Citations

Abstract Background: The ATEMPT trial primary analysis found that one year of adjuvant trastuzumab emtansine (T-DM1) achieved a 3-year iDFS of 97.8% for patients with stage I HER2+ breast cancer, but was not associated with fewer clinically relevant toxicities (CRTs) compared with paclitaxel and trastuzumab (TH). In this end-of-study analysis, we report 5-year survival outcomes and correlative analyses from the trial. Methods: Patients with stage I centrally confirmed HER2+ breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for one year or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or paclitaxel 80 mg/m2 IV with weekly trastuzumab IV followed by trastuzumab for 9 months. The co-primary objectives were to compare the incidence of CRTs between the 2 arms and to evaluate iDFS in patients receiving T-DM1. To investigate proteomic correlates of recurrence, spatial proteomic analyses were performed on samples from 13 patients experiencing iDFS events (cases) and 24 matched controls using the NanoString GeoMx Digital Spatial Profiler. The impact of HER2 heterogeneity on outcomes was investigated among 17 cases and 51 matched controls by fluorescence in-situ hybridization (FISH). HER2 genetic heterogeneity was assessed by scrutinizing the whole tumor area and defined as the occurrence of HER2 gene amplification in >5% but < 50% invasive tumor cells. The risk of recurrence was evaluated centrally with the HER2DX genomic assay from 225 primary tumor samples. Germline whole genome sequencing (WGS) was conducted among 55 patients experiencing T-DM1-induced thrombocytopenia and/or bleeding and 55 matched controls to identify genomic correlates for this side effect. Results: A total of 497 patients who initiated protocol therapy were included in this analysis (383 T-DM1 and 114 TH). After a median follow up 5.8 years, among patients receiving T-DM1 there were a total of 11 iDFS events, with 3 distant recurrences. The 5-year iDFS for T-DM1 was 97.0% (95% CI, 95.3-98.8%), the 5-year recurrence-free interval (RFI) was 98.6% (95% CI: 97.4-99.8%) and the 5-year overall survival (OS) for T-DM1 was 97.8 % (95% CI, 96.3-99.3%). Although the study was not powered to evaluate the efficacy of TH, among the 114 patients receiving TH, a total of 9 iDFS events were observed, including 2 distant events; the 5-year iDFS with TH was 91.3% (95% CI: 86.0-96.9%), 5-year RFI was 93.3% (95% CI: 88.6-98.2%) and 5-year OS was 97.9% (95% CI: 95.2-100%). A total of 56 samples were evaluable for heterogeneity analyses, among which 14% (n=8) harbored HER2 genetic heterogeneity. Spatial proteomic analyses found that NF1 (adjusted p=0.72 × 10-6) and CTLA-4 (adjusted p=0.15 × 10-3) were significantly upregulated in primary samples from cases, while cleaved caspase 9, CD25, GITR, ICOS, p53 and PD-L2 were significantly upregulated in controls (all with adjusted p< 0.05). Germline WGS found that the top gene associations with thrombocytopenia and thrombocytopenia or bleeding were ALMS1 (p=0,19 × 10-3) and APBA3 (p=0,23 × 10-3), respectively, although none reaching the threshold for genome wide significance. rs62143195 and rs114169776 were the top single nucleotide polymorphisms associated with thrombocytopenia and thrombocytopenia or bleeding, respectively. Data on the impact of HER2 heterogeneity and of HER2DX score on survival outcomes will be presented. Conclusion: With longer follow-up, adjuvant T-DM1 confirmed outstanding long-term outcomes among patients with stage I HER2+ breast cancer, demonstrating a 5-year RFI of 98.6%. Spatial proteomic analyses identified a potential association between NF1 and CTLA-4 expression with recurrence. Details on the impact of HER2 heterogeneity and HER2DX assay on prognosis will be presented. Citation Format: Paolo Tarantino, Nabihah Tayob, Chau T Dang, Denise Yardley, Steven J. Isakoff, Vicente Valero, Meredith Faggen, Therese Mulvey, Ron Bose, Douglas Weckstein, Antonio C. Wolff, Katherine Reeder-Hayes, Hope Rugo, Bhuvaneswari Ramaswamy, Dan Zuckerman, Lowell Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit Cheng, Audrey Merrill Garrett, Paul K. Marcom, Kathy S. Albain, Patricia DeFusco, Nadine Tung, Blair Ardman, Rita Nanda, Rachel C. Jankowitz, Mothaffar Rimawi, Vandana Abramson, Paula R. Pohlmann, Catherine Van Poznak, Andres Forero-Torres, Minetta C. Liu, Kathryn Ruddy, Yue Zheng, Romualdo Barroso-Sousa, Adrienne Waks, Michelle K. DeMeo, Molly K. DiLullo, Giuseppe Curigliano, Harold Burstein, Ann Partridge, Eric Winer, Giuseppe Viale, Winnie Hui, Elizabeth A. Mittendorf, Bryan P. Schneider, Aleix Prat, Ian Krop, Sara Tolaney. Adjuvant Trastuzumab Emtansine Versus Paclitaxel plus Trastuzumab for Stage I HER2+ Breast Cancer: 5-year results and correlative analyses from ATEMPT (TBCRC033) [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 PD18-01.

