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LINKED CONTENTThis article is linked to Wijarnpreecha et al and Huang & Nguyen papers. To view these articles, visit https://doi.org/10.1111/apt.16590 and https://doi.org/10.1111/apt.16576

SummaryBackgroundPrevious studies have demonstrated an association between nonselective beta‐blockers (NSBBs) and lower risk of hepatocellular carcinoma (HCC) in cirrhosis. However, there has been no population‐based study investigating the risk of HCC among cirrhotic patients treated using carvedilol.AimsTo determine the risk of HCC among cirrhotic patients with NSBBs including carvedilol.MethodsThis retrospective cohort study utilised the Cerner Health Facts database in the United States from 2000 to 2017. Kaplan‐Meier estimate, Cox proportional hazards regression, and propensity score matching (PSM) were used to test the HCC risk among the carvedilol, nadolol, and propranolol groups compared with no beta‐blocker group.ResultsThe final cohort comprised 107 428 eligible patients. The 100‐month cumulative HCC incidence of NSBBs was significantly lower than the no beta‐blocker group (carvedilol (11.24%) vs no beta‐blocker (15.69%), nadolol (27.55%) vs no beta‐blocker (32.11%), and propranolol (26.17%) vs no beta‐blocker (28.84%) (P values < 0.0001). NSBBs were associated with a significantly lower risk of HCC (Hazard ratio: carvedilol 0.61 (95% CI 0.51‐0.73), nadolol 0.74 (95% CI 0.63‐0.87), propranolol 0.75 (95% CI 0.66‐0.84) after PSM in the multivariate cox analysis. In subgroup analysis, NSBBs reduced the risk of HCC in cirrhosis with complications and non‐alcoholic cirrhosis.ConclusionsNSBBs, including carvedilol, were associated with a significantly decreased risk of HCC in patients with cirrhosis when compared with no beta‐blocker regardless of complications status. Future randomised‐controlled studies comparing the incidence of HCC among NSBBs should elucidate which NSBB would be the best option to prevent HCC in cirrhosis.

The anti‐parallel nature of DNA permits continuous synthesis of DNA on the leading strand and discontinuous DNA synthesis on the lagging strand. On the lagging strand, Okazaki fragments are joined by the catalytic action of DNA ligase I. An individual with a DNA ligase I deficiency exhibited growth retardation, sunlight sensitivity and severe immunosuppression, likely due to accumulation of DNA damage. Surprisingly, little is known about the DNA damage response (DDR) in DNA ligase I‐deficient cells. We utilized Saccharomyces cerevisiae as a model system to address this question. We uncovered a novel pathway, which facilitates ubiquitination of proliferating cell nuclear antigen (PCNA) on lysine 107. Unlike PCNA ubiquitination at lysine 164 in response to UV irradiation, which triggers translesion synthesis and is dependent on Rad6 and Rad18, modification at lysine 107 requires the E2 variant Mms2 in conjunction with Ubc4 and Rad5. Surprisingly, DNA ligase I‐deficient cdc9‐1 cells that carry a PCNAK107R mutation are inviable, because they cannot activate a robust DDR. Our data show that depending on the type of damage that a cell encounters, PCNA is ubiquitinated at different lysine residues. We propose a “DNA Damage code” that allows cells to recognize different types of DNA damage through differential PCNA ubiquitination, allowing the cells to activate the appropriate repair response.

PURPOSE The ATEMPT trial was designed to determine if treatment with trastuzumab emtansine (T-DM1) caused less toxicity than paclitaxel plus trastuzumab (TH) and yielded clinically acceptable invasive disease-free survival (iDFS) among patients with stage I human epidermal growth factor receptor 2–positive (HER2+) breast cancer (BC). METHODS Patients with stage I centrally confirmed HER2+ BC were randomly assigned 3:1 to T-DM1 or TH and received T-DM1 3.6 mg/kg IV every 3 weeks for 17 cycles or T 80 mg/m 2 IV with H once every week × 12 weeks (4 mg/kg load →2 mg/kg), followed by H × 39 weeks (6 mg/kg once every 3 weeks). The co-primary objectives were to compare the incidence of clinically relevant toxicities (CRTs) in patients treated with T-DM1 versus TH and to evaluate iDFS in patients receiving T-DM1. RESULTS The analysis population includes all 497 patients who initiated protocol therapy (383 T-DM1 and 114 TH). CRTs were experienced by 46% of patients on T-DM1 and 47% of patients on TH ( P = .83). The 3-year iDFS for T-DM1 was 97.8% (95% CI, 96.3 to 99.3), which rejected the null hypothesis ( P < .0001). Serially collected patient-reported outcomes indicated that patients treated with T-DM1 had less neuropathy and alopecia and better work productivity compared with patients on TH. CONCLUSION Among patients with stage I HER2+ BC, one year of adjuvant T-DM1 was associated with excellent 3-year iDFS, but was not associated with fewer CRT compared with TH.

