Improvement In Disease-free Survival Research Articles

EE495 Cost-Effectiveness Analysis of Adjuvant Atezolizumab Versus Best Supportive Care in the Treatment of Patients With Resectable Early-Stage Non-Small Cell Lung Cancer and PD-L1≥50% Expression

Adjuvant atezolizumab vs. best-supportive care (BSC) after complete resection and adjuvant platinum-based chemotherapy in patients with early-stage resected non-small cell lung cancer (NSCLC) was evaluated in IMpower010 trial, showing an improvement in disease-free survival (DFS) in favor of atezolizumab. We aimed to assess the cost-effectiveness of adjuvant atezolizumab in the treatment of early-stage NSCLC patients (stage II-IIIA) with expression of programmed death-ligand 1 PD-L1≥50% without mutations in EGFR or ALK rearrangements in Spain.

The efficacy of postoperative radiotherapy for patients with non-small cell lung cancer: An updated systematic review and meta-analysis.

The controversy over the efficacy of postoperative radiotherapy (PORT) has existed for a long time. The present study reassessed the overall survival (OS) and disease-free survival (DFS) data to investigate whether PORT can improve survival in resectable non-small cell lung cancer (NSCLC) patients. The following databases were used to perform literature search: PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Embase (from January 1, 1986 to July 5, 2021). The results of overall survival (OS) and disease-free survival (DFS) were calculated as hazard ratio (HR). Confidence intervals are chosen with 95% confidence intervals. A total of 12 RCTs and 19 retrospective cohort studies were found to meet the inclusion criteria. A significant DFS improvement was detected in the PORT group (4111 patients from 15 studies), although statistical difference was not detected for OS between the non-PORT and PORT groups (31 studies, 49,342 total patients). PORT prolonged OS in patients undergoing PORT plus postoperative chemotherapy (POCT) and in pN2 patients. Patients with a median radiation dose of 50.4 Gy and a median radiation dose of 54 Gy had a better OS after PORT. However, if the total radiotherapy dose went up to 60 Gy, PORT increased the risk of death in NSCLC patients. Significant difference in OS was not found in the results of studies with regard to treatment methods, pathologic stages, study type, radiation beam quality, and radiation dose. Patients undergoing postoperative chemoradiotherapy and pN2 patients can benefit from PORT. Patients exposed to median radiation doses of 50.4 and 54 Gy demonstrated relatively good efficacy. For patients with non-small-cell lung cancer, PORT has not been proven to extend OS, but its effect on DFS remains strong.

Effect of Adjuvant Radiation Dose on Survival in Patients with Esophageal Squamous Cell Carcinoma.

Background: For patients with esophageal squamous cell carcinoma (ESCC) treated with surgery alone, the incidence of local-regional recurrence remains unfavorable. Postoperative radiotherapy (PORT) has been associated with increased local-regional recurrence-free survival (LRFS), although its application is limited by concerns of PORT-related toxicities. Methods: Among 3591 patients with ESCC analyzed in this study, 2765 patients with T3-4N0 and T1-4N1-3 lesions and specific local-regional status information were analyzed in a subsequent analysis of adjuvant radiation dose (aRTD) effect. Application of the restricted cubic spline regression model revealed a non-linear relationship between aRTD and survival/radiotoxicity. Linear regression analysis (LRA) was performed to evaluate correlations between LRFS and overall survival (OS)/ disease-free survival (DFS). Results: For patients staged T1−2N0, T1−2N1−3, T3−4N0, and T3−4N1−3, 5-year OS in PORT and non-PORT groups were 77.38% vs. 72.91%, p = 0.919, 52.35% vs. 46.60%, p = 0.032, 73.41% vs. 61.19%, p = 0.005 and 38.30% vs. 25.97%, p < 0.001. With aRTD escalation, hazard ratios (HRs) of OS/DFS declined until aRTD exceeded 50Gy, then increased, whereas that of LRFS declined until aRTD exceeded 50 Gy, then remained steady. HR of treatment-related mortality was stable until aRTD exceeded 50 Gy, then increased. LRA revealed strong correlations between LRFS and OS/DFS (r = 0.984 and r = 0.952, respectively). An absolute 1% advancement in LRFS resulted in 0.32% and 0.34% improvements in OS and DFS. Conclusions: An aRTD of 50Gy was well-tolerated, with favorable survival resulting from PORT-related LRFS improvement in patients staged T3−4N0 or T1-4N1−3. Further stratification analyses based on tumor burden would help determine potential PORT-beneficiaries.

Estimating recurrences prevented and costs avoided with atezolizumab in early non-small cell lung cancer in the United States.

