Inferior Disease-free Survival Research Articles

Outcomes of very young women and adolescent (VYWAA) with breast cancer (BC) in rural and urban Saskatchewan: A population-based cohort study.

1571 Background: BC is uncommon in VYWAA (≤ 35 years) and accounts for about 1.8% of all BC. As BC screening is typically recommended for women aged 50-74 years there is a risk of delayed diagnosis of BC in VYWAA especially those with rural residence. The current study aims to assess outcomes of a cohort of VYWAA with BC in relation to their place of residence in the province of Saskatchewan over a period of 20 years. Methods: In this population-based retrospective cohort study all women ≤ 35 years with histologically documented epithelial BC during 2000-2019 were evaluated. Survival of the entire cohort and its subgroups was estimated using the Kaplan−Meier method, and the survival distribution of different groups was compared by the log rank test. A multivariate Cox proportional hazard model was performed. Various clinical and demographic variables were examined for their prognostic importance of overall survival (OS) for all stages and disease-free survival (DFS) for early-stage BC. Results: 248 eligible women with a median age of 32 years were identified, 24% were <30 years of age. Of all patients, 51% had node positive disease, 7% had DCIS, 15% stage I, 42% stage II, 22% stage III and 11% had stage IV disease at initial presentation. Among them 42% had hormone receptor +, 28% had HER2 + and 23% had triple negative BC (TNBC).16% developed BC within 1-year of pregnancy. 53% were rural resident and 47% were urban resident. Significant differences were noted between the two groups regarding smoking history (42 vs. 25%), HER2+BC (35% vs. 20%) and mean platelet count (285 vs. 258). Median follow up for all women was 91 months with a total follow up period of 294 months. Median DFS of VYWAA with stage I to III disease has not reached. 10-year estimated DFS of all women was 66%. 10-year DFS for stage I and II was 73% and 75%, respectively, vs. 43% for stage III (p<0.001). Median OS of entire cohort with stage 0-IV BC has not reached. 10-year OS of all VYWAA was 69%. 10 years OS of urban women was 79% compared to 65% for rural resident (p=0.041). 10-year OS of women age >30 years was 74% compared to 62% for age 26-30 years and 55% for age <26 (p=0.35).10 years OS of VYWAA with non-TNBC was 73% compared to 63% for with TNBC (p=0.028). On multivariate analysis for women with early-stage disease, stage III BC, HR, 3.0 (1.80-4.92) and grade III BC were significantly correlated with inferior DFS. On a multivariate analysis for OS of all VYWAA with stage 0 to IV disease, rural residence, HR, 1.75 (1.08-2.81); TNBC, HR, 2.25 (1.34-3.80), and stage IV disease, HR, 8.1 (4.72-13.94) were correlated with inferior OS. Conclusions: Very young women and adolescent with BC have a high incidence of node-positive disease and HER2+ and TNBC subtypes. TNBC and grade III disease were associated with inferior DFS in stage I-III disease whereas stage IV BC, TNBC and rural residence were correlated with inferior survival in women with stage 0-IV disease.

Abstract PO5-02-12: Comparison of survival outcomes according to axillary ultrasonography findings and cytology results in early-stage breast cancer patients

Abstract Purpose: Axillary lymph node dissection and sentinel lymph node biopsy are associated with increased risk of post-surgical complications including lymphedema and recent trials have raised questions about the therapeutic benefit of axillary operation in early-stage breast cancer patients. While treatment options for lymph nodes with negative findings on axillary ultrasonography (AUS) or positive findings on fine needle aspiration biopsy (FNAB) are evident, data regarding lymph nodes that are suspicious on AUS but negative by FNAB are limited. Thus, we aimed to compare clinicopathological characteristics of AUS positive and FNAB negative patients with those of AUS negative or FNAB positive patients. Materials and Methods: Medical records of patients who underwent breast cancer surgery between January 2010 and December 2017 were reviewed. Patients were grouped into the following three groups: (a) negative findings on AUS, (b) suspicious findings on AUS but negative on FNAB, (c) and FNAB positive. A total of 4,506 patients were included for analysis, with 3,771 patients with no suspicious lymph nodes on AUS, 557 patients who had suspicious AUS findings but were negative on FNAB, and 178 patients with positive findings on both AUS and FNAB. Primary endpoints were disease free survival (DFS) and recurrence free survival (RFS), and secondary endpoint was overall survival (OS). Results: At a median follow-up period of 92 months, DFS and RFS was significantly higher in the AUS negative group compared to the other two groups (10-year-DFS: 91.6% vs 87.5% vs 75.7%, 10-year-RFS: 95.0% vs 89.9% vs 77.1%, p < 0.001). In terms of OS, AUS negative group and the AUS positive and FNAB negative group did not show statistically significant survival difference (10-year-OS: 94.5% vs 92.8%, p = 0.061), while the FNAB positive group showed significantly lower survival rates (10-year-OS: 81.8%, p < 0.001). Multivariable analysis revealed that not AUS positive and FANB negative but positive FNAB was significantly associated with poor RFS. Moreover, hormone receptor (HR) positive and HER2 negative subtype showed poor DFS and RFS in subgroup analysis. Conclusion: Early breast cancer patients with suspicious findings on AUS but negative FNAB results had similar OS but inferior DFS and RFS compared to those with negative features on AUS, especially in HR(+)HER2(-) subtype. While further prospective trials are warranted to determine whether additional treatment is necessary, close surveillance is recommended for this subgroup of patients. Figure1. Overall survial and Disease free survival according to axillay US and FNAB status Table1. patients' characteristics Table2. prognostic factors for overall survival and disease free survival related to axillary US and FNAB status Citation Format: Suk Jun Lee. Comparison of survival outcomes according to axillary ultrasonography findings and cytology results in early-stage breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-02-12.