520 Background: Systemic inflammation may contribute to cancer progression (PMC2803035), including recurrence of early breast cancer (PMC4828958). We hypothesized that inflammatory cytokines and/or chemokines may be associated with distant recurrence (DR). Methods: We performed a case:control study in women with stage II-III Her2-negative breast cancer, all of whom had surgery and adjuvant chemotherapy (doxorubicin/cyclophosphamide, then weekly paclitaxel) with/without bevacizumab, plus endocrine therapy if ER-positive (PMC6118403). Propensity score matching was used to identify approximately 250 case:control pairs (with/without DR). Serum samples obtained before adjuvant chemotherapy were analyzed using the MSD V-Plex Human Cytokine 36-Plex Kit for detection of human cytokines and chemokines involved in the Th1/Th2 pathway, chemotaxis, the Th17 pathway, angiogenesis, and immune system regulation. Conditional logistic regression analysis, with models fit via maximum likelihood, were used to estimate hazard ratios (HRs) and test for associations. Due to skewed nature of cytokines, HRs are reported on log base 2 scale. If adjusted for multiple testing including 36 markers, a p value of < 0.0014 would be required for statistical significance. Results: A total 249 matched pairs (498 patients) were identified. Covariates used for propensity score matching included age, menopausal status (post 54% vs. pre/peri 46%), ER/PR status (one/both pos 64% vs. both neg 36%) tumor size ( < = 2cm 17%, > 2-5cm 67%, > 5cm 16%) nodal status (neg 15%,1-3+ 32%, 4+ 53%), and grade (low 3%, int. 31%, high 66%). The only biomarker associated with a significantly increased DR risk when adjusted for multiple testing was the proinflammatory cytokine IL-6 (HR 1.37, 95% confidence intervals [CI] 1.15, 1.65, p = 0.0006). Others associated with a 2-sided p value < 0.05 included the chemokine MDC(macrophage-derived chemokine/CCL22) (1.90, 95% CI 1.17, 3.1, p = 0.0098), the T helper cell inflammatory cytokine IL-17A (HR 1.36, 95% CI 1.10, 1.67, p = 0.0052), and the cytokine VEGF-A (HR 1.13 for, 95% CI 1.01, 1.27, p = 0.037). There was no statistical interaction between VEGF-A and bevacizumab benefit. The median and mean value for IL-6 was 0.95 and 7.5 pg/ml (range 0.04-2761.24 pg/ml). Conclusions: This analysis provides level 1B evidence indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher DR risk in high-risk stage II-III breast cancer despite optimal adjuvant systemic therapy. This provides a foundation for confirmatory validation of IL-6 as a prognostic biomarker, and potentially as a predictive biomarker for testing therapeutic interventions targeting the IL-6/JAK/STAT3 pathway. Supported by NCI U10CA180820,180794,180821; UG1CA189859,232760,233290, 233196; Komen Foundation; Breast Cancer Research Foundation. Clinical trial information: NCT00433511.

Background To describe the effect of the COVID-19 pandemic on emergency general surgery operative volumes during governmental shutdowns secondary to the pandemic and characterize differences in disease severity, morbidity, and mortality during this time compared to previous years. Methods This retrospective cohort study compares patients who underwent emergency general surgery operations at a tertiary hospital from March 1st to May 31st of 2020 to 2019. Average emergent cases per day were analyzed, comparing identical date ranges between 2020 (pandemic group) and 2019 (control group). Secondary analysis was performed analyzing disease severity, morbidity, and mortality. Results From March 1st to May 31st, 2020, 2.5 emergency general surgery operations were performed on average daily compared to 3.0 operations on average daily in 2019, a significant decrease ( P = .03). No significant difference was found in presenting disease severity, morbidity, or mortality between the pandemic and control groups. Discussion This study demonstrates a decrease of 65% in emergency general surgery operations during governmental restrictions secondary to the COVID-19 pandemic. This decrease in operations was not associated with worse disease severity, morbidity, or mortality.

PURPOSE CALGB 40601 assessed whether dual versus single human epidermal growth factor receptor 2 (HER2) –targeting drugs added to neoadjuvant chemotherapy increased pathologic complete response (pCR). Here, we report relapse-free survival (RFS), overall survival (OS), and gene expression signatures that predict pCR and survival. PATIENTS AND METHODS Three hundred five women with untreated stage II and III HER2-positive breast cancer were randomly assigned to receive weekly paclitaxel combined with trastuzumab plus lapatinib (THL), trastuzumab (TH), or lapatinib (TL). The primary end point was pCR, and secondary end points included RFS, OS, and gene expression analyses. mRNA sequencing was performed on 264 pretreatment samples. RESULTS One hundred eighteen patients were randomly allocated to THL, 120 to TH, and 67 to TL. At more than 7 years of follow-up, THL had significantly better RFS and OS than did TH (RFS hazard ratio, 0.32; 95% CI, 0.14 to 0.71; P = .005; OS hazard ratio, 0.34; 95% CI, 0.12 to 0.94; P = .037), with no difference between TH and TL. Of 688 previously described gene expression signatures, significant associations were found in 215 with pCR, 45 with RFS, and only 22 with both pCR and RFS (3.2%). Specifically, eight immune signatures were significantly correlated with a higher pCR rate and better RFS. Among patients with residual disease, the immunoglobulin G signature was an independent, good prognostic factor, whereas the HER2-enriched signature, which was associated with a higher pCR rate, showed a significantly shorter RFS. CONCLUSION In CALGB 40601, dual HER2-targeting resulted in significant RFS and OS benefits. Integration of intrinsic subtype and immune signatures allowed for the prediction of pCR and RFS, both overall and within the residual disease group. These approaches may provide means for rational escalation and de-escalation treatment strategies in HER2-positive breast cancer.

3010 Background: Our initial vaccine studies showed that optimally treated breast cancer patients can be immunized against HER2 during active immunization. The majority of patients developed T-cell immunity to HER2 peptides and protein and also epitope spreading (ES). The goal of this study was to determine if patients previously immunized with a HER2 vaccine had persistent immunity years after active immunization and to assess their clinical outcome in terms of overall survival (OS). Methods: Subjects eligible for this IRB-approved long term follow-up (LTFU) study: (1) had HER2+ breast cancer and were immunized between 1996–1999 in a phase I HER2 peptide vaccine trial, (2) were at least 1 year out from their last vaccine, and (3) if donating blood samples could not be receiving chemotherapy. 52 patients (37 stage IV, 15 stage III) were identified and 21/52 patients (12 stage IV, 9 stage III) were determined to be living. All 21 subjects were contacted by letter and sent a LTFU Questionnaire. OS was defined as the time between date of vaccine study entry and death or last follow-up and was estimated using the Kaplan-Meier method. Cox proportional hazards were used to determine associations between OS and known clinical and vaccine-related immunologic factors; analyses included all 52 subjects. Long-term T-cell immunity was evaluated using IFN-γ ELISPOT assay. Results: Median follow-up time for the 21 patients still alive was 112 months (range, 104–126 months). Blood samples were collected in 10/21 subjects and 6/8 (75%) evaluble patients had persistent T-cell immunity to immunizing HER2 peptides; and 7/8 patients (88%) had T-cell immunity specific for HER2 protein and peptides not contained in their immunizing mix (defined as ES). In multivariate analysis, number of chemotherapy regimens prior to vaccination (HR=5.7 (CI 95%, 1.5–23; p=<0.001)), and development of ES after HER2 vaccination (HR=0.34 (CI 95%, 0.12–1.0; p=0.05)) were independent predictors of OS. Median OS for 33 subjects who developed ES was 84 months vs 25 months for 16 subjects who did not develop ES. Conclusions: HER2-specific T-cell immunity elicited with active immunization is durable years after vaccination has ended and the generation of ES is an independent predictor of OS. No significant financial relationships to disclose.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

Abstract Background: CRA is a surrogate for ovarian toxicity and associated risk of infertility and long-term menopausal symptoms. Therefore, it is important to assess and report the rate of CRA when we study a new neoadjuvant treatment regimen. In the Adjuvant Paclitaxel and Tratuzumab (APT) trial, we found that CRA rate associated with adjuvant TH (12 weeks of paclitaxel and a year of trastuzumab) for human epidermal growth factor receptor-2 (HER2)-positive breast cancer was lower than historically seen with cyclophosphamide-based regimens. The ATEMPT trial allowed a direct comparison of the CRA rate associated with TDM1 and TH. Methods: The ATEMPT trial randomized patients (pts) with Stage I HER2+ breast cancer 3:1 to T-DM1 3.6 mg/kg IV every 3 weeks (w) x17 vs. T 80 mg/m2 IV with H qw x 12 (4 mg/kg load →2 mg/kg), followed by H (6 mg/kg q3w x 13). Participants who reported that they were premenopausal at enrollment were asked to complete menstrual surveys at baseline and every 6-12 months throughout a 36 month follow-up period. For this analysis, CRA was defined as report of no menstruation within the prior six months on a survey completed 18 months after enrollment. Results: Of 512 ATEMPT enrollees, 497 began protocol therapy, 130 (26%) were premenopausal at enrollment and answered baseline menstrual questions, 42 of these 130 were excluded from the current analyses because they did not complete the 18-month survey, and 7 of the remaining 88 had received gonadotropin-releasing hormone agonist before 18 months, leaving 81 for analysis. None had undergone hysterectomy or oophorectomy. Median age was 44 (range 23-53) among the TH patients (n=20), and 46 (range 34-54) among the T-DM1 patients (n=61). On the 18-month survey, 45% of women treated with TH reported at least one one episode of menses during the prior 6 months compared to 75% of women in the T-DM1 arm (p=0.011). Among those ≤ 40 years old, 50% of TH patients and 100% of T-DM1 patients reported menstruation at that timepoint. Please see Table for additional data in subgroups. Conclusions: In this relatively small sample, CRA at 18 months was less common after adjuvant T-DM1 than after TH (though even with TH, nearly half of women did menstruate after chemotherapy, even in the subset aged 41+). This will be reassuring to young patients with HER2-positive breast cancer who seek to maintain ovarian function. Larger studies are needed to confirm this finding and to assess a possible differential impact of these drugs on subgroups based on age, endocrine therapy, and body mass index. Additional research should also focus on menopausal symptoms and actual fertility after receipt of T-DM1. Menstruation in 61 T-DM1 arm patients with informative surveys at 18 monthsMenstruation in 20 TH arm patients with informative surveys at 18 monthsAge at study entry95% CI95% CI≤4012/12 (100%)74-100%4/8 (50%)16-84%41+34/49 (69%)55-82%5/12 (42%)15-72%BMI&lt;3040/52 (77%)63-87%6/16 (38%)15-65%30+6/9 (67%)30-93%3/4 (75%)19-99%Endocrine therapy currentlyYes27/39 (69%)52-83%2/12 (17%)2-48%No19/22 (86%)65-97%7/9 (78%)40-97% Citation Format: Kathryn J. Ruddy, Lorenzo Trippa, Jiani Hu, William T. Barry, Chau T. Dang, Denise A. Yardley, Steven J. Isakoff, Vincente V. Valero, Meredith G. Faggen, Therese M. Mulvey, Ron Bose, Douglas J. Weckstein, Antonio C. Wolff, Katherine E. Reeder-Hayes, Hope S. Rugo, Bhuvaneswari Ramaswamy, Dan S. Zuckerman, Lowell L. Hart, Vijayakrishna K. Gadi, Michael Constantine, Kit L. Cheng, Frederick M. Briccetti, Bryan P. Schneider, A. Merrill Garrett, P. Kelly Marcom, Kathy S. Albain, Patricia A. DeFusco, Nadine M. Tung, Blair M. Ardman, Rita Nanda, Rachel C. Jankowitz, Michelle K. DeMeo, Harold J. Burstein, Eric P. Winer, Ian E. Krop, Ann H. Partridge, Sara M. Tolaney. Chemotherapy-related amenorrhea (CRA) after adjuvant trastuzumab emtansine (T-DM1) compared to paclitaxel in combination with trastuzumab (TH) (TBCRC033: ATEMPT trial) [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 P2-13-02.