Recurrence of early-stage non-small cell lung cancer (eNSCLC) is associated with significant mortality and costs. Atezolizumab (ATZ) was recently approved as adjuvant treatment following resection and platinum-based chemotherapy for adults with stage II-IIIA NSCLC with PD-L1 expression ≥1% after demonstrating significant improvement in disease-free survival (DFS) relative to best supportive care (BSC) in the IMpower010 trial (NCT02486718). This study evaluated the population-level impact of ATZ as adjuvant treatment for eNSCLC in the United States by estimating the number and costs of recurrences avoided. A Monte Carlo simulation model estimated the cumulative number of recurrences and deaths prevented, along with direct, indirect, and terminal care costs, by treating eNSCLC patients with ATZ compared to BSC. The model included eligible patients treated in any given year and followed over a 5-year period. Recurrence and mortality rates and costs were based on the IMpower010 data and supplemented by estimates from published literature. An estimated 4400 eNSCLC patients in the United States were eligible for adjuvant ATZ in any given year, of whom 2387 would experience recurrence within 5 years with BSC. Following the introduction of ATZ, 1030 (95% confidence interval [CI]: 1023, 1036) recurrences and 369 (95% CI: 362, 376) deaths would be avoided with estimated reductions in cumulative recurrence-related direct, indirect, and terminal care costs of $785million, $15million, and $32million, respectively, over a 5-year time horizon. Adjuvant ATZ is estimated to prevent a significant number of recurrences and reduce the economic burden of eNSCLC.

Afatinib maintenance therapy following post-operative radiochemotherapy in head and neck squamous cell carcinoma: Results from the phase III randomised double-blind placebo-controlled study BIB2992ORL (GORTEC 2010–02)

ObjectiveWe investigated the efficacy and safety of afatinib maintenance therapy in patients with head and neck squamous cell carcinoma (HNSCC) with macroscopically complete resection and adjuvant radiochemotherapy (RCT). MethodsThis French multicentric randomised phase III double-blind placebo-controlled study included adult patients with ECOG-PS≤2, normal haematological, hepatic and renal functions, and non-metastatic, histologically confirmed HNSCC of the oral cavity, oropharynx, larynx or hypopharynx, with macroscopically complete resection and adjuvant RCT (≥2 cycles of cisplatin 100 mg/m2 J1, J22, J43 and 66Gy (2Gy/fraction, 5 fractions/week, conventional or intensity modulated radiotherapy ≥60Gy). Randomised patients were planned to receive either afatinib (afa arm) or placebo (control arm (C)) as maintenance therapy for one year. Primary endpoint was disease free survival (DFS). A 15% improvement in DFS was expected at 2 years with afatinib (from 55 to 70%). ResultsAmong the 167 patients with resected HNSCC included in 19 cancer centres and hospitals from Dec 2011, 134 patients were randomised to receive one-year maintenance afatinib or placebo (afa:67; C:67). Benefit/risk ratio was below assumptions and independent advisory committee recommended to stop the study in Feb 2017, the sponsor decided premature study discontinuation, with a 2-year follow-up for the last randomised patient. 2y-DFS was 61% (95% CI 0.48–0.72) in the afatinib group and 64% (95% CI 0.51–0.74) in the placebo group (HR 1.12, 95% CI 0.70–1.80). ConclusionMaintenance therapy with afatinib compared with placebo following post-operative RCT in patients with HNSCC did not significantly improve 2y-DFS and should not be recommended in this setting outside clinical trials.ClinicalTrials.gov identifier NCT01427478.

Abstract 15445: Combination Therapy With Pde5-mtor Inhibitors Attenuates Cardiotoxicity While Enhancing Cancer Cell Death Following Treatment With Doxorubicin and Human Epidermal Growth Factor Receptor 2 Inhibitor

Backgound: Chemoimmunotherapy with Doxorubicin (DOX) and Trastuzumab (Trast, a monoclonal antibody against human epidermal growth factor receptor 2, ERBB2) has synergistic effects with immense improvement in disease-free survival in breast cancer patients. However, because of the high incidence of heart failure, the concomitant treatment with DOX and trastuzumab has been restricted. In the present study, we examined whether a novel combination therapy with the phosphodiesterase 5 (PDE5) inhibitor (sildenafil, Sild) and mTOR inhibitor (rapamycin, Rapa) can attenuate cardiotoxicity-induced by DOX+Trast. Methods &amp; Results: Human ventricular cardiomyocytes (AC16) and ErbB2 + breast cancer cells (SKBr3) were treated with DOX (1μM), AG-825 (ERBB2 inhibitor, 5μM) and/or Sild (10μM) and Rapa (100 nM) for 24 hours. AC16 cell death was significantly higher with DOX+AG825 as compared to the single drug treatment, which was significantly reduced with Sild+Rapa treatment (Fig. A ). Contrarily, the enhanced SKBr3 cell death with DOX+AG825 treatment was further increased by Sild+Rapa treatment (Fig. B ). To evaluate therapeutic effect of Sild+Rapa against cardiotoxicity, C57BL/6J mice were treated for 2 weeks with DOX (6 mg/kg/twice/week, i.p.). After 1week interval, mice were treated with Trast for 2 weeks (2.5 mg/kg/twice/week, i.p.) (Fig. C ). Rapa (0.25 mg/kg/twice/week, i.p.) and Sild (0.4 mg/ml in drinking water) were administered for 12 weeks. Body weight, left ventricular ejection fraction (LVEF) and E/A ratio as well as survival were significantly decreased in mice with the sequential treatment of DOX and Trast as compared to DOX alone (Fig. D-G ). Treatment with Sild+Rapa significantly improved body weight and survival with restoration of cardiac function in mice treated with DOX±Trast. Conclusion: Combination treatment with Sild and Rapa could be a novel strategy to attenuate cardiotoxicity associated with DOX±Trast and improvement of cancer chemotherapy.

PO34 Presentation Time: 10:30 AM: Oncologic Outcomes and Toxicities in Gynecologic Cancer Patients Treated with Post-Procedure MRI-Guided Interstitial Brachytherapy at a Single Institution

<h3>Purpose</h3> High-dose rate interstitial brachytherapy (ISBT) with implantation of the Syed-Neblett template and use of three-dimensional, CT-based planning plays an important role in the management of patients with locally advanced or recurrent gynecologic cancers. ISBT is often utilized in patients with bulky disease that is not amenable to intracavitary approaches. Previous studies have suggested there is a higher risk of fistula formation in patients treated with ISBT, as high as 18% - 32%. There is a paucity of data on ureteral strictures in patients undergoing ISBT, with only one series suggesting 4.3% of patients without baseline hydronephrosis will develop ureteral stricture. The current study examines the oncologic outcomes and treatment-related toxicities associated with ISBT for patients treated at our institution. <h3>Materials and Methods</h3> We conducted a retrospective case series of all patients who received ISBT for a gynecologic cancer at our institution from January 2015 - January 2022. Patients were identified using ICD-10 and CPT codes for ISBT. Demographics, prior oncologic treatment, treatment-related toxicities, and oncologic outcomes were collected from our institution's electronic medical record (EMR). Kaplan-Meier analysis was used for assessment of oncologic outcomes. <h3>Results</h3> Thirty patients treated with external beam radiation (EBRT) and ISBT were identified, with twenty-six patients (86.7%) treated for primary disease. The most common malignancy was cervical (N = 19, 63.3%). The most common malignancy histology was squamous cell carcinoma (N = 21, 70%). Most patients had either stage III or stage IV disease at the time of ISBT (N = 22, 73.3%). Eleven patients (36.7%) had percutaneous nephrostomy (PCN) or ureteral stent (US) placed prior to their EBRT. Twenty-nine (96.7%) had no previous history of RT. Of these cases, twenty-six (86.7%) underwent post-procedural MRI-guided ISBT to a median dose of 2750 cGy (1400 - 3250 cGy) over mostly 5 fractions. Median follow-up was 9 months (range 1 day - 4 years); disease-free survival was 61.1% at 1 year and 50.9% at 2 years, with overall survival of 84% at 1 year and 63% at 2.5 years. Univariate analysis did not reveal any significant predictors of improvement in disease-free survival based on baseline characteristics. Five patients (16.7%) required a PCN or US after treatment, only one (out of 19, 5.3%) of whom did not have pre-treatment PCN/US. Three patients (10%) developed post-treatment fistula. The most common toxicities noted included vaginal symptoms (N = 20, 66.7%), post-treatment pain (N = 18, 60%), urinary symptoms (N = 15, 50%), and rectal symptoms (N = 10, 33.3%). <h3>Conclusions</h3> MRI-guided ISBT using the Syed-Neblett template provides effective disease control and tolerable toxicity in this high-risk patient cohort. While risk of new ureteral stricture was similar to previous series, rates of fistula formation were lower than historical controls.

189 (PB-102) Poster - Ovarian function suppression in early & locally advanced breast cancer: an audit of practice

Background: Tamoxifen has been considered the mainstay of adjuvant endocrine therapy for premenopausal women diagnosed with early and locally advanced breast cancer for many years. However, a long standing debate over the potential benefit of ovarian function suppression (OFS) has resulted in recently updated national clinical guidelines. Trials investigating the use of OFS plus either tamoxifen or an aromatase inhibitor (AI) demonstrated improved disease free survival (DFS) and lower recurrence rates in those having had the combination of OFS and hormone therapy.