Abstract PO2-24-02: Molecular characterization of primary tumors associated with various CTCs’ subpopulation

Abstract Background: Circulating tumor cells (CTCs) are prognostic in primary breast cancer (BC) patients and represent a heterogeneous population of cells with different phenotypes and biological value. However, molecular characterization of primary tumors associated with various CTCs’ subpopulation is lacking. This study aimed to identify expression of genes associated with the presence of different CTCs subpopulations in primary BC patients using a comprehensive genomics approach. Methods: This prospective ongoing study included 312 patients (pts) with non-metastatic BC enrolled from March 2012 to February 2015. CTCs were detected on day -1 to 0 before surgery. Isolated peripheral blood mononuclear cells (PBMC) were depleted of hematopoietic cells using RossetteSepTM kit negative selection with anti-CD45 antibody. RNA extracted from CD45-depleted (CD45-) PBMC was interrogated for expression of EMT-inducing transcription factors (TWIST1, SNAIL1, SLUG, ZEB1) and epithelial (CK19) gene transcripts by quantitative reverse transcription-PCR. Expressions of gene transcripts in CD45- PBMC of patients were compared to those of CD45- PBMC of 60 healthy donors. Formalin-fixed paraffin-embedded tumor tissue was subject for gene expression analysis performed by HTG EdgeSeq Oncology Biomarker panel (HTG Molecular Diagnostics, Inc., Tucson, USA). Results: CTCs with epithelial phenotype (CTC_EP) were detected in 30 (9.6%) pts, CTC with EMT (epithelial-to-mesenchymal transition) were detected in 54 (17.3%), while blood of 79 (25.3%) pts exhibit at least one type of CTC. Patients with detectable CTC in peripheral blood had inferior disease-free survival compared to patients without detectable CTC (HR = 0.62, 95% CI 0.37-1.06, P=0.048). There was no association between epithelial CTCs and analysed patients/tumour variables. Genes expression analysis identified 7 differentially expressed genes in patients with the CTC_EP phenotype (CHGA, MESP1, COL2A1, MT2A, COMP, MMP7 and ORM2), 200 genes associated with CTC_EMT phenotype (top 10 genes included CHGA, CECR6, SMAD2, HUS1, FGF10, HNF1A, SEC61G, CDK4, CD44 and F3). Analysis identified that low expression of CHGA and MMP7 was consistently associated with any CTC subpopulations. Conclusions: In this study for the first-time revealed gene expressions associated with various CTC subpopulations. We suppose that these genes could represent potential therapeutic target aimed to inhibit metastatic cascade in breast cancer. Citation Format: Michal Mego, Gabriel Minarik, Milan Hucko, Katarina Kalavska, Marian Karaba, Juraj Benca, Tatiana Sedlackova, Lucia Kucerova, Jozef Mardiak, Lubos Klucar, Zuzana Cierna. Molecular characterization of primary tumors associated with various CTCs’ subpopulation [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-24-02.

Persistent or New Cytopenias Predict Relapse Better than Routine Bone Marrow Aspirate Evaluations After Hematopoietic Cell Transplantation for Acute Leukemia or Myelodysplastic Syndrome in Children and Young Adult Patients

The clinical value of serial routine bone marrow aspirates (rBMAs) in the first year after allogeneic hematopoietic cell transplantation (alloHCT) to detect or predict relapse of acute leukemia (AL) and myelodysplastic syndrome (MDS) in pediatric and young adult patients is unclear. The purpose of this analysis was to determine if assessment of minimal residual disease (MRD) by multiparameter flow cytometry (MFC, MFC-MRD) or donor chimerism (DC) in rBMAs or serial complete blood counts (CBCs) done in the year after alloHCT predicted relapse of AL or MDS in pediatric and young adult patients. We completed a retrospective analysis of patients with AL or MDS who had rBMAs performed after alloHCT between January 2012 and June 2018. Bone marrow (BM) was evaluated at approximately 3, 6, and 12 months for disease recurrence by morphology, MFC-MRD, and percent DC by short tandem repeat molecular testing. CBCs were performed at every clinic visit. The main outcome of interest was an assessment of whether MFC-MRD or DC in rBMAs or serial CBCs done in the year after alloHCT predicted relapse in AL or MDS pediatric and young adult patients. A total of 121 recipients with a median age of 13 years (range 1 to 32) were included: 108 with AL and, 13 with MDS. A total of 423 rBMAs (median 3; 0 to 13) were performed. Relapse at 2 years was 23% (95% CI: 16% to 31%) and at 5 years 25% (95% CI: 18% to 33%). One hundred fifty-four of 157 (98%) rBMAs evaluated for MRD by MFC were negative and did not preclude subsequent relapse. Additionally, low DC (<95%) did not predict relapse and high DC (≥95%) did not preclude relapse. For patients alive without relapse at 1 year, BM DC (P = .74) and peripheral T-cell DC (P = .93) did not predict relapse. Six patients with low-level T-cell and/or BM DC had a total of 8 to 20 BM evaluations, none of these patients relapsed. However, CBC results were informative for relapse; 28 of 31 (90%) relapse patients presented with an abnormal CBC with peripheral blood (PB) blasts (16 patients), cytopenias (9 patients), or extramedullary disease (EMD, 3 patients). Two patients with BM blasