Months Of Disease-free Survival Research Articles

Preliminary results correlating post-operative ctDNA status with disease-free survival in patients with stage II (high risk)/III colorectal cancer in the BNT000-001 epidemiology study.

3526 Background: Despite standard-of-care surgical resection and adjuvant chemotherapy (ACT), disease recurrence in patients (pts) with stage II or III colorectal cancer (CRC) remains high. Circulating tumor DNA (ctDNA) analysis post-surgery with curative intent may help to identify pts with minimal residual disease at risk for recurrence. We report preliminary results of the BNT000-001 study exploring the prevalence and prognostic value of ctDNA positivity post-surgery in pts with stage II (high-risk) / III CRC. Methods: The BNT000-001 (NCT04813627) epidemiological study is enrolling pts in US, Germany (including screening through the Colopredict registry study), Spain, and Belgium with resected high-risk (per NCCN guidelines) stage II / III CRC for longitudinal follow up of their ctDNA status post-surgery and ACT. The primary objective of the study is to estimate the prevalence of ctDNA positivity after surgery. Other objectives include evaluation of the prognostic value of ctDNA and identification of ctDNA positive pts who might be candidates for the interventional clinical trial BNT122-01 (NCT04486378). Disease-free survival (DFS) was measured from the post-surgery visit to disease recurrence/death and analyzed for all eligible pts who remain on study. ctDNA was analyzed using the laboratory developed AVENIO Oncology Assays (AOA) Surveillance test and reported as detected (“positive”), not detected (“negative”), or no result (“non-evaluable”). Results: 1094 pts have been screened, of which 874 pts were analyzed for post-surgery ctDNA status (data cutoff 15 Dec 2023). 142 pts were non-evaluable, resulting in 732 pts with defined ctDNA status. Prevalence of post-operative ctDNA positivity was 12.3% (90*/732). 87.7% (642/732) of pts were ctDNA negative. 826 pts were followed for the prognostic value of post-surgery ctDNA-positivity, excluding 48 ctDNA positive pts who transferred to the BNT122-01 treatment study. At a median follow-up time of 25.9 months, the median DFS of ctDNA positive pts was 12.16 months vs. median DFS not reached for ctDNA negative pts. The 12-month DFS rate was 55% for ctDNA positive vs. 92% for ctDNA negative pts. Of note, our analyses support the identification of ctDNA negative T4N2 pts as a high-risk group for recurrence. Post-surgery ctDNA positivity was associated with significantly increased risk for disease recurrence or death, with a hazard ratio of 10.2. Conclusions: This study supports existing evidence of the prognostic value of post-operative ctDNA in CRC pts. In ctDNA positive pts, the 12-month DFS rate was almost halved (55% vs. 92% in ctDNA negative). Clinical trial information: NCT04813627 . [Table: see text]

Abstract A008: Racial differences in characteristics and outcomes of adjuvant nivolumab for muscle-invasive urothelial carcinoma (MIUC) in the real-world setting

Abstract Objectives: Historically, African-American/Black patients with bladder cancer have worse clinical outcomes compared with White/Caucasian patients. In the CheckMate 274 trial, nivolumab demonstrated a significant improvement in disease-free survival compared with placebo among patients with MIUC at high risk of recurrence following radical surgery; however, African-American/Black patients were underrepresented (< 1%). The objective of this analysis was to describe the characteristics and outcomes of MIUC patients treated with adjuvant nivolumab across different racial subgroups in a real-world setting. Methods: This US retrospective medical chart review included African-American/Black and White/Caucasian patients with MIUC treated with adjuvant nivolumab following radical resection between 01-Sep-2021 and 10-Sep-2022. Patient characteristics and outcomes were abstracted from the medical charts by treating oncologists. Patient characteristics and landmark survival estimates based on Kaplan-Meier analyses were summarized descriptively. Results: The analysis included 223 patients (African-American/Black: 62; White/Caucasian: 161). A numerically higher proportion of African-American/Black vs White/Caucasian patients, respectively, was male (74.2% vs 66.5%), less than 60 years old (27.4% vs 20.5%), unemployed (16.1% vs 5.6%), and had Medicaid at therapy initiation (14.5% vs 6.2%). Similar proportions in both groups had ECOG performance status 0-1 (82.3% vs 82.6%), received neoadjuvant therapy (58.1% vs 56.5%), and completed adjuvant therapy (67.7% vs 66.5%). The median follow-up time (12.5 months vs 13.1 months) and median duration of adjuvant therapy (11.0 months vs 11.3 months) were comparable. Similar estimates were observed for 12-month overall survival (96.7% vs 91.4%), 12-month disease-free survival (88.3% vs 88.4%), and 12-month distant metastasis-free survival (88.3% vs 88.4%). Conclusions: Despite higher rates of socio-economic risk factors among African-American/Black patients, this real-world study suggests similar effectiveness of adjuvant nivolumab among MIUC patients across African-American/Black and White/Caucasian patient populations. Citation Format: Regina Barragan-Carrillo, Alexander Chehrazi-Raffle, Bruce Feinberg, William S. John, Taavy A. Miller, Sarah Lucht, Prathamesh Pathak, Emily Bland, Sarah Gordon, JaLyna Laney, Andrew J. Klink, Hedyeh Ebrahimi, Nisha Singh, Carmelo Alonso, Miraj Patel, Lisa Rosenblatt, Xin Yin. Racial differences in characteristics and outcomes of adjuvant nivolumab for muscle-invasive urothelial carcinoma (MIUC) in the real-world setting [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A008.