Aspirin Use is Associated with Improvement in Distant Metastases Outcome in Patients with Residual Disease after Neoadjuvant Chemotherapy

<h3>Purpose/Objective(s)</h3> Previous data has suggested that aspirin (ASA) use may be associated with improved outcomes in patients at higher risk for distant metastases after completion of curative therapy. Patients with breast cancer (BC) that do not obtain a pathologic complete response (pCR), particularly those with residual nodal disease (ypN+) after neoadjuvant chemotherapy (NAC) are at higher risk of worse outcomes. To date, there are no reported studies of potential benefit of ASA use within this subgroup. Our hypothesis is that ASA use can reduce the risk of distant metastases and improve outcome in ypN+ patients after NAC. <h3>Materials/Methods</h3> Patients at two institutions with BC treated with NAC who did not achieve pCR between 2005-2018 were reviewed (IRB protocol STU- 052012-019). Pertinent data, including evidence of ASA use (initiated during remission period), and clinico-pathologic parameters were analyzed. Overall survival (OS), disease free survival (DFS), and distant metastases free survival (DMFS) were obtained using Kaplan Meier analysis. Univariate and multivariate (MVA) logistic regression models were constructed and analyzed. <h3>Results</h3> 637 patients were evaluated, of which 138 were ASA users. Median follow-up for the control group was 3.8 (IQR 2.2-6.3) years and 3.8 (IQR 2.5-6.4) years for the ASA group. Nearly all patients had stage II or III disease (IIA: 75, IIB: 171, IIIA: 120, IIIB: 72, IIIC: 43). 416 patients underwent mastectomy, and 221 patients underwent partial mastectomy. 387 patients were HR+ (hormone receptor positive), 194 HER2+, and 157 were triple negative. 422 patients remained ypN+. The aspirin and non-aspirin groups did not show significant differences in patient characteristics analyzed. Clinico-pathologic characteristics analyzed for association with outcome included age, race, ASA use, molecular profile, pathologic and clinical stage, LVI, and clinical grade. On univariate analysis, ASA use, PR status, ypT, ypN, and clinical stage showed significance for improvements in DMFS, while ASA use, ER/PR status, ypT, ypN, and clinical stage showed significance for improvements in DFS. On MVA, ASA use remained significantly associated with improvements in 5-year DFS (p=.02, 87.0% vs 79.6%) and trended for 5-year DMFS improvement (p=.08, 92.8% vs 89.2%). In the ypN+ patients, ASA use was significantly associated with improvement in 5-year DMFS (p=.03, 85.7% vs 70.7%) on MVA. <h3>Conclusion</h3> Patients at higher risk for worse outcome, particularly those that are unable to achieve nodal clearance after NAC, demonstrated significant outcome benefits with ASA use initiated during remission period. These hypotheses-generating results suggest consideration for development of prospective clinical trials of augmented ASA use in these high-risk BC patients.

Postoperative Radiotherapy for Completely Resected Thymoma: What Can We Learn in the Precision Radiation Era?

<h3>Purpose/Objective(s)</h3> The optimal role of radiotherapy (PORT) after complete thymectomy for thymoma remains controversial. We investigate the role of postoperative radiotherapy in the complete resection of Masaoka-Koga stage Ⅱ/Ⅲ thymoma with precision radiotherapy techniques. <h3>Materials/Methods</h3> From January 2000 to December 2017, patients with Masaoka-Koga stage Ⅱ/Ⅲ thymoma who underwent complete resection or complete surgical resection and underwent radiotherapy with precision techniques were included and analyzed. Clinical, pathological, therapeutic and follow-up information was collected. Kaplan-Meier estimates of overall survival (OS), disease-specific survival (DSS) and disease-free survival (DFS), and univariate and multivariate Cox proportional hazards regression analyses were performed. <h3>Results</h3> A total of 244 patients met the selection criteria, 142 (58.1%) of whom were received PORT. Of these, 172 (70.5%) patients with stage Ⅱ thymoma, 72 patients (29.5%) with stage Ⅲ. The median follow-up was 76 months. The 5-year and 10-year OS in the surgical and PORT groups were 93.8% vs 95.4% and 83.6% vs 86.9%, respectively (p=0.34), while the DSS was 93.8% vs 99.0% and 86.3% vs 93.9%, respectively (p=0.038), and the DFS was 85.0% vs 76.9% and 75.9% vs 65.5%, respectively (p=0.65). In stage Ⅲ patients,5-year and 10-year OS was 83.0% vs 95.8%, 54.4% vs 84.4% (HR 0.31, p=0.038) and DSS was 83.0% vs 97.6%, 54.4% vs 91.8% (HR 0.14, p=0.002) for surgery alone vs the PORT group. On multivariate analysis, stage Ⅲ was associated with poorer OS (HR 2.36, <i>p</i>=0.045) and DSS (HR 3.61, <i>p</i>=0.020), and PORT were associated with better DSS (HR=0.26, <i>p</i>=0.012). <h3>Conclusion</h3> Masaoka-Koga stage Ⅱ/Ⅲ thymoma complete resection after radiotherapy with precision radiotherapy techniques resulted in improved DSS but not significant improvement in OS and DFS; Subgroup analysis showed a more pronounced benefit of PORT in stage Ⅲ patients, with benefits in DSS and OS, suggesting that postoperative radiotherapy can be beneficial in more advanced thymoma.

