Citations

Abstract Background: Knowledge regarding risk of treatment-induced premature ovarian insufficiency (POI) is crucial for appropriate oncofertility counseling. While the gonadotoxicity of anthracycline- and cyclophosphamide-based chemotherapy (CT) in young breast cancer (BC) patients (pts) is well established, the impact of anti-HER2 agents remains largely unknown and limited conflicting evidence exists for taxanes. Anti-Mullerian hormone (AMH) is an established biomarker of ovarian reserve; its measurements during systemic therapies may aid in diagnosis and prediction of POI. The NeoALTTO trial represented a unique setting to explore the acute gonadotoxicity of anti-HER2 therapy alone and in combination with weekly paclitaxel in pts not previously exposed to any other potentially gonadotoxic anticancer treatment. Methods: NeoALTTO (NCT00553358) is a multicenter, open-label, randomized phase III neoadjuvant trial in HER2-positive early BC pts randomized to receive lapatinib (L), trastuzumab (T), or their combination (L+T) alone for 6 weeks followed by the addition of paclitaxel for 12 weeks before surgery.The present analysis included only premenopausal women aged ≤45 years with available frozen serum samples at baseline (i.e. before administering any anticancer treatment), at week 2 (i.e. “biological window” of anti-HER2 therapy alone) and/or at surgery (i.e. after completion of paclitaxel plus anti-HER2 therapy). Central AMH testing was performed at Erasme Hospital (Brussels, Belgium) with the Roche Elecsys® AMH Plus assay (LoD=0.010 ng/ml). AMH levels during anti-HER2 therapy alone and then combined with paclitaxel were assessed as a measure of treatment impact on ovarian reserve. The impact of different anti-HER2 agents (T and/or L), pts’ age and baseline AMH levels on treatment gonadotoxicity were also investigated. Results: The present analysis included 130 pts with a median age of 38 years (IQR: 33-42 years), of whom 86 (66.2%) were ≤40 years. At baseline, median AMH levels were 1.29 ng/mL (IQR 0.56 - 2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median value: 1.10 ng/mL, IQR 0.45 - 2.09 ng/mL, p<0.001; median cumulative decrease: -12.5%, IQR -37.6% - 12.4%). At surgery, there was a large significant decline in AMH levels (median value: 0.01 ng/mL, IQR 0.01 - 0.03 ng/mL, p<0.001; median cumulative decrease: -99.9%, IQR -100.0% - -98.7%). Type of anti-HER2 treatment (L vs. L vs. T+L) did not impact the results: there was no significant difference between treatment arms in degree of reduction in AMH levels at week 2 (p=0.763) or at surgery (p=0.700). Age and pre-treatment ovarian reserve had a major impact on treatment-induced gonadotoxicity risk, with a more profound decrease in AMH levels observed for older pts (p<0.001) and those with lower baseline AMH levels (p<0.001). Among pts aged <35 years, there was no significant difference in AMH levels between those with (n=7) or without (n=35) a subsequent pregnancy at baseline (p=0.316), week 2 (p=0.463) or at surgery (p=0.610). Conclusions: This biomarker analysis of the NeoALTTO trial showed for the first time the potential acute gonadal damage induced by anti-HER2 therapies alone and with the addition of weekly paclitaxel. We observed a small but significant reduction in AMH levels during T and/or L alone and then a profound reduction to almost undetectable levels following the addition of weekly paclitaxel, without differences by specific anti-HER2 regimen. Age and pre-treatment AMH levels strongly impacted gonadotoxicity risk. While this analysis is limited by lack of AMH measurement in longer term follow-up, findings have important implications for future research and oncofertility counseling of premenopausal women with HER2-positive BC. Citation Format: Matteo Lambertini, Marcello Ceppi, Richard A. Anderson, David A. Cameron, Marco Bruzzone, Maria Alice Franzoi, Claudia Massarotti, Sarra El-Abed, Yingbo Wang, Christophe Lecocq, Paolo Nuciforo, Rebecca Rolyance, Lajos Pusztai, Joohyuk Sohn, Jacopo Ligato, Maria Maddalena Latocca, Luca Arecco, Barbara Pistilli, Kathryn J. Ruddy, Alberto Ballestrero, Lucia Del Mastro, Fedro A. Peccatori, Ann H. Partridge, Cristina Saura, Michael Untch, Martine Piccart, Serena Di Cosimo, Evandro de Azambuja, Isabelle Demeestere. Impact of anti-HER2 therapy alone and in association with weekly paclitaxel on the ovarian reserve of young women with HER2-positive early breast cancer: Biomarker analysis of the NeoALTTO trial [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 PD5-05.