Pembrolizumab monotherapy for high-risk non-muscle-invasive bladder cancer without carcinoma in situ and unresponsive to BCG (KEYNOTE-057): a single-arm, multicentre, phase 2 trial

The KEYNOTE-057 trial evaluated activity and safety of pembrolizumab in patients with BCG-unresponsive high-risk non-muscle-invasive bladder cancer who were ineligible for or declined radical cystectomy. In cohort A (patients with carcinoma in situ, with or without papillary tumours) of the KEYNOTE-057 study, pembrolizumab monotherapy led to a complete response rate of 41% at 3 months, and 46% of responders maintained a response lasting at least 12 months. Here, we evaluate pembrolizumab monotherapy in cohort B of patients with papillary tumours without carcinoma in situ. KEYNOTE-057 is a single-arm, phase 2 study in 54 sites (hospitals and cancer centres) in 14 countries. Cohort B eligible patients were aged 18 years and older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had BCG-unresponsive high-risk non-muscle-invasive bladder cancer with papillary tumours (high-grade Ta or any-grade T1) without carcinoma in situ. Transurethral resection of bladder tumour within 12 weeks of first pembrolizumab dose was required. Patients received pembrolizumab 200 mg intravenously every 3 weeks for a maximum of 35 cycles. Primary endpoint was 12-month disease-free survival of high-risk non-muscle-invasive bladder cancer or progressive disease as assessed by cystoscopy, cytology, and central pathology and radiology review. Activity was assessed in all patients who received at least one dose of the study drug and had a baseline evaluation. Safety was assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov number, NCT02625961, and is ongoing. Between April 12, 2016, and June 17, 2021, 132 patients (104 [79%] men and 28 [21%] women) who had received a median of ten (IQR 9-15) previous BCG instillations were enrolled into cohort B of the study. Patients received a median of 10 cycles (IQR 6-27) of pembrolizumab. At data cutoff date, Oct 20, 2022, median follow-up was 45·4 months (IQR 36·4-59·3) and five (4%) of 132 patients remained on treatment. The 12-month disease-free survival was 43·5% (95% CI 34·9-51·9). Treatment-related adverse events occurred in 97 (73%) of 132 patients; 19 (14%) had a grade 3 or 4 treatment-related adverse event; the most common grade 3 or 4 treatment-related adverse events were colitis (in three [2%] patients) and diarrhoea (in two [2%]). 17 (13%) of 132 patients experienced serious treatment-related adverse events, of which colitis (three patients [2%]) was most common. No treatment-related deaths occurred. Pembrolizumab monotherapy showed antitumour activity and manageable toxicity in patients with BCG-unresponsive high-risk Ta or T1 bladder cancer without carcinoma in situ and could potentially be a suitable treatment option for patients who decline or are ineligible for radical cystectomy. Findings will need to be confirmed in a randomised controlled trial. Merck Sharp & Dohme.

Outcome and Factors Related to Isolated Liver Metastasis due to Breast Cancer.

To determine the associated risk factors for isolated liver metastasis in breast cancer patients and to detect the prognostic factors related to survival. Analytical study. Place and Duration of the Study: Department of General Surgery, The University of Health Sciences, Istanbul, Turkiye, from January 2011 to November 2020. Patients with breast cancer liver metastasis who experienced surgery were retrospectively analysed for breast cancer and metastases-related characteristics. Descriptive statistical methods were used in the evaluation of data. Survival analyses were estimated by the Kaplan-Meier method. Log-rank and univariable Cox regression tests were utilised to search for prognostic factors' impact on survival. Out of 12 patients, 11 had recurrent disease after a median of 36 months of disease-free survival (DFS) and one patient had de novo metastasis. Grade 3 tumours and increased expression of Ki-67 had a negative effect on DFS. The median follow-up period was 66 months. Survival analysis showed 2- and 3-year progression-free survival (PFS); overall survival rates were 82%, 69%, 92%, and 82%, respectively. Development of liver metastasis in 3 years following breast cancer treatment was linked to worse PFS (p = 0.040). Long-term survival is possible for breast cancer survivors with liver metastasis. Disease-free interval is an important determinant. Longer progression-free survival was detected in patients who had developed metastasis after three years of breast cancer treatment. Breast cancer, Liver metastasis, Hepatic surgery.

Abstract 2400: Determinants of early recurrence in surgically-resected colon cancer: A multi-omics analysis

Abstract Introduction: Colon cancer is the third most common cancer worldwide. The mainstay treatment for localized disease is surgical resection, often followed by adjuvant chemotherapy in stage III patients, and stage II patients with high-risk features. Unfortunately, some patients experience early local and/or distant recurrence. Besides classic anatomical/pathological tumor features, insight into the genomic determinants of early recurrence in colon cancer is lacking. Herein, we utilize a multi-omics approach to identify early-recurrence-specific features that could aid in more accurate risk stratification. Methods: We utilized the Cancer Genomic Atlas Colon Adenocarcinoma (TCGA-COAD) Database. Clinical, histopathological and genomic data were retrieved through the cBioPortal database. Our analysis was limited to patients with stage 2 or 3 (n = 390) disease based on the American Joint Committee on Cancer Code. Early recurrence (ER) was defined as disease relapse/recurrence within 12 months of sample acquisition post-surgery. Accordingly, patients were categorized into the ER and non-early recurrence (NER) groups based on a cut-off point of 12 months of disease-free survival. Results: The colon cancer ER and NER group included 45 and 345 patients, respectively. Comparable age, sex and race percentages were found between both groups. The ER group had significantly worse overall, progression-free, and disease-specific survival (HR: 0.083 95% CI: 0.031-0.220, HR: 0.035 95% CI: 0.011-0.0109, HR: 0.021 95% CI: 0.006-0.076, respectively). ER patients had a significantly higher proportion of patients with T4 and N2 disease based on the TNM staging system. ER patients had significant (P< 0.05) expression of TRIM46, TRPC4, ELOVL7, CSMD1, BCLAF1, and CD70 mutations, while tumor mutational burden was comparable between both groups (median TMB in ER vs NER: 4.2 vs 3.62, p = 0.28). Differential gene expression analysis revealed 68 genes to be upregulated in the ER group which were found to be enriched in hypoxia and interleukin-11 pathway genes. Genes upregulated in the NER group (n = 49) were enriched in interferon-alpha response and glycolysis/gluconeogenesis pathway genes. Proteomics analysis revealed significantly higher levels of EIF4E, CCNE1, SRSF1, SCD, and PECAM1 proteins in NER patients .Conclusion: Our results highlight insights into molecular and genomic features unique to colon cancer patients with early recurrence. Understanding such predictors for early recurrence will aid in risk stratification and help in determining patients who would derive the most benefit from adjuvant treatment considerations. Citation Format: Salma Al-Aomar, Hassan Abushukair, Alaa Zaitoun, Sara Zytoon, Sara Illeyyan, Husam Almomani, Ghayda'a Al-Majali, Arafat Hammad, Khaled Obeidat, Fuad Turfah, Awni Shahait, Fadwa Ali. Determinants of early recurrence in surgically-resected colon cancer: A multi-omics analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2400.