ALL-056 Late Intensification With Autologous HSCT After Non-Myeloablative CEAM Conditioning Can't Improve Results of Therapy in Adults With T-Cell Acute Lymphoblastic Leukemia (ALL) Treated by Non-Intensive Protocol: Data of the Multicentral Prospective Randomized RALL Study

The Russian ALL group applied a protocol based on a less intensive and also non-interruptive approach. RALL-2009 study showed that fulfilled auto-hematopoietic stem cell transplantation (HSCT) in T-cell ALL could reliably improve disease free survival (DFS). This is a non-randomized trial, and selection is limited to patients with auto-HSCT vs chemotherapy (ChT) only. To appreciate the role of fulfilled auto-HSCT in T-ALL adult patients treated by RALL-2006 protocol. In RALL-2016 protocol all T-ALL patients who achieved complete response (CR) were brought to randomization after the informed consent to one of two groups: auto-HSCT vs ChT only. 267 Ph-negative ALL adult patients were included from Dec 2016 until Apr 2022. 111 patients had T-ALL, 74% were male, and median age was 31. 5y overall survival (OS) and DFS in T-ALL patients were 68% and 66%, respectively. We observed that early T-cell precursor (ETP)-ALL is group of patients with reliably poor prognosis, with high probability of relapse (PR) (52% in 1st year after CR). 87 T-ALL patients (pts) were randomized: 43 pts to ChT, and 44 to auto-HSCT. 1 patient refused in ChT group, and 4 refused in auto-HSCT; patients were censored on data of refuse. We observed similar number of deaths in CR in both arms, and similar cases of patients who went to allo-HSCT - mixed-lineage leukemia (MLL) leukemia, Niimegem syndrome or long MRD persistence). 25 auto-HSCT were done. For transplanted patients: time from CR to transplant was 7 months. All pts were conditioned with iomustine, etoposide, cytarabine, and melphalan (CEAM) before auto-HSCT. Maintenance start was 1.5 months after HSCT. Transplant-related mortality was 5%. Landmark analysis from a median of 7 months post-HSCT, didn't detect differences in DFS and PR (67% vs 78%, and 25% vs 22% auto-HSCT vs ChT). Auto-HSCT does not improve DFS in T-ALL with MRD after induction. In both auto-HSCT and only ChT groups with MRD persistence after induction have poor DFS (MRD-: 86% vs 81% and MRD+: 67% and 40%, respectively ChT vs auto-HSCT). We didn't detect that auto-HCST could improve long-term result for T-cell ALL. ETP-phenotype is an independent poor prognostic factor. Addition of auto-HSCT as late high-dose consolidation for T-ALL with MRD persistence does not improve results of therapy.

351. SUPERIOR MEDIASTINAL DISSECTION DURING MINIMALLY INVASIVE ESOPHAGECTOMY FOR ESOPHAGEAL CANCER—A MULTICENTER PROPENSITY SCORE MATCHED (PSM) ANALYSIS