Abstract Although there is a lack of data in trimethoprim-sulfamethoxazole (TMP-SMX) serum monitoring utility for invasive nocardial infections, therapeutic drug monitoring is widely used to optimize dosing and avoid adverse reactions that may cause treatment interruption. We retrospectively reviewed all adults who received TMP-SMX to treat nocardial brain abscess and had SMX serum level testing from 2010 to 2020. Twenty-two patients received treatment with TMP-SMX for Nocardia species brain abscess and 16 (72.7%) had a reported SMX level, with a median patient age of 65.5 years (interquartile range, IQR 59.5–72.5). Compared to those who did not have a documented SMX serum level, patients with SMX levels had a shorter median course of TMP-SMX treatment (322 days [IQR 188–365] vs. 365 [IQR 224–365]; P = .31) and higher therapeutic induction dose (10 [62.5%] vs. 3 [50%]; P = .92). Similarly, they were more frequently on hemodialysis (3 [13.6%] vs. 1 [4.5%]; P = > .99). The median peak level was 158.5 (IQR 120–218) μg/mL, collected at 2 hours (75%) post-administration in the induction phase (81.3%). Patients with documented SMX levels had fewer reported drug toxicity (5 [31.3%] vs. 4 [66.7%]; P = .1) than those without SMX levels. Among the five patients who reported TMP-SMX-related toxicity, 4 (80%) had an SMX peak level >150 μg/mL. There was no difference in the cure, relapse, and death rates among the two groups. While SMX level was not associated with Nocardia species brain abscess cure rates and mortality, most patients with SMX peak >150 μg/mL experienced drug toxicity.

Abstract Cytogenetics has long represented a critical component in the clinical evaluation of hematologic malignancies. Chromosome banding studies provide a simultaneous snapshot of genome-wide copy number and structural variation, which have been shown to drive tumorigenesis, define diseases, and guide treatment. Technological innovations in sequencing have ushered in our present-day clinical genomics era. With recent publications highlighting novel sequencing technologies as alternatives to conventional cytogenetic approaches, we, an international consortium of laboratory geneticists, pathologists, and oncologists, describe herein the advantages and limitations of both conventional chromosome banding and novel sequencing technologies and share our considerations on crucial next steps to implement these novel technologies in the global clinical setting for a more accurate cytogenetic evaluation, which may provide improved diagnosis and treatment management. Considering the clinical, logistic, technical, and financial implications, we provide points to consider for the global evolution of cytogenetic testing.

Abstract Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation (AF) is known to cause dilation in both the mitral (MA) and the tricuspid (TA) annuli. Few studies have investigated MA dynamics and function in AF compared to sinus rhythm (SR). However, no study addressed this issue in TA. Hence, we set forth to describe TA dynamics in AF and SR and its relationship with severity of tricuspid regurgitation (TR). Methods 3D echocardiographic imaging data were acquired from adult patients in AF or SR with varying degrees of TR between 2018 and 2020. TA was automatically tracked throughout the cardiac cycle using a commercially available software (TomTec 4MV software; Figure 1) over 4-6 cardiac cycles per patient. Time to minimal area as percentage of the R-R interval was recorded in each of the cycles. Absolute change in TA area was calculated as the difference between maximal and minimal TA area in each cardiac cycle and was averaged over 4-6 cycles per patient. This measurement was used to reflect the dynamic range of TA deformation during the cardiac cycle. Right atrial (RA) and right ventricular (RV) volumes and longitudinal strain were also measured (speckle tracking, 4-ch view). Results A total of 70 patients were studied (35 AF; 35 SR; 54% males in each group). Patients with AF were older [median (IQR) of 81 (72-86) years vs. 69 (59-78) years in SR, p < 0.001], had larger maximal TA area and circumference (p < 0.001 for both), larger RA size (p < 0.001), lower RA reservoir strain (p < 0.001) and RV free-wall strain (p < 0.001). Absolute change in TA area was significantly decreased in AF [2.3 (1.7-2.7) cm2] vs. 3.1 (2.3-3.5) cm2 in SR, p = 0.002. Patients with ≥ moderate TR (n = 41, 59%) had lower absolute change in TA area [2.4 (1.7-3.1) cm2 vs. 2.8 (2.2-3.5) cm2 in < moderate TR, p = 0.05]. Female sex was associated with lower absolute change in TA area [2.3 (1.7-3.2) cm2 vs. 2.7 (2.2-3.6) cm2 in males, p = 0.02] on univariate analysis. AF patients had more frequently ≥ moderate TR [28 AF vs. 13 SR, p < 0.001]. On multivariate analysis including sex, rhythm, TR severity, RA and RV strains, and averaged maximal TA area, independent factors associated with lower absolute change in TA area were AF, ≥ moderate TR, and larger maximal TA area (p < 0.05 for all). Time to minimal TA size was achieved in (0-40%) of the R-R interval in 70% of patients in SR compared to only 41% of patients in AF (Figure 2) and in 73% in patients with < moderate TR compared to 43% in patients with ≥ moderate TR. Conclusion AF is associated with blunted TA dynamics resulting in lower decrease in TA size and with a heterogenous timing of minimal TA size throughout the cardiac cycle. The blunted and discoordinated annular contraction may reduce systolic tricuspid valve competence and be involved in the pathophysiology of functional TR. Future studies are needed to confirm this hypothesis and evaluate the effect of restoration of SR on TA dynamics and time to minimal TA size. Abstract Figure 1Abstract Figure 2