Role of Intraoperative Frozen Section Assessment of Proximal Bile Duct Margins and the Impact of Additional Re-Resection in Perihilar Cholangiocarcinomas.

Intraoperative frozen section (FS) analysis to assess the bile duct margin status is commonly used to assess the completeness of resection during surgery for perihilar cholangiocarcinoma (pCCA) resection. However, the impact of additional re-section on the long-term outcome after obtaining an initial positive margin remains unclear. Patients diagnosed as pCCA on preoperative imaging and subjected to curative intent surgery from May 2013 to June 2021 with a minimum follow-up of 2years were included. Intraoperative FS analysis of the proximal bile duct margin was performed in all patients. A positive margin was defined by the presence of invasive cancer. Out of the 62 patients with a preoperative diagnosis of pCCA on imaging, 35 patients were included for final analyses after excluding patients with inoperable disease (on staging laparoscopy or local exploration) and other/benign pathology on the final histopathology report. Out of the 35 patients, patients with postoperative 90-day mortality were excluded from the final survival analysis. FS analysis revealed an initial positive margin in 10 (28.5%) patients. Among 10 patients who underwent re-resection to achieve negative proximal margins, only 5 patients achieved a negative margin (secondary R0). An initial positive margin was associated with poor long-term outcomes. Median disease-free survival (DFS) and overall survival (OS) were 16 and 19.6months for patients with an initial positive margin, but 36 and 58.2months for patients with an initial negative margin, respectively (p = 0.012). The median DFS and OS were significantly lower for those with secondary R0 as compared to primary R0 (16 vs. 36months for DFS, p = 0.117 and 19.6 vs. 58.2months for OS, p = 0.027, respectively). An intraoperative FS positive proximal hepatic duct margin dictates poor long-term outcomes for patients with resectable pCCA. Additional resection has a questionable benefit on survival, when a secondary negative margin is achieved.

Phase II Trial of Reduced-Intensity Fludarabine, Melphalan, and Total Body Irradiation Conditioning Results in Favorable Outcomes with Haploidentical Donor Peripheral Blood Stem Cell Transplant

Introduction High risk hematologic malignancies are curable with allogeneic hematopoietic cell transplant (HCT). Haploidentical (haplo) HCT with post-transplant cyclophosphamide (PTCy) has improved access to transplant in patients lacking an HLA matched donor. However, traditional reduced-intensity conditioning (RIC) with fludarabine/cyclophosphamide/total body irradiation (TBI) for haplo HCT with PTCy is marred by high rates of relapse. This study seeks to optimize the RIC haplo HCT with PTCy platform in older adults with a slight intensification in conditioning and the use of peripheral blood stem cell (PBSCT) grafts in lieu of bone marrow grafts (BMT). Additionally, tacrolimus was substituted by sirolimus based on prior phase II data suggesting favorable rates of graft-versus-host disease (GVHD) after haplo PBSCT with PTCy (Bejanyan, Blood Adv. 2021). We hypothesized that this approach could successfully reduce the risk of relapse and improve disease-free survival (DFS) without substantially increasing non-relapse mortality (NRM). Methods: This single arm, single center phase II trial of haplo PBSCT used a RIC regimen consisting of Melphalan 70 mg/m 2 IV on day -6, fludarabine 30mg/m 2 IV daily on days -6 to -2, and TBI 200 cGy on day -1 (NCT04191187). Subjects received haplo PBSCT with a target dose of 5 x 10 6 CD34+ cells/kg and capped at 7 x 10 6 CD34+ cells/kg. GVHD prophylaxis consisted of PTCy 50 mg/kg on days +3 and +4, mycophenolate mofetfil (MMF) 1 gram three times daily from days +5 to +35, and sirolimus initiated at a target trough of 8-14 ng/mL on day +5 and tapered off between days +100 and +180. Eligibility criteria required a hematologic malignancy as the indication for allogeneic HCT and either age >55 years or a hematopoietic cell transplant comorbidity index (HCT-CI) > 3. The primary endpoint of this study is DFS with a hypothesis that the experimental regimen would have an 18 month DFS of 60% compared to a historic DFS of 40% and 90% power to reject the null hypothesis. Results: A total of 34 subjects were treated on the trial. The median age was 66 years (range: 31-74 years). The HCT-CI score was > 3 in 41%. Acute myeloid leukemia (AML, 44%) was the predominant indication for transplant followed by myelodysplastic syndromes (MDS, 29%). Nine patients (26%) were from underrepresented racial/ethnic minorities (those other than non-Hispanic white). Five patients (15%) received tacrolimus for GVHD prophylaxis before a protocol amendment changed the regimen to sirolimus for the remaining 29 patients (85%). The median follow-up time for 25 surviving patients was 28.5 months . The trial met the primary endpoint with 18-month DFS of 70.5% (90% CI > 59.1%, p=0.002). We observed no primary graft failure events. Neutrophil engraftment by day 30 was achieved in 30 patients (88%), and platelet engraftment by day 60 was achieved in 28 patients (82%). The cumulative incidence of grade II-IV acute GVHD at day 100 was 11.8% (95% CI: 3.6-25.1%). The cumulative incidence of moderate to severe chronic GVHD at 18 months was 9.1% (95% CI: 2.2-22.0%). At 18 months, the cumulative incidence of NRM was 17.7% (95% CI: 7.0-32.2%) and of relapse was 11.9% (3.7-25.4%). GVHD-free relapse-free survival at 18 months was 61.4% (95% CI: 42.9-75.5%) and the overall survival at 18 months was 73.3% (95% CI: 54.9-85.1%). Conclusion: In this completed phase II trial of fludarabine, melphalan 70 mg/m 2, TBI with haplo PBSCT and PTCy/sirolimus/MMF, the primary endpoint was met with an 18-month DFS that was superior to historical control. This was attributable to low rates of relapse without excessive NRM. Acute and chronic GVHD rates were favorable. Pharmacogenomic and pharmacokinetic correlative data is pending and will be included in the final presentation. These promising results merit further investigation to potentially establish this platform as a new standard approach to RIC haplo PBSCT.

