andrew A Davis, Whitney L Hensing, Katherine Clifton, Ami N Shah, Paolo D'Amico, Charles S Dai, Elyssa N Denault, Cynthia X Ma, Seth A Wander, Dejan Juric, Massimo Cristofanilli, Bruce A Chabner, Aditya Bardia. Genomic predictors of rapid progression to first line endocrine and CDK4/6 inhibitor combination therapy in patients with estrogen receptor positive (ER+) HER-2 negative (HER2-) advanced breast cancer (ABC) [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 P2-07-02.

Background: The correlation of ERBB2 copy number gain (CNG) from tissue or circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) with standard HER2 tissue evaluation is not well understood. Materials and Methods: We retrospectively identified patients with ERBB2 CNG on commercial NGS. We described their clinical-pathologic features and calculated the positive predictive value (PPV) of ERBB2 CNG by NGS for HER2-positivity by IHC and FISH testing. Results: 176 patients had NGS revealing an ERBB2 CNG (112 by tumor tissue and 91 by ctDNA). The cancer subtypes with the most cases with ERBB2 CNG by NGS were breast (n = 67), non-small cell lung (n = 25), colorectal (n = 18), gastroesophageal (n = 17), pancreatic (n = 11), and uterine (n = 11). The PPV of ERBB2 CNG in determining HER2 positivity by standard IHC/FISH definitions was 88% for tissue NGS (n = 57) and 80% for ctDNA (n = 47). The PPV among breast cancer patients for tissue NGS was 97% (n = 35) and ctDNA was 93% (n = 39). However, for non-breast cancer cases, the PPV of ERBB2 amplification by tissue NGS dropped to 76% (n = 22) and by ctDNA to 44% (n = 7). Conclusions: ERBB2 CNG by NGS is detected in numerous malignancies for which HER2 testing is not standard. Detection of ERBB2 CNG by tissue NGS and ctDNA has a high PPV for true HER2-positivity by standard IHC and/or FISH testing in breast cancer.

Objectives SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients with Methods CONQUER participants who had completed a baseline and 12-month Gastrointestinal Tract Questionnaire (GIT 2.0) and a Resource Utilization Questionnaire (RUQ) were included in this analysis. Patients were categorized by total GIT 2.0 severity: none-to-mild (0–0.49); moderate (0.50–1.00), and severe-to-very severe (1.01–3.00). Clinical features and medication exposures were examined in each of these categories. The 12-month RUQ responses were summarized by GIT 2.0 score categories at 12 months. Results Among the 211 CONQUER participants who met the inclusion criteria, most (64%) had mild GIT symptoms, 26% had moderate symptoms, and 10% severe GIT symptoms at 12 months. The categorization of GIT total severity score by RUQ showed that more upper endoscopy procedures and inpatient hospitalization occurred in the CONQUER participants with severe GIT symptoms. These patients with severe GIT symptoms also reported the use of more adaptive equipment. Conclusion This report from the CONQUER cohort suggests that severe GIT symptoms result in more resource utilization. It is especially important to understand resource utilization in early disease cohorts when disease activity, rather than damage, primarily contributes to health-related costs of SSc.

Supplemental Table 1: Treatments by subgroup. Supplemental Figure 1A-D: Association of baseline MAF and NOA with survival

Background: Most health surveys ask women whether they have had a recent mammogram, all of which report mammography use (past 2 years) at about 70% to 80% regardless of race or residence. We examined the potential extent of overreporting of mammography use in low income African-American and Latina women, and whether self-report inaccuracies might bias estimated associations between patient characteristics and mammography use.Methods: Using venue-based sampling in two poor communities on the west side of Chicago, we asked eligible women living in two west side communities of Chicago to complete a survey about breast health (n = 2,200) and to provide consent to view their medical record. Of the 1,909 women who screened eligible for medical record review, 1,566 consented (82%). We obtained medical records of all women who provided both permission and a valid local mammography facility (n = 1,221). We compared the self-reported responses from the survey with the imaging reports found in the medical record (documented). To account for missing data, we conducted multiple imputations for key demographic variables and report standard measures of accuracy.Results: Although 73% of women self-reported a mammogram in the last 2 years, only 44% of self-reports were documented. Overreporting of mammography use was observed for all three ethnic groups.Conclusions: These results suggest considerable overestimation of prevalence of use in these vulnerable populations.Impact: Relying on known faulty self-reported mammography data as a measure of mammography use provides an overly optimistic picture of utilization, a problem that may be exacerbated in vulnerable minority communities. Cancer Epidemiol Biomarkers Prev; 23(8); 1649–58. ©2014 AACR.