Abstract Background Breast cancers in women with a germline BRCA1/2 mutation (gBRCAm) have homologous recombination deficiency (HRD) and are sensitive to therapies causing double-strand DNA breaks. In TBCRC 031 (INFORM), both neoadjuvant cisplatin and doxorubicin/cyclophosphamide (“AC”) in gBRCAm carriers resulted in a complete pathologic response in 18% and 26% respectively in patients with newly diagnosed HER2–negative breast cancer. Herein, we describe molecular features from tumor whole exome (WES) and transcriptome sequencing (RNAseq) associated with response. Methods TBCRC 031 (the INFORM Trial - NCT01670500) was a randomized phase II neoadjuvant trial comparing the efficacy of cisplatin versus AC in gBRCAm carriers with stage I-III HER2–negative breast cancer. Of 118 patients enrolled, 92 patients provided fresh frozen research biopsies, collected prior to chemotherapy initiation, which were subjected to WES and RNAseq. Variants were called using GATK best practices and intratumoral heterogeneity was inferred from mutations and variant allele frequencies using Mutant Allele Tumor Heterogeneity (MATH) scores. Mutational Signature 3 (Sig3) and Genomic Instability Score (GIS) were calculated with SigMA and scarHRD, respectively. RNAseq data were utilized to perform differential gene expression and functional analyses, while cellular deconvolution was performed with CIBERSORTx trained against breast cancer single cell data. Patients were grouped according to their residual cancer burden (RCB) as responders (RCB-0 or 1), or non-responders (RCB-2 or 3). P-values ≤ 0.05 were considered statistically significant and when appropriate, adjustment for multiple testing was performed using a false discovery rate ≤ 5%. Results Of the 92 patients with gBRCAm, 59 (64%) had triple-negative and 33 (36%) were hormone-receptor positive HER2-negative breast cancer, 40 (43%) were classified as responders and 52 (57%) as non-responders. WES analysis revealed that indices of HRD were high (Sig3 exposure predominant and GIS ≥ 42) across most samples irrespective of receptor status and not significantly different among responders and non-responders. In contrast, responders exhibited lower levels of intratumor heterogeneity than non-responders (median MATH 42.9 vs. 33.5, p = 0.01). 223 genes were differentially expressed between responders and non-responders following control for tumor hormone receptor status, BRCA1/2 mutation, and menopausal status. Pathways identified as significantly enriched in upregulated genes were indicative of intrinsic immune activation in responders (e.g., T-cell activation, immune response-signaling, and regulation of leukocyte activation). Cellular deconvolution of the tumor microenvironment confirmed that responders presented a higher proportion of T-cells (p = 0.025) and myeloid cells (p = 0.003) in the tumor samples, while perivascular-like cells were enriched in non-responders (p = 0.034). Conclusion In this analysis of the largest cohort of treatment-naïve gBRCAm breast cancer to date, we found that response to cytotoxic chemotherapy is associated with a transcriptional program of intrinsic immune activation and an increased population of intratumoral T-cells and myeloid cells. Lower levels of intratumor heterogeneity and higher immune activation were associated with response to chemotherapy gBRCAm carriers while HRD scores were not. Citation Format: Felipe Batalini, Doga C. Gulhan, Xanthi Lida Katopodi, Nikolas Kalavros, Antuan Tran, Dimitra Karagkouni, Emily Stern-Gatof, Stuart Schnitt, Judy E. Garber, Gerburg M. Wulf, Peter J. Park, Ioannis Vlachos, Nadine Tung. Intratumor heterogeneity and intrinsic immune activation are associated with response to chemotherapy in BRCA-related breast cancers [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 P5-12-03.