Final Analysis for the Primary End-Point of Gimema AML1718, a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) poses significant challenges, especially in intermediate and high-risk cases due to modest rates of complete remission (CR) of 50-60% yelding a 2-year survival probability of about 30-40%. Preliminary results from the AML1718 part 1 trial have demonstrated remarkable improvements, with a composite complete remission (CCR) rate reaching an impressive 82%, and a 1-year survival probability of 72%. These findings represent a substantial advancement compared to historical data. Hereby, we present the comprehensive results of the AML1718 study, with a primary focus on the CCR as the primary endpoint. Methods: The safety and efficacy of venetoclax (VEN) in combination with FLAI (fludarabine, cytarabine, and idarubicin as a first-line treatment for newly diagnosed adult patients with ELN 2017 intermediate- or high-risk AML) was investigated in the GIMEMA AML1718 phase 1/2 multicenter trial (NCT03455504). The study followed a modified two-stage Simon's design, including safety run-in cohorts (SRI-C1 and SRI-C2), an extension phase (Part 1 with P1-C1 and P1-C2 cohorts), and a confirmatory cohort (P2). VEN was administered at a daily dose of 400 mg in combination with FLAI (V-FLAI 400) in SRI-C1 and P1-C1, while in SRI-C2 and P1-C2, the VEN dose was escalated to 600 mg/day (V-FLAI 600). In P2 we used the lower effective dosage of V-FLAI 400, with centralized measurable residual disease (MRD) assessment with flow cytometry following ELN guidelines. After V-FLAI induction, consolidation therapy with cytarabine-based regimens and consideration for allogeneic stem cell transplant (HSCT) were conducted. Adjustments to the VEN dose were made for patients concurrently receiving posaconazole. VEN administration was discontinued until recovery for patients achieving remission by day 21 and during consolidation courses. Results: Since February 2019, a total of 124 patients were treated in this study, 6 in SRI-C1, 6 in SRI-C2, 22 in P1-C1, 23 in P1-C2, and 67 in P2. Among them, 95 patients received V-FLAI 400 and 29 patients received V-FLAI 600. Posaconazole was administered to 115 patients (93%) as antifungal prophylaxis during the first course. The patient population had a median age of 55 years (ranging from 18 to 66), with 70 patients (56%) being male. According to ELN 2017 risk, 67 patients (54%) were classified as intermediate- and 57 patients (46%) as high-risk. Sixteen (13%) patients had a seconday AML. Genetic mutation analysis showed that 4/56 tested patients (7.1%) had IDH1, 11/55 (20%) IDH2, 16/108 (14.7%) FLT3 ITD, 3/112 ( 2.8%) NPM1 mutation; TP53 data are not yet available. The primary endpoint, the CCR, was achieved in 93 out of 124 patients (75%) after the 1 st course (table 1). One patient initially in partial remission (PR) achieved CR after the second V-FLAI induction. In P2, 47/67 patients achieved CCR (70.0%, with 9 patients not yet tested). Central MRD analysis showed that that 31 out of 48 tested patients obtained MRD negativity at day 28 of course 1 (64.5%, treshold 0.1% by flow). With a median follow-up of 10 months, 60 patients (49%) underwent hematopoietic stem cell transplant (HSCT) in CR, and 1 patient underwent HSCT in partial remission. The median overall survival (OS) was 22.4 months (95% confidence interval [C.I.] 13.4 months - not reached, Figure 1), with a 12-month OS probability of 64% (95% C.I. 54% - 76%). The median disease-free survival (DFS) was 20.7 months (95% C.I. 12.1 months - not reached), and the 12-month DFS probability was 64% (95% C.I. 50% - 76%). The treatment was found to be safe, with only 4 deaths recorded during induction (3.2%), and a 60-day mortality rate of 6% including disease progression-related deaths. Infections were the most commonly reported grade 3+ adverse events. Overall, the safety profile of the treatment regimen was consistent with any intensified AML induction regimen. Among transplanted patients, no instances of graft failure or higher-than-expected incidence of graft-versus-host disease (GVHD) were observed. No significant differences were observed between the 400 mg and 600 mg arms. Conclusions: V-FLAI demonstrated remarkable efficacy without any safety concerns. Impressive CCR rate and MRD-negativity qualify the combination for randomized comparisons . A virtual-randomized phase 3 trial is currently being prepared.

Neoadjuvant cemiplimab and surgery for stage II–IV cutaneous squamous-cell carcinoma: follow-up and survival outcomes of a single-arm, multicentre, phase 2 study

We previously reported rates of pathological complete responses (51% [95% CI 39-62] per independent central review, the primary endpoint) and major pathological responses (13% per independent central review, a secondary endpoint) to neoadjuvant cemiplimab (an anti-PD-1 inhibitor) among 79 patients with locoregionally advanced, resectable cutaneous squamous cell carcinoma. Here, we present follow-up data, including event-free, disease-free, and overall survival. This single-arm, multicentre, phase 2 study included patients aged 18 years or older with resectable stage II-IV (M0) cutaneous squamous cell carcinoma and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received up to four planned doses of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by curative-intent surgery. After surgery, per investigator discretion, patients received either adjuvant cemiplimab for up to 48 weeks, radiotherapy, or observation alone. Secondary endpoints included in this follow-up analysis are event-free survival, disease-free survival, and overall survival, all summarised using the Kaplan-Meier method. Activity and safety endpoints were analysed for all enrolled patients who received at least one dose of neoadjuvant cemiplimab. In this report, safety data are reported for all patients who received at least one dose of adjuvant cemiplimab. This trial is registered with ClinicalTrials.gov, NCT04154943, has completed enrolment and follow-up is ongoing. Between March 20, 2020, and July 8, 2021, 79 patients were enrolled. Median age was 73 years (IQR 66-81), 67 (85%) patients were male, 12 (15%) were female, 69 (87%) were White, one was Asian (1%), one was other race (1%), and race was not reported for eight (10%). As of data cutoff (Dec 1, 2022), median follow-up was 18·7 months (IQR 15·6-22·1) for all 79 patients. Among 70 patients who had surgery, 65 (93%) had post-surgical management data: 32 (49%) of 65 were observed postoperatively, 16 (25%) received adjuvant cemiplimab, and 17 (26%) received adjuvant radiotherapy. 11 (14%) of 79 patients had event-free survival events, with an estimated 12-month event-free survival of 89% (95% CI 79-94) for all patients. None of 40 patients who had a pathological complete response and one (10%) of ten patients with major pathological response had recurrence. Six (9%) of 70 patients who completed surgery had a disease-free survival event, with an estimated 12-month disease-free survival of 92% (95% CI 82-97). Nine (11%) of 79 patients died, with an estimated 12-month overall survival for all patients of 92% (95% CI 83-96). Four (25%) of 16 patients who received adjuvant cemiplimab treatment had grade 3 adverse events, including one (6%) who had increased blood potassium, one (6%) who had traumatic limb amputation, and two who had serious adverse events (one [6%] cardiomyopathy and one [6%] hypophysitis). There were no grade 4 adverse events or treatment-related deaths. For patients with resectable stage II-IV cutaneous squamous cell carcinoma, neoadjuvant cemiplimab followed by surgery might be a potential treatment option, addressing a substantial unmet need. Regeneron Pharmaceuticals and Sanofi.

Comparison of Neoadjuvant Immunotherapy Plus Chemotherapy versus Neoadjuvant Chemoradiotherapy for Patients with Esophageal Squamous Cell Carcinoma: A Propensity Score Matching Study.

This study compares the efficacy and safety of neoadjuvant immunotherapy combined with chemotherapy (NICT) and neoadjuvant chemoradiotherapy (NCRT) combined with radical esophagectomy in patients with resectable, locally advanced esophageal squamous cell cancer (ESCC). Patients with locally advanced ESCC treated with NICT or NCRT combined with esophagectomy between March 2016 and May 2022 were retrospectively analyzed and propensity score matched (PSM) in a 1:2 ratio to balance potential bias. After PSM, 110 patients who received NCRT and 55 patients who received NICT were selected for the final analysis. The probability of tumor regression grade 0 and the rate of pathological complete remission (pCR) were significantly higher in the NCRT group than in the NICT group (57.3% vs 32.7%, P=0.003 and 48.2% vs 29.1%, P=0.030, respectively). The incidence of postoperative complications in the NCRT group was not significantly different from that in the NICT group (P=0.082). Patients in the NCRT group had significantly better disease-free survival (DFS) and overall survival (OS) than those in the NICT group (12-month DFS rate: 94.3% vs 81.8%, P=0.006; 12-month OS rate: 100.0% vs 95.4%, P=0.032). However, the results of the 24-month follow-up showed that there was also a statistically significant difference in DFS between the two groups. Patients with postoperative pCR had a longer DFS (P< 0.001). Short-term follow-up results show that NCRT has a significantly better pathologic response and prognosis than NICT in the treatment of patients with locally advanced ESCC. NCRT and NICT have similar safety profiles.

Dynamic change of immune phenotype assessed by artificial intelligence (AI)-powered analysis of tumor-infiltrating lymphocytes (TILs) during neoadjuvant durvalumab with or without tremelimumab (D+/-T) in head and neck squamous cell carcinoma (HNSCC).

2578 Background: The results of a phase II trial evaluating preoperative durvalumab with or without tremelimumab (D+/-T) in resectable HNSCC (NCT03737968) suggest that the neoadjuvant immunotherapy is associated with pathologic tumor regression with manageable safety profiles. Here, we applied AI-powered spatial TIL analyzer, Lunit SCOPE IO, to tumor specimens of the patients included in the trial to assess the impact of spatial TIL density and inflamed immune phenotype (IIP) on immunotherapy responses. Methods: H&amp;E-stained whole-slide images (WSIs) of pre- and post-treatment tumor specimens from HNSCC pts enrolled in the aforementioned D+/-T trial were collected. Patients with locally advanced but operable HNSCC were randomly assigned in 1:1 to receive a single dose of D (1,500mg) or D+T (1,500mg+75mg) followed by surgery, at Severance Hospital in Seoul, Korea. Lunit SCOPE IO was used to segment tumor epithelium and stroma to identify and quantify intratumoral TIL (iTIL) and stromal TIL. IIP was defined as the proportion of high iTIL area more than 33.3% of analyzable area. Clinical data and the combined positive scores (CPS) of PD-L1 were also collected. Results: A total of 39 paired tumor samples of pre- and post-treatment WSI (23 from D+T and 16 from D) were included. Overall, tumor regression grade 2 (TRG2, ≥ 50% of tumor regression) was achieved in 15.4% (6/39) pts, and downstaging after treatment was achieved in 35.9% (14/39) pts. By pre-treatment WSIs, 38.5% (15/39) samples were classified as IIP, and subgroups of D+T and D had 34.8% (8/23) and 43.8% (7/16), respectively. In the D+T arm, the proportions of TRG2 were 25% (2/8) in IIP versus 13.3% (2/15) in non-IIP, whereas D arm had 28.6% (2/7) TRG2 in IIP, but no TRG2 in non-IIP (0/9), respectively. Comparing the WSI of pre- and post- D+/-T samples, the proportion of IIP was significantly increased to 66.7% from 38.5 ( p = 0.015). The increase in IIP proportion was prominent in the D+T arm (34.8% to 69.6%, p = 0.043), but not in the D arm (43.8% to 62.5%, p = 0.37). Similarly, PD-L1 CPS increased after therapy, especially in the D+T group (mean CPS 6.0 to 20.7, p = 0.009). Interestingly, pts who remained non-IIP in both pre- and post-treatment (25.6%, 10/39) had significantly poor prognosis compared to the others, as the 12-month disease-free survival (DFS) rate was 50.0% vs 93.1% (median DFS 13.4m vs not reached, hazard ratio [HR] 4.26, 95% confidence interval [CI] 1.32-13.8, p = 0.009). This prognostic impact was prominent in the D+T arm (HR 6.75, 95% CI 1.49-30.6, p = 0.004). Conclusions: Neoadjuvant durvalumab +/- tremelimumab promotes dynamic change toward inflamed immune phenotype, resulting in favorable clinical outcomes. Resistance mechanism of stand-still-non-inflamed patients even on D+/-T should be further investigated. Clinical trial information: NCT03737968 .