Aberrant activation of members of the Src family of nonreceptor protein tyrosine kinases is common in solid tumor malignancies and may contribute to the development and/or progression of these tumors. As a result, four Src inhibitors are now in more than 50 clinical trials for at least 14 different types of solid tumors. In this review, we briefly discuss the preclinical rationale for Src inhibitors, the development strategies most likely to be successful in the clinic, and the rationale for Src inhibitors in combination with other agents as part of a more comprehensive therapeutic strategy. As the use of Src family inhibitors in clinical trials on solid tumors is in its infancy, further studies on the roles of Src family kinases in tumor progression, chemoresistance, epidermal-to-mesenchymal transition, and other properties of tumor progression will be important in designing the most effective clinical trials using these inhibitors.

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Purpose: Allogeneic hematopoietic stem-cell transplantation (HSCT) is a curative treatment for many hematologic cancers. Use of haploidentical (mismatched) donors increases HSCT availability but is limited by severe graft-versus-host disease (GvHD) and delayed immune reconstitution. Alloanergization of donor T cells is a simple approach to rebuild immunity while limiting GvHD after haploidentical HSCT, but the optimal T-cell dose and impact on immune reconstitution remain unknown.Patients and Methods: We performed a multicenter phase I trial of alloanergized donor lymphocyte infusion (aDLI) after CD34-selected myeloablative haploidentical HSCT. The primary aim was feasibility and safety with secondary aims of assessing the less frequently addressed issue of impact on immune reconstitution.Results: Nineteen patients with high-risk acute leukemia or myelodysplasia were enrolled. Engraftment occurred in 18 of 19 patients (95%). Pre-aDLI, 12 patients (63%) had bacteremia, nine of 17 at-risk patients (53%) reactivated CMV, and one developed acute GvHD. Sixteen patients received aDLI at dose levels 1 (103 T cells/kg, n = 4), 2 (104, n = 8), and 3 (105, n = 4). After aDLI, five patients developed clinically significant acute GvHD, and four of 14 at-risk patients (29%) reactivated CMV. T-cell recovery was significantly greater, and functional virus- and tumor-associated antigen-specific T cells were detectable earlier in patients receiving dose level 2 or 3 versus dose level 1/no aDLI. Alloanergization of donor cells expanded the CD4+ T-regulatory cell frequency within aDLI, which increased further in vivo without impeding expansion of virus- and tumor-associated antigen-specific T cells.Conclusions: These data demonstrate safety and a potential role for aDLI in contributing to immune reconstitution and expanding tolerogenic regulatory T cells in vivo after CD34-selected myeloablative haploidentical HSCT. Clin Cancer Res; 24(17); 4098–109. ©2018 AACR.

Supplementary Table S1 from Src Continues Aging: Current and Future Clinical Directions

Table S1 Patients, donors, HLA-mismatches and conditioning; Table S2 Cell doses in stem cell transplant, engraftment and chimerism; Table S3 ADLI dose and timing and allostimulator source; Table S4 Patient outcomes; Figure S1 Schema for clinical study; Figure S2 Alloanergization efficiency of DLI by centre and by dose level; Figure S3 Residual alloreactivity in aDLI and occurrence of acute GvHD after T-cell depleted haploidentical HSCT and aDLI; Figure S4 Phenotype of CD4+ regulatory T-cell (Treg) in patient peripheral blood after T-cell depleted haploidentical HSCT and aDLI