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Background: With the development of novel antibody drug conjugates (ADC), it is increasingly important to understand the changes that occur in cell-surface targets over time from early-stage to metastatic breast cancer. Discordance in HER2 expression per immunohistochemistry (IHC) has been reported between primary and metastatic tumors in patients (pts) with HER2-negative breast cancer defined per ASCO/CAP guidelines, with both gain and loss of expression described. Representation of HR-negative (TNBC) tumors has been limited in these studies, and HER2 status at multiple time points in TNBC has not been described. Here we report changes in HER2 IHC in patients diagnosed with TNBC, using a collection of matched tumor samples over time. Methods: Pts were identified from two sources: 1) an institutional database including all consecutive pts who underwent surgery for stage I-III breast cancer at Dana-Farber/Brigham Cancer Center between 2015-2018, and 2) a prospective research biopsy protocol for pts with known or suspected metastatic breast cancer. Pts were included in the present analysis if they received neoadjuvant chemotherapy (NAC) for stage I-III TNBC (eTNBC), or if they were diagnosed with any stage TNBC and ultimately developed metastatic TNBC (mTNBC). Clinical pathology records were reviewed for HER2 IHC results of samples collected at: initial diagnosis (DX); residual disease (RD) post-NAC, if applicable; and at recurrence (M). HER2 IHC was classified as HER2-0 if HER2 IHC 0, and HER2-low if 1+ or 2+ (and ISH non-amplified). For matched comparisons, if IHC was performed in more than one DX sample (e.g., breast, node), only the breast was considered; if more than one M sample, only the first M biopsy with available IHC was considered. Results: Among 110 pts in this cohort, 101 were initially diagnosed with eTNBC (79 received NAC; 22 underwent surgery as first intervention) and 9 with de novo mTNBC. Median age was 48.7 years (range 19.8-71.6). Among all pts, a total of 292 samples (136 DX, 53 RD, 103 M) had available HER2 IHC scores. When restricting to one sample per time point, HER2-low prevalence was 49/102 (48.0%) in DX breast tumors, 21/53 (39.6%) in RD, and 13/58 (22.4%) in first M samples (with all remaining samples HER2-0, except one HER2 3+ sample). In eTNBC pts, HER2 IHC scores were available for 50 paired DX and RD, and 48 paired DX and M samples. Among 50 pts with paired DX and RD, HER2 IHC was discordant in 56% (28/50) (Table 1). Of the 21 HER2-0 DX tumors, 23.8% (5/21) became HER2-low at RD. Of the 29 HER2-low DX tumors, 51.7% (15/29) became HER2-0 at RD. Among 48 eTNBC pts who recurred and had paired DX and M samples, HER2 IHC was discordant in 50% (24/48) (Table 1). Change from HER2-0 to low was 12.5% (3/24), and from HER2-low to HER2-0 was 66.7% (16/24). Among 9 de novo mTNBC pts, 5 had HER2 IHC available in paired DX breast and M prior to starting therapy; 3 were concordant (IHC 0, n=2; IHC 1+, n=1), one had IHC 0 in DX breast and IHC 2+ in M (liver), one had IHC 1+ in DX breast and IHC 0 in M (node). Conclusions: HER2 IHC classification was discordant in about half of the TNBC cases we examined, with more frequent rates of conversion from HER2-low to HER2-0 in both paired DX/RD post-NAC, and paired DX/M samples. Additional analyses will be presented exploring HER2 IHC changes among multiple metastases per patient. Genomic and molecular analysis, including whole exome sequencing, RNA sequencing, and methylation profiling, are underway in these samples to further elucidate HER2 evolutionary dynamics. Citation Format: Ana C. Garrido-Castro, Lan D. Ngo, Edward T. Richardson, Allison Frangieh, Ayesha Mohammed-Abreu, Melissa E. Hughes, Jorge Gomez Tejada Zanudo, John Navarro, Paolo Tarantino, Elizabeth A. Mittendorf, Sara Tolaney, Tari King, Eric Winer, Nancy U. Lin, Nikhil Wagle. HER2-10 Dynamics of HER2-low expression in triple-negative breast cancer [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 HER2-10.

BackgroundAims of the study were to determine the effects of humerus intraosseous (HIO) versus intravenous (IV) administration of epinephrine in a hypovolemic, pediatric pig model. We compared concentration maximum (Cmax), time to maximum concentration (Tmax), mean concentration (MC) over time and return of spontaneous circulation (ROSC).MethodsPediatric pig were randomly assigned to each group (HIO (n=7); IV (n=7); cardiopulmonary resuscitation (CPR)+defibrillation (defib) (n=7) and CPR-only group (n=5)). The pig were anesthetized; 35% of the blood volume was exsanguinated. pigs were in arrest for 2 min, and then CPR was performed for 2 min. Epinephrine 0.01 mg/kg was administered 4 min postarrest by either route. Samples were collected over 5 min. After sample collection, epinephrine was administered every 4 min or until ROSC. The Cmax and MC were analyzed using high-performance liquid chromatography. Defibrillation began at 3 min postarrest and administered every 2 min or until ROSC or endpoint at 20 min after initiation of CPR.ResultsAnalysis indicated that the Cmax was significantly higher in the IV versus HIO group (p=0.001). Tmax was shorter in the IV group but was not significantly different (p=0.789). The MC was significantly greater in the IV versus HIO groups at 90 and 120 s (p2 indicated the IV group (5 out of 7) had significantly higher rate of ROSC than the HIO group (1 out of 7) (p=0.031). One subject in the CPR+defib and no subjects in the CPR-only groups achieved ROSC.DiscussionBased on the results of our study, the IV route is more effective than the HIO route.

Background Epidural analgesia and intravenous analgesia with opioids are two techniques for the relief of labor pain. The goal of this study was to develop a cost-identification model to quantify the costs (from society's perspective) of epidural analgesia compared with intravenous analgesia for labor pain. Because there is no valid method to assign a dollar value to differing levels of analgesia, the cost of each technique can be compared with the analgesic benefit (patient pain scores) of each technique. Methods The authors created a cost model for epidural and intravenous analgesia by reviewing the literature to determine the rates of associated clinical outcomes (benefit of each technique to produce analgesia) and complications (e.g., postdural puncture headache). The authors then analyzed data from their institution's cost-accounting system to determine the hospital cost for parturients admitted for delivery, estimated the cost of each complication, and performed a sensitivity analysis to evaluate the cost impact of changing key variables. A secondary analysis was performed assuming that the cost of nursing was fixed (did not change depending on the number of nursing interventions). Results If the cesarean section rate equals 20% for both intravenous and epidural analgesia, the additional expected cost per patient to society of epidural analgesia of labor pain ranges from $259 (assuming nursing costs in the labor and delivery suite do not vary with the number of nursing interventions) to $338 (assuming nursing costs do increase as the number of interventions increases) relative to the expected cost of intravenous analgesia for labor pain. This cost difference results from increased professional costs and complication costs associated with epidural analgesia. Conclusions Epidural analgesia is more costly than intravenous analgesia. How the cost of the anesthesiologist and nursing care is calculated affects how much more costly epidural analgesia is relative to intravenous analgesia. Published studies have determined that epidural analgesia provides relief of labor pain superior to intravenous analgesia, quantified in one study as 40 mm better on a 100-mm scale during the first stage of labor and 29 mm better during the second stage of labor. Patients, physicians, and society need to weigh the value of improved pain relief from epidural analgesia versus the increased cost of epidural analgesia.