Abstract Funding Acknowledgements Type of funding sources: None. Background Tricuspid regurgitation (TR) is a prevalent valvular lesion with three broad morphologic subtypes: primary due to intrinsic pathology of the valve or subvalvular apparatus; secondary due to pulmonary hypertension; and isolated TR associated with chronic atrial fibrillation. The complex pathophysiological, clinical and echocardiographic features between these subtypes require further investigation. Purpose We aimed to identify the different phenotypes of TR using cluster analysis, and determine differences (if present) in clinical outcomes associated with these phenotypes. Methods We included 13611 patients with ≥ moderate TR, either primary or secondary, in the final analyses. The demographic, clinical and echocardiographic data of these patients were evaluated using Ward’s minimum variance cluster analysis including a total of 38 variables. Survival analysis for all-cause mortality was performed using the Kaplan-Meier method, and groups were compared using the log-rank test. Results The mean age of patients was 72.5 ± 13.4 years, 7590 (56%) were females. The clustering identified 5 distinct phenotypes. Cluster 1 represented "low-risk TR" with lesser severity likely related to chronic atrial fibrillation. This cluster had less severe TR, normal sized right ventricle and fewer comorbidities. Clusters 2-5 represented "higher severity TR", "TR associated with lung disease", "TR associated with coronary artery disease and ischemic cardiomyopathy" and "TR associated with chronic kidney disease" respectively (Figure 1). Cluster 1 had the best overall survival, followed by clusters 2, 3 and 4, and lastly cluster 5, with the worst outcome (Figure 2). Conclusions Cluster analysis identifies 5 phenotypically distinct novel subgroups of TR with differences in all-cause mortality. This phenotype-based classification improves our understanding of interaction of different co-morbidities with this complex valve lesion and can inform clinical decision making. Abstract Figure. Cluster Dendrogram Abstract Figure. Kaplan-Meier survival curves

Background: Panniculectomy is a commonly performed body contouring procedure to address skin laxity and its related complications. This study aimed to assess clinical outcomes of abdominal panniculectomy and identify predictors of complications at a tertiary academic healthcare center. Methods: A retrospective review of patients who underwent panniculectomy between January 2010 and January 2020 at our institution was performed. Exclusion criteria were a history of prior panniculectomy or abdominoplasty. Patient characteristics and clinical outcomes were collected. Univariate and multivariable analyses were performed to assess the risk factors of complications. Results: The mean age in the included 238 patients was 51.7 ± 12.7 years, and the mean body mass index (BMI) at the time of panniculectomy was 33 ± 7.5 kg/m 2 . Median resection weight was 2.7 kg (range: 0.15–14.6) and median length of hospital stay was 2 days (range: 0–24). Mean follow-up time was 50 ± 37 months. The rate of major complications was 22.3%. Revision surgery was performed in 3.4% of the cases. Multivariable analyses demonstrated that increase in BMI ( P = 0.007) and active smoking ( P = 0.026) were significantly associated with increased odds of major complication, and increase in BMI ( P = 0.0004), history of venous thromboembolism ( P = 0.034) and having a concomitant ventral hernia repair ( P = 0.0044) were significantly associated with having a length of hospital stay of 3 days or more. Conclusions: Panniculectomy is generally safe to perform, with major postoperative complication rate of 22.3% in our series. Increase in BMI and active smoking were significantly associated with having a major complication. Higher BMI, concomitant hernia repair, and a history of venous thromboembolism were associated with length of hospital stay of 3 days or more.