AN0025, a novel antagonist of PGE2-receptor E-type 4 (EP4), in combination with total neoadjuvant treatment of advanced rectal cancer

PurposeTo assess the safety and efficacy of AN0025 in combination with preoperative radiotherapy and chemotherapy in either short course (SCRT) or long course radiotherapy (LCRT) settings for those with locally advanced rectal cancer. Patients and methodsTwenty-eight subjects with locally advanced rectal cancer participated in this multicenter, open-label, Phase Ib trial. Enrolled subjects received either 250 mg or 500 mg of AN0025 once daily for 10 weeks with either LCRT or SCRT with chemotherapy (7 subjects/group). Participants were assessed for safety/efficacy starting from the first dose of study drug administration and were followed for 2 years. ResultsNo treatment-emergent adverse or serious adverse events meeting dose-limiting criteria were observed, with only 3 subjects discontinuing AN0025 treatment due to adverse events. Twenty-five of 28 subjects completed 10 weeks of AN0025 and adjuvant therapy and were evaluated for efficacy. Overall, 36.0% of subjects (9/25 subjects) achieved a pathological complete response or a complete clinical response, including 26.7% of subjects (4/15 subjects who underwent surgery) who achieved a pathological complete response. A total of 65.4% of subjects had magnetic resonance imaging-confirmed down-staging ≤ stage 3 following completion of treatment. With a median follow-up of 30 months. The 12-month disease-free survival and overall survival were 77.5% (95% confidence interval [CI]: 56.6, 89.2) and 96.3% (95% CI: 76.5, 99.5), respectively. ConclusionsTreatment with AN0025 administered for 10 weeks along with preoperative SCRT or LCRT did not appear to worsen the toxicity in subjects with locally advanced rectal cancer, was well-tolerated and showed promise in inducing both a pathological and complete clinical response. These findings suggest its activity deserves further investigation in larger clinical trials.

Molecular subtypes predict the preferential site of distant metastasis in advanced breast cancer: a nationwide retrospective study.

This study aimed to explore possible associations between molecular subtypes and site of distant metastasis in advanced breast cancer (ABC). 3577 ABC patients were selected from 21 hospitals of seven geographic regions in China from 2012-2014.A questionnaire was designed to collect medical information regarding demographic characteristics, risk factors, molecular subtype, recurrence/metastasis information, and disease-free survival (DFS). The cancers were classified into Luminal A, Luminal B, HER2-enriched and Triple Negative subtypes. Chi-square test and multivariate Cox proportional hazard models were performed to explore the associations between molecular subtypes and distant metastasis sites. A total of 2393 cases with molecular subtypes information were finally examined. Patients with Luminal A (51.1%) and Luminal B (44.7%) were most prone to bone metastasis, whereas liver metastasis was more frequently observed in HER2-enriched ABC patients (29.1%).The cumulative recurrence and metastasis rates of ABC patients at 36 months of DFS were the most significant within molecular types, of which Triple Negative was the highest (82.7%), while that of Luminal A was the lowest (58.4%). In the adjusted Cox regression analysis, Luminal B, HER2-enriched and Triple Negative subtypes increased the risk of visceral metastasis by 23%, 46% and 87% respectively. In addition, Triple Negative patients had a higher probability of brain metastasis (HR 3.07, 95% CI: 1.04-9.07). Molecular subtypes can predict the preferential sites of distant metastasis, emphasizing that these associations were of great help in choices for surveillance, developing appropriate screening and cancer management strategies for follow-up and personalized therapy in ABC patients.

Prognostic Factors in Patients with Clinic Locally Advanced T4 Lung Cancer: Surgical Considerations.

Inclusion of surgery in the treatment of T4 lung cancer has been a debate for the last two decades. The aim of this study is to investigate the potential prognostic factors which could affect the outcome. Fifty-seven clinical T4 non-small cell lung carcinoma (NSCLC) patients out of 716 lung resections, who were operated at a single institution in 7 years period, were included in this study. Patients are grouped into three groups as patients with neoadjuvant treatment group (group 1 n: 16), salvage surgery group (surgery after 3 months of definitive chemotherapy and radiotherapy) (group 2 n: 14), and straightforward surgery group (group 3 n: 27) with adjuvant treatment. Groups were analyzed and compared in terms of postoperative complications, 30 days of mortality, disease free survival, and overall survival. Mean overall survival (OS) was 48.43 ± 4.4 months and mean disease-free survival (DFS) 40.55 ± 4.46 months for all patients. Thirty days mortality was 5.2% and complication rates were 63.1%. Two years OS was 61.4 ± 6.4%, DFS was 58.1 ± 7.8%. Group 1, Group 2, and Group 3 patients had mean 39.14 ± 5.6, 44.7 ± 7.1, and 62.9 ± 4.8 months for OS (p: 0.09), and 29.6 ± 7.2, 38.4 ± 9.1, and 46.9 ± 6 months for DFS (p: 0.27). Patients who received blood transfusion showed significantly worse outcomes (p: 0.001 for DFS and p: 0.004 for OS). According to our outcomes, surgery should be included in the treatment of clinical T4 lung cancer when physiologically and oncologically possible with careful patient selection. This study demonstrates that patients receiving straightforward surgery have longer survival, in spite of higher perioperative mortality rate. Risks and benefits should be considered carefully.