BACKGROUND: Increased burnout and decreased professional fulfillment among intensive care physicians is partly due to intensive care unit (ICU) workload. Although the SARS-CoV-2 (COVID-19) pandemic increased ICU workload, it also may have increased feelings of personal fulfillment due to positive public perceptions of physicians caring for COVID patients. We surveyed critical care anesthesiologists to identify the effect of provider demographics, ICU workload, and COVID-19–related workload, on professional fulfillment and burnout. METHODS: We performed an exploratory survey of 606 members of the Society of Critical Care Anesthesiologists (SOCCA) in January and February 2022. We used the Stanford Professional Fulfillment Index (PFI) to grade levels of professional fulfillment and markers of burnout (ie, work exhaustion and disengagement). Univariable and multivariable models were used to identify associations between provider demographics and practice characteristics and professional fulfillment and work exhaustion. RESULTS: One hundred and seventy-five intensivists (29%) responded. A total of 65% were male and 49% were between 36 and 45 years old. The overall median PFI score—0 (none) to 24 (most professional fulfillment)—was 17 (IQR, 1–24), with a wide distribution of responses. In multivariable analysis, factors associated with higher professional fulfillment included age >45 years ( P =.004), ≤15 weeks full-time ICU coverage in 2020 ( P =.02), role as medical director ( P =.01), and nighttime home call with supervision of in-house ICU fellows ( P =.01). CONCLUSIONS: Professional fulfillment and work exhaustion in this cross-sectional survey were associated with several demographic and practice characteristics but not COVID-19–related workload, suggesting that COVID-19 workload may not have either positive or negative perceptions on professional fulfillment.

Abstract Extra copies of centrosomes are frequently observed in cancer cells. To survive and proliferate, cancer cells have developed strategies to cluster extra-centrosomes to form bipolar mitotic spindles. The aim of this study was to investigate whether centrosome clustering (CC) inhibition (CCi) would preferentially radiosensitize non–small cell lung cancer (NSCLC). Griseofulvin (GF; FDA-approved treatment) inhibits CC, and combined with radiation treatment (RT), resulted in a significant increase in the number of NSCLC cells with multipolar spindles, and decreased cell viability and colony formation ability in vitro. In vivo, GF treatment was well tolerated by mice, and the combined therapy of GF and radiation treatment resulted in a significant tumor growth delay. Both GF and radiation treatment also induced the generation of micronuclei (MN) in vitro and in vivo and activated cyclic GMP-AMP synthase (cGAS) in NSCLC cells. A significant increase in downstream cGAS-STING pathway activation was seen after combination treatment in A549 radioresistant cells that was dependent on cGAS. In conclusion, GF increased radiation treatment efficacy in lung cancer preclinical models in vitro and in vivo. This effect may be associated with the generation of MN and the activation of cGAS. These data suggest that the combination therapy of CCi, radiation treatment, and immunotherapy could be a promising strategy to treat NSCLC.