TPS514 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), which represent approximately 70% of NETs, frequently develop metastatic disease with limited treatment options. Current standard therapies for well-differentiated high grade 2 and grade 3 GEP-NETs include cytoreductive procedures, somatostatin analogues, molecular targeted therapies (everolimus or sunitinib), chemotherapy and peptide receptor radionuclide therapy (PRRT), with no specified sequence of use. PRRT may stabilize disease and induce objective tumor responses. This treatment uses radiolabeled somatostatin analogues to selectively target somatostatin receptor expressing (SSTR+) tumor cells. 177 Lu-edotreotide is an innovative radiolabeled somatostatin analogue with a favorable safety profile and promising efficacy. Retrospective data in metastatic GEP-NETs treated with two or more 177 Lu-edotreotide cycles demonstrated a progression free survival (PFS) of at least 30 months. The currently recruiting Phase III COMPETE trial compares the efficacy and safety of 177 Lu-edotreotide, versus everolimus, in grade 1 and grade 2 GEP-NETs. Methods: COMPOSE (NCT04919226) is a prospective, randomized, controlled, open-label, multi-center Phase III study, in patients with well-differentiated high grade 2 and grade 3 (Ki-67 index 15−55%), SSTR+, GEP-NETs. This trial is to evaluate the efficacy, safety and patient-reported outcomes of first- or second-line treatment with 177 Lu-edotreotide PRRT compared to best standard of care. It aims to randomize 202 patients 1:1 to a defined number of cycles of 177 Lu-edotreotide or an active comparator (either chemotherapy [CAPTEM or FOLFOX] or everolimus, according to investigator´s choice). The primary endpoint is PFS, assessed every 12 weeks until disease progression (RECIST v1.1), or death, whichever occurs earlier. Secondary outcomes include overall survival, assessed up to 2 years after disease progression. Study recruitment for COMPOSE commenced in September 2021. It is expected that COMPOSE will inform optimal treatment options for patients with well-differentiated high grade 2 and grade 3 SSTR+ GEP-NETs, including for first-line therapy. Clinical trial information: NCT04919226.

BRCA2 is essential for homologous recombination DNA repair. BRCA2 mutations lead to genome instability and increased risk of breast and ovarian cancer. Similarly, mutations in BRCA2-interacting proteins are also known to modulate sensitivity to DNA damage agents and are established cancer risk factors. Here we identify the tumor suppressor CDK5RAP3 as a novel BRCA2 helical domain-interacting protein. CDK5RAP3 depletion induced DNA damage resistance, homologous recombination and single-strand annealing upregulation, and reduced spontaneous and DNA damage-induced genomic instability, suggesting that CDK5RAP3 negatively regulates double-strand break repair in the S-phase. Consistent with this cellular phenotype, analysis of transcriptomic data revealed an association between low CDK5RAP3 tumor expression and poor survival of breast cancer patients. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Our results uncover CDK5RAP3 as a critical player in DNA repair and breast cancer outcomes.

Patients with decompensated cirrhosis, particularly those with acute‐on‐chronic liver failure (ACLF), show profound alterations in plasma metabolomics. The aim of this study was to investigate the effect of treatment with simvastatin and rifaximin on plasma metabolites of patients with decompensated cirrhosis, specifically on compounds characteristic of the ACLF plasma metabolomic profile. Two cohorts of patients were investigated. The first was a descriptive cohort of patients with decompensated cirrhosis (n = 42), with and without ACLF. The second was an intervention cohort from the LIVERHOPE‐SAFETY randomized, double‐blind, placebo‐controlled trial treated with simvastatin 20 mg/day plus rifaximin 1,200 mg/day (n = 12) or matching placebo (n = 13) for 3 months. Plasma samples were analyzed using ultrahigh performance liquid chromatography–tandem mass spectroscopy for plasma metabolomics characterization. ACLF was characterized by intense proteolysis and lipid alterations, specifically in pathways associated with inflammation and mitochondrial dysfunction, such as the tryptophan–kynurenine and carnitine beta‐oxidation pathways. An ACLF‐specific signature was identified. Treatment with simvastatin and rifaximin was associated with changes in 161 of 985 metabolites in comparison to treatment with placebo. A remarkable reduction in levels of metabolites from the tryptophan–kynurenine and carnitine pathways was found. Notably, 18 of the 32 metabolites of the ACLF signature were affected by the treatment. Conclusion: Treatment with simvastatin and rifaximin modulates some of the pathways that appear to be key in ACLF development. This study unveils some of the mechanisms involved in the effects of treatment with simvastatin and rifaximin in decompensated cirrhosis and sets the stage for the use of metabolomics to investigate new targeted therapies in cirrhosis to prevent ACLF development.