The Efficacy of Chidamide Maintenance Therapy after CAR-T Therapy for Refractory or Relapsed B-Cell Acute Lymphoblastic Leukemia

Introduction Anti-CD19 chimeric antigen receptor (CAR) T-cells therapy has achieved unprecedented efficacy in refractory or relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL) patients, with up to a 90% complete remission (CR) rate. However, a large body of clinical data has shown that the relapse rate post CD19 CAR-T therapy remains high. Our published study of 254 patients with R/R B-ALL treated with CD19 CAR-T showed the median time to relapse following CAR-T cells infusion was 100 days. Patients who received consolidative allogeneic hematopoietic stem cell transplantation (allo-HSCT) post CAR-T therapy demonstrated much higher overall survival (OS) and leukemia-free survival (LFS) compared to those who received CAR-T therapy alone (1-year OS of 77.8% vs. 35.4%, p<0.0001; 1-year LFS of 70.9% vs. 33.3%, p<0.0001, respectively). However, there are still many patients who cannot undergo allo-HSCT, including those who have relapsed following allo-HSCT and elderly patients. Prolonging disease-free survival (DFS) after CAR-T therapy in these patients remains a challenge for physicians. Studies have shown that the histone deacetylase (HDAC) inhibitor chidamide can up-regulate T-cell activity and down-regulate derived suppressor cell (MDSC) expression. Chidamide also promotes the expression of CD22 on the surface of B-cell tumor cells in vitro and in vivo, and enhances CAR-T function. Here we explore the efficacy of chidamide as maintenance therapy post CAR-T in B-ALL. Patients and methods We analyzed 19 patients with R/R B-ALL who received CD19 CAR-T at our center (NCT04546893) between October 2019 and July 2022. All patients achieved CR on day 30 following CD19 CAR-T cells infusion and were unable to bridge to allo-HSCT within 3 months. We administered chidamide as maintenance therapy to all 19 patients between 30 to 90 days after CAR-T infusion. Chidamide was continuously administered until the patient relapsed, transferred to transplant, or had intolerable side effects. Results On Day 30 post CD19 CAR-T, 19/19 (100%) patients achieved CR or CR with incomplete count recovery (CRi)(Figure 1). Sixteen of 18 (88.89%) who had bone marrow involvement achieved minimal residual disease (MRD)-negative CR. The median time from CAR-T cell infusion to start chidamide therapy was 30 days (range: 30-90 days) and the median duration of chidamide administration was 90 days (range: 12-420 days). No patient experienced cytokine release syndrome (CRS) or encephalopathy while taking chidamide. All side effects that occurred were mild. Two patients experienced nausea and vomiting and one patient had mild bone marrow suppression. No other side effects occurred. The median follow-up time was 12 months (range: 1-33 months), the 12-month OS rate was 83.1% and the 12-month DFS rate was 62.4% (Figure 2). Five patients received allo-HSCT following chidamide maintenance and 13 patients who did not undergo transplantation had 12-month OS of 83.3%, 12-month DFS of 62.9%. Six patients were monitored for the proportion of CAR-T cells in T lymphocytes following chidamide therapy. In all six patients, the proportion of CAR-T cells increased but to different degrees. Conclusions For those patients with R/R B-ALL for whom allo-HSCT is not available following CD19 CAR-T therapy, HDAC inhibitor chidamide as maintenance therapy is a viable option to reduce the risk of relapse rate following CD19 CAR-T therapy. This study demonstrated that chidamide could prolong OS and DFS in some patients who achieved CR after CD19 CAR-T therapy. Chidamide was safe, inexpensive and convenient to take orally. The inclusion of more patients and extended observation time is needed for further evaluation of chidamide maintenance therapy following CAR-T cell therapy in patients with R/R B-ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Preliminary experience on laparoscopic pancreaticoduodenal combined with major venous resection and reconstruction anastomosis.

ObjectiveThis study aims to summarize our experience in laparoscopic pancreatoduodenectomy (LPD) combined with major venous resection and reconstruction, as well as to evaluate its safety and discuss the surgical approach.MethodsWe retrospectively analyzed 14 cases of patients diagnosed with pancreatic tumors invaded the superior mesenteric vein or portal vein who had undergone LPD combined with major venous resection and reconstruction in our center from May 2016 to May 2020. Clinical data of these 14 patients were collected and analyzed, including general information (age, gender, pathological diagnosis, body mass index, etc.), intraoperative data (operation time, intraoperative blood loss, transit rate, blood transfusion, tumor diameter, R0 resection rate, cleaning lymph node number, removal vessel length, venous reconstruction time), and postoperative results (gastrointestinal function recovery, postoperative hospital time, complications, and fatality rate). Patients were followed up after surgery, and data were collected for statistical analysis.ResultsA total of 14 patients (9 males and 5 females) received LPD combined with major venous resection and reconstruction by arterial approach. The mean age was 52.5 (43–74) years old. Three of these 14 patients had routine wedge resection, 9 had opposite-to-end anastomosis after venous resection, 2 had artificial venous replacement, and the average length of removal vessel was 3.1 (2–4.5) cm. The operation time was 395 (310–570) min; the venous blocking time was 29.7 (26–50) min; the hospitalization stay was 13.6 (9–39) days. There was no grade B or C postoperative pancreatic fistula (POPF) that occurred, only one patient had biochemical fistula. One patient had upper gastrointestinal bleeding after subcutaneous injection of low molecular weight (LMW) heparin, and the condition was alleviated after conservative treatment, and one had pulmonary infection. The 12-month disease-free survival rate was 85.7%, and the 12-month overall survival rate was 92.8%. No patients had 30-day re-admission or death.ConclusionOn the basis of the surgeon’s proficiency in open pancreatoduodenectomy combined with venous resection and reconstruction and standard LPD, the arterial approach for LPD combined with major venous resection and reconstruction is safe and feasible.

Breast Cancer Subtypes and Prognosis: Answers to Subgroup Classification Questions, Identifying the Worst Subgroup in Our Single-Center Series

PurposeMany studies report the triple negative breast cancer (TNBC) as the worst subgroup, as such patients do not benefit from anti-hormonal therapy and human epidermal growth factor receptor 2 (HER2) antagonists. While HER2 overexpression was a poor prognostic factor in breast cancer before trastuzumab (Herceptin) was available, TNBC is often reported as the worst BC subgroup since targeted therapy is currently not possible. Since the patience-specific experiences and the current literature did not always align, we aimed to determine the BC subgroup with the shortest survival in our center.MethodsThe records of patients with BC who were admitted to Trakya University Faculty of Medicine Department of Medical and Radiation Oncology between July 1999 and December 2019 were reviewed. Patients were divided into four main groups (Luminal A, Luminal B, TNBC, and HER2-enriched) according to the St Gallen International Consensus Panel and four subgroups in accordance with estrogen receptor, progestin receptor and HER2 positivity. Patient characteristics, treatment characteristics and clinical outcomes of the four main subgroups were evaluated. Survival curves were generated using the Kaplan–Meier method, and the significance of survival differences among the selected variables was compared by using the Log rank test. Factors affecting disease-free survival (DFS) and overall survival (OS) were analyzed by Cox regression analysis.ResultsStatistical analysis was performed on 2017 patients, after excluding patients with phyllodes tumor, carcinoma-in-situ and missing information from a total of 2474 patients with BC. There were 952 (47.1%) patients in the Luminal A group, 236 (34.1%) in the Luminal B group, 236 (11.7%) in the TNBC group and 142 (7.1%) patients in the HER2 enriched group. HER2-enriched patients had the shortest survival (p < 0.001), with 113.70 ± 7.17 months of DFS and 125.45 ± 3.03 months of OS. For patients who received Herceptin, DFS was 101.50 ± 6.4 months and OS was 118.14 ± 6.16. Patients who did not receive Herceptin had 92.79 ± 18 months of DFS and 94.44 ± 15.23 months of OS.ConclusionThe HER2-enriched subgroup had the worst prognosis despite receiving targeted therapy. While the duration of DFS and OS had no significant difference between TNBC and Luminal A-B subgroups, HER2 enriched subgroup had significantly shorter survival when compared to any other subgroup. HER2-enriched subgroup had a 10-fold greater risk of death compared to the Luminal A subgroup.

2450-MHz microwave ablation of liver metastases under 3.0 T wide-bore magnetic resonance guidance: a pilot study

To investigate the feasibility and effectiveness of 3.0 T wide-bore magnetic resonance (MR)-guided microwave ablation (MA) of liver metastases (LM). From October 2018 to May 2020, 39 patients with 63 LM were treated with 3.0 T wide-bore MR-guided 2450-MHz MA therapy. The procedure parameters, technical success, complications, biochemical index changes, local tumor response, local tumor progression (LTP), 12-month disease-free survival (DFS) and 12-month overall survival (OS) were recorded and analyzed. The mean tumor maximum diameter and total procedure time were 3.0 cm and 55.2 min, respectively. Technical success was 100%, but 5 cases (12.8%) had grade-1 complications. Alanine transaminase, aspartate transaminase and total bilirubin showed a slight transient increase on day 3 (P < 0.05) and returned to normal by day 30 (P > 0.05). The complete ablation rates for ≤ 2.5 and > 2.5 cm lesions were 100% and 92.5%, respectively. During the median follow-up of 12.0 months, the LTP rate was 4.8% (3/63), and the 12-month DFS and OS rates were 61.3% and 92.2%, respectively. 3.0 T wide-bore MR-guided MA for LM is a safe and effective approach, especially for small LM.

Lymph node yield in the pathological staging of resected nonmetastatic colon cancer: The more the better?

IntroductionGuidelines recommend regional lymphadenectomy with a lymph node yield (LNY) of at least 12 lymph nodes (LN) for adequate colon cancer (CC) staging. LNY ≥22LN may improve survival, especially in right-sided CC [Lee et al., Surg Oncol, 27(3), 2018]. This multicentric retrospective cohort study evaluated the impact of LNY and tumor laterality on CC staging and survival. Materials and methodsPatients with stage I-III CC that underwent surgery from 2012 to 2018 were grouped according to LNY: <22 and ≥ 22. Primary outcomes were LN positivity (N+ rate) and disease-free survival (DFS). Overall survival (OS) was the secondary outcome. Exploratory analyses were performed for laterality and stage. ResultsWe included 795 patients (417 < 22LN, 378 ≥ 22LN); 53% had left-sided CC and 29%/37%/38% had stage I/II/III tumors. There was no association between LNY ≥22LN and N+ rate after adjustment for grade, T stage, lymphovascular invasion (LVI) and perineural invasion; a trend for a higher N+ rate in left-sided CC was identified (interaction p = 0.033). With a median follow-up of 63.6 months for DFS and 73.2 months for OS, 254 patients (31.9%) relapsed and 207 (26.0%) died. In multivariate analysis adjusted for age, ASA score, laparoscopic approach, T/N stage, mucinous histology, LVI and adjuvant chemotherapy, LNY ≥22LN was significantly associated with both DFS (HR 0.75, p = 0.031) and OS (HR 0.71, p = 0.025). Restricted cubic spline analysis showed a more significant benefit for right-sided CC. ConclusionLNY ≥22LN was associated with longer DFS and OS in patients with operable CC, especially for right-sided CC.

Predictive Value of Ultrasound Characteristics for Disease-Free Survival in Breast Cancer.

The main objective of this study was to determine the predictive value of US characteristics for disease-free survival (DFS) in BC patients. We retrospectively analyzed the ultrasonic images and clinical data of BC patients who had previously undergone breast surgery at least 10 years before study enrollment and divided them into a case group and a control group according to the cutoff value of 120 months for DFS. Correlation analysis was performed to identify US characteristics as independent predictors for DFS by multivariable logistic regression and Kaplan–Meier survival analysis. A total of 374 patients were collected, including 174 patients in the case group with short-DFS and 200 patients in the control group with long-DFS. Three US characteristics (size on US, mass shape, mass growth orientation) and two clinical factors (axillary lymph node (ALN), molecular subtypes) were identified as independent predictors for DFS (p < 0.05). The ROC curve showed good performance of the multivariate linear regression model with the area under the curve being 0.777. The US characteristics of large size, irregular shape, and nonparallel orientation were significantly associated with short-DFS, which is a promising supplementary for clinicians to optimize clinical decisions and improve prognosis in BC patients.