Abstract Minimally invasive esophagectomy (MIE) is currently the preferred approach of surgery for esophageal cancer. Systematic superior mediastinal lymphadendectomy along bilateral recurrent laryngeal nerve is enhanced by the magnified view in thoracoscopy, and is increasingly performed to achieve complete nodal dissection. Both participating centers began MIE with systematic superior mediastinal dissection in recent 5 years. In the current study, we aim to compare the short- and medium-term outcomes of MIE with or without superior mediastinal dissection. Consecutive patients who received MIE for esophageal cancers from 2004 to 2021 were recruited, data were collected from a prospectively maintained database. Patients were divided into ‘systematic superior mediastinal dissection’ and ‘control’ groups, and propensity score matching was performed with age, tumor location, tumor stage and neoadjuvant therapy. Total 157 patients were recruited, 67 (42.7%) in the extended superior mediastinal dissection group. After PSM, 48 patients were identified in each group. Short term surgical outcomes as well as medium term survival results were compared. Operative time was significantly longer with extended superior mediastinal dissection. Higher number of lymph nodes were yielded in total and from the superior mediastinum. Recurrent laryngeal nerve palsy developed in 52.1% and 43.8% of the MIE with or without extended dissection respectively, but significantly fewer palsies required intervention in the extended dissection group. Higher rate of anastomotic leakage was observed in the extended dissection group, but there was no difference in the overall severe adverse event (&amp;gt; = Grade III: 31.3% vs 35.4%). There was no statistical difference in the survival, but a trend towards improved 2 year disease-free survival was observed. Minimally invasive esophagectomy with systematic superior mediastinal dissection achieved a higher lymph node yield and a trend towards improved disease free survival. The overall adverse event rate was similar with conventional dissection. While better cancer staging could be achieved with extended dissection, further research is required to confirm the oncological benefit of extended dissection.

Efficacy and Safety of the Addition of Internal Mammary Irradiation to Standard Adjuvant Radiation in Early-Stage Breast Cancer: A Systematic Review and Meta-Analysis.

Background: Existing data on adding internal mammary nodal irradiation (IMNI) to the regional nodal fields are inconsistent. Methods: Randomized trials investigating the addition of IMNI to standard adjuvant radiation were identified. Hazard ratios (HRs) and 95% confidence intervals (CI) were extracted for overall-survival (OS), breast cancer specific-survival (BCSS), and disease-free survival (DFS) as well as distant-metastasis free survival (DMFS). The odds ratios (ORs) for regional and loco-regional recurrence, non-breast cancer mortality, secondary non-breast cancer, contralateral breast cancer, and cardiovascular morbidity and mortality were also extracted. Results: Analysis included five trials comprising 10,994 patients, predominantly with higher risk, lymph node positive disease. Compared to the control group, IMNI was associated with significant improvement in OS (HR = 0.91, p = 0.004), BCSS (HR = 0.84, p < 0.001), DFS (HR = 0.89, p= 0.01), and DMFS (HR = 0.89, p = 0.02). IMNI was also associated with reduced odds for regional (OR = 0.58, p < 0.001) and loco-regional recurrence (OR = 0.85, p = 0.04). The odds for cardiotoxicity were not statistically significantly higher (OR = 1.23, p = 0.07). There were comparable odds for cardiovascular mortality (OR = 1.00, p = 1.00), non-breast cancer mortality (OR = 1.05, p = 0.74), secondary cancer (OR = 0.95, p = 0.51), and contra-lateral breast cancer (OR = 1.07, 95% 0.77–1.51, p = 0.68). Conclusions: Compared to the control group, the addition of IMNI in high-risk patients is associated with a statistically significant improvement in survival, albeit with a magnitude of questionable clinical meaningfulness.

Effectiveness of adjuvant radiotherapy for high recurrence risk patients with upper tract urothelial carcinoma.

A recent study has shown that upper tract urothelial carcinoma (UTUC) patients with high-risk factors have a high local recurrence rate. The purpose of this work was to investigate the benefit of adjuvant radiotherapy (ART) for patients with high recurrence factors. Four hundred twenty-four UTUC patients who received radical nephroureterectomy (RNU) in our hospital between 2010 and 2018 were reviewed. The significance of factors on cancer-specific survival (CSS) and recurrence-free survival (RFS) were assessed using Cox multivariate analysis. In patients with high recurrence factors, propensity score matching was used to adjust the confounding factors for ART. The median follow-up time was 40 (range 3-77) months. Multivariate analysis showed that multifocal tumor, G3, pT3/4 stage and positive lymph node (N+) were independent predictors for worse RFS. Multifocal tumor and pT3/4 stage were independent predictors of worse CSS in UTUC after surgery. A total of 286 patients with these high recurrence factors were identified: 192 (67.1%) patients received RNU only, and 94 (32.9%) patients received ART. Overall, ART did not improve CSS (ART 86.1% vs. RNU 78.5%.; P = 0.11). After propensity score matching, ART significantly improved the CSS of patients with high recurrence factors. The 3-year CSS was 73.1% in patients treated with RNU alone vs. 86.1% in patients treated with ART (P = 0.016). Results of our study demonstrated benefit of adjuvant radiotherapy in cancer specific survival in UTUC patients with high recurrence factors(multifocal tumor ,pT3/4,G3 and positive lymph node).