Study Design: Case Series and Technical Note, Objective: UBS has been extensively used in open surgery. However, the use of UBS during UBESS has not been reported in the literature. The aim of this study was to describe a new spinal surgical technique using an ultrasonic bone scalpel (UBS) during unilateral biportal endoscopic spine surgery (UBESS) and to report the preliminary results of this technique. Methods: We enrolled patients diagnosed with lumbar spinal stenosis who underwent single-level UBESS. All patients were followed up for more than 12 months. A unilateral laminotomy was performed after bilateral decompression under endoscopy. We used the UBS system after direct visualization of the target for a bone cut. We evaluated the demographic characteristics, diagnosis, operative time, and estimated blood loss of the patients. Clinical outcomes included the visual analog scale (VAS), the Oswestry Disability Index (ODI), the modified MacNab criteria, and postoperative complications. Results: A total of twenty patients (five males and fifteen females) were enrolled in this study. The mean follow-up period was 13.2 months (range 12–17 months). The VAS score, ODI, and modified MacNab criteria classification improved after the surgery. A minimal mean blood loss of 22.1 mL was noted during the operation. Only one patient experienced neuropraxia, which resolved within 2 weeks. There was no durotomy, iatrogenic pars fracture, or infection. Conclusions: In conclusion, our study represents the first report of the use of UBS during UBESS. Our findings demonstrate that this technique is safe and efficient, with improved clinical outcomes and minimal complications. These preliminary results warrant further investigation through larger clinical studies with longer follow-up periods to confirm the effectiveness of this technique in the treatment of lumbar spinal stenosis.

AbstractBackgroundThe purpose of this study was to estimate the cumulative risks of all cancers in women from 50 to 75 years of age with a BRCA1 or BRCA2 pathogenic variant.MethodsParticipants were women with BRCA1 or BRCA2 pathogenic variants from 85 centers in 16 countries. Women were eligible if they had no cancer before the age of 50 years. Participants completed a baseline questionnaire and follow‐up questionnaires every 2 years. Women were followed from age 50 until a diagnosis of cancer, death, age 75, or last follow‐up. The risk of all cancers combined from age 50 to 75 was estimated using the Kaplan–Meier method.ResultsThere were 2211 women included (1470 BRCA1 and 742 BRCA2). There were 379 cancers diagnosed in the cohort between 50 and 75 years. The actuarial risk of any cancer from age 50 to 75 was 49% for BRCA1 and 43% for BRCA2. Breast (n = 186) and ovarian (n = 45) were the most frequent cancers observed. For women who had both risk‐reducing mastectomy and bilateral salpingo‐oophorectomy before age 50, the risk of developing any cancer between age 50 and 75 was 9%.ConclusionWomen with a BRCA1 or BRCA2 pathogenic variant have a high risk of cancer between the ages of 50 and 75 years and should be counselled appropriately.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

BACKGROUND: Intraventricular metastases (IVMs) are uncommon, and their optimal management remains debatable. OBJECTIVE: To define the safety and efficacy of stereotactic radiosurgery (SRS) in the treatment of IVMs. METHODS: This retrospective, multicenter study included patients managed with SRS for IVMs. SRS-induced adverse events, local tumor or intracranial progression, and the frequency of new-onset hydrocephalus or leptomeningeal spread were documented. Analyses of variables related to patient neuroimaging or clinical outcomes were also performed. RESULTS: The cohort included 160 patients from 11 centers who underwent SRS for treatment of 1045 intracranial metastases, of which 196 were IVMs. The median survival from SRS was 10 months. Of the 154 patients and 190 IVMs with imaging follow-up, 94 patients (61%) experienced distant intracranial disease progression and 16 IVMs (8.4%) progressed locally. The 12- and 24-month local IVM control rates were 91.4% and 86.1%, respectively. Sixteen (10%) and 27 (17.5%) patients developed hydrocephalus and leptomeningeal dissemination post-SRS, respectively. Adverse radiation effects were documented in 24 patients (15%). Eleven patients (6.9%) died because of intracranial disease progression. CONCLUSION: SRS is an effective treatment option for IVMs, with a local IVM control rate comparable with SRS for parenchymal brain metastases. Leptomeningeal spread and hydrocephalus in patients with IVM occur in a minority of patients, but these patients warrant careful follow-up to detect these changes.