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

Simple SummaryDynamic chromatin remodeling is regulated by different epigenetic modifications of histones to adapt chromatin to specific cellular functions. Targeting histone epigenetic enzymes will interfere with the correct mechanisms of DNA repair. Therefore, targeting epigenetic enzymes is a potential novel strategy for synthetic lethality to facilitate tumor cell death in response to current genotoxic treatments.Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear or chromatin kinases, all of which are druggable targets. Among epigenetic enzymes, there are four major families: histones acetylases, deacetylases, methylases and demethylases. All these enzymes are druggable. Among chromatin kinases are those associated with DNA damage responses, such as Aurora A/B, Haspin, ATM, ATR, DNA-PK and VRK1—a nucleosomal histone kinase. All these proteins converge on the dynamic regulation chromatin organization, and its functions condition the tumor cell viability. Therefore, the combined targeting of these epigenetic enzymes, in synthetic lethality strategies, can sensitize tumor cells to toxic DNA-damage-based treatments, reducing their toxicity and the selective pressure for tumor resistance and increasing their immunogenicity, which will lead to an improvement in disease-free survival and quality of life.

Optimal Choice of Neoadjuvant Chemotherapy for HER2-Negative Breast Cancer: Clinical Insights.

The neoadjuvant setting provides immense opportunities for translational research and drug development. The acceptance of pathological complete response (pCR) as a surrogate endpoint for clinical benefit has led to the widespread use of neoadjuvant treatment. Optimal neoadjuvant therapies are determined based on their ability to achieve the highest rates of pCR. Predicted rates of pCR for triple negative breast cancer (TNBC) treated with sequential taxane/anthracycline regimens range from 35% to 48%. With the addition of a platinum agent pCR rates of 55% are predicted. Further increases have been observed with the addition of immune checkpoint inhibitors to this standard chemotherapy backbone. In the pivotal KEYNOTE-522 clinical trial pCR rates of 65% and 69% were reported for chemotherapy plus pembrolizumab in the overall and PD-L1-positive subgroup respectively. The role of the neoadjuvant chemotherapy is less clear in hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer. In general, HR–positive cancers have the least chance of achieving a pCR after neoadjuvant chemotherapy, especially if they are low-grade. If neoadjuvant chemotherapy is given for high-risk HR-positive, HER2-negative breast cancer, standard adjuvant anthracycline/taxane regimens are appropriate. Optimum endocrine therapy is the standard-of-care in the adjuvant setting regardless of pCR. There are several genomic signatures available to guide decisions regarding adjuvant chemotherapy use however these assays are not routinely used in the neoadjuvant setting. For high-risk patients meeting the criteria for the monarchE trial adjuvant abemaciclib in addition to endocrine therapy is associated with an improvement in disease free survival (DFS) at 3 years. Based on the OlympiA trial patients with germline BRCA mutations should be considered for adjuvant olaparib therapy. In this article we review neoadjuvant clinical trials that guide optimum treatment options for TNBC and HR-positive, HER2-negative breast cancer.

A narrative review of the evolving role of immunotherapy in the management of esophageal and gastric cancer.

Background and ObjectiveDespite recent advances in the multidisciplinary management of esophagogastric cancer, overall prognosis remains poor. There is a need for improved treatment options, along with predictive biomarkers that improve therapeutic decision-making.MethodsWe conducted an extensive review of immunotherapy articles in the PubMed database between December 2013 and October 2021. Articles in English were included. We included phase 1, 2, and 3 clinical trials for immunotherapy review, and prospective, retrospective, and meta-analyses for biomarker review.Key Content and FindingsInitial studies of immunotherapy were performed in patients with relapsed refractory metastatic disease and demonstrated a modest survival benefit. Subsequent studies have evaluated the use of these agents in combination with first line chemotherapy for metastatic disease. Finally, recent data indicates that immunotherapy in the adjuvant setting after concurrent chemoradiation and surgery improves disease free survival. Both microsatellite instability high (MSI-H) status and Epstein-Barr virus (EBV) positivity predict response to immunotherapy, but many patients without these biomarkers still benefit. The predictive impact of programmed cell death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) have been variable, and the optimal cutoff point for these biomarkers remains poorly defined.ConclusionsWhile immunotherapy agents have demonstrated clinical benefit and are now incorporated into the current standard of care, novel immunotherapy approaches such as dual immunotherapy combinations, chimeric antigen receptor (CAR) T cells, and tumor vaccines need to be further investigated. As the era of precision medicine beckons, refined biomarkers to predict benefit are needed.

Efficacy and Safety of Capecitabine for Triple-Negative Breast Cancer: A Meta-Analysis.

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with limited treatment options and poor prognosis. Capecitabine, as a novel adjuvant chemotherapy for TNBCs, remains controversial. Therefore, we conducted this meta-analysis to assess the efficacy and safety of capecitabine for early-stage TNBCs combined with neo-/adjuvant chemotherapy.MethodsWe searched Medline, Embase, Web of Science, and Cochrane databases updated on Mar 18, 2022 for relevant RCTs. In all, 11 RCTs with 5,175 patients were included. We used hazard ratios (HRs) and odds ratios (ORs) to assess the differences between disease-free survival (DFS), overall survival (OS), and adverse events.ResultsOur study demonstrated significance differences in both DFS and OS (DFS: HR=0.77; 95% CI 0.68–0.86; OS: HR=0.73, 95% CI 0.63–0.85). In subgroup analysis, the lower dosage group showed higher DFS (HR=0.79, 95% CI 0.69–0.91), higher frequency (HR=0.72, 95%CI 0.62–0.83), and adjuvant chemotherapy (HR=0.74, 95% CI 0.65–0.84). However, capecitabine was also associated with a higher risk of diarrhea (OR=3.10, 95% CI 2.32–4.15), hand–foot syndrome (OR=25.79, 95% CI 15.32–43.42), and leukopenia (OR=2.08, 95% CI 1.13–3.84).ConclusionThe addition of capecitabine to early-stage TNBC patients receiving standard adjuvant chemotherapy showed significant DFS and OS improvement with tolerable adverse events. The lower dosage and higher frequency of capecitabine combined with adjuvant chemotherapy demonstrated a better survival outcome.

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Abstract 1711: A multi-modal analysis approach leveraging multiplexed spatial phenotyping and multi-omics analysis to better understand the prognostic value of tertiary lymphoid structures in non-small cell lung cancer

Abstract Introduction: Tertiary Lymphoid Structures (TLS) are highly organized ectopic lymphoid structures found in inflamed or tumor tissues, acting as sites of lymphoid recruitment and immune activation. A high TLS density within the tumor is commonly associated with an increased prognostic effect of TILs and with an improved disease free survival and overall survival for patients. However, the existence of conflicting studies suggest that multiple TLS features should be taken into account when assessing their prognostic value, such as their location, cellular composition, maturation stage and spatial organisation, as those may affect their functionalities. Methods: With the aim of gaining insights into TLS biology and evaluating the prognostic role of TLS in Non-Small Cell Lung Carcinoma (NSCLC) according to their multiple features, we developed a TLS multiplex immunofluorescent (mIF) panel that includes T cell (CD3, CD8), B cell (CD20), Follicular Dendritic cell (CD21, CD23) and mature dendritic cell (DC-LAMP) markers. We deployed this panel across a cohort of primary tumors from NSCLC patients (n=408) and established a mIF image analysis workstream to assess the status and spatial location of each cell within the tissue. A H&amp;E staining of the same tissue section was performed to evaluate mIF spatial data in relation to the tumor context. Additional multi-omics assessments were conducted across the same cohort including; whole exome sequencing, NanoString transcriptomics, and immunohistochemistry (e.g. PD-L1, FOXP3). We have leveraged clinical metadata, including demographics (e.g. age, sex, smoking status) and clinical risk factors (e.g. stage, grade, Standard of Care treatment) with clinical follow up (e.g. OS, PFS) for prevalence analysis, novel biomarker identification, and survival association. Results: Assessment of the prevalence of each cell phenotype within the tumor tissue and TLS (tumor centre vs invasive margin; tumor epithelium vs stroma), the distance between each cell type, and the distance of non-TLS immune cells to the closest TLS will be described, demonstrating the different types of lymphoid aggregates and TLS and their functional status. An integrative analysis combining these spatial biology data with multi-omics and clinical data will be presented evaluating the prognostic value of TLS composition, maturation status and spatial organization, in correlation with additional biomarkers and clinical characteristics. Conclusion: This exploratory study using cutting-edge technologies enables us to better understand how TLS orchestrate an organised anti-tumour response, defining TLS spatial biomarker signatures, TLS gene signatures, and TLS features associated with NSCLC patient outcomes to evaluate in the clinic. Citation Format: Julie Berthe, Felix Segerer, Emily C. Jennings, Alma Andoni, Marco Testori, Megha Saraiya, Miljenka Vuko, Harald Hessel, Andreas Spitzmüller, Mari Heininen-Brown, Jorge Blando, Felicia Ng, Emma Jones, Sophie Willis, Michael Surace, Rieneke van de Ven, Tanja De Gruijl, Helen Angell. A multi-modal analysis approach leveraging multiplexed spatial phenotyping and multi-omics analysis to better understand the prognostic value of tertiary lymphoid structures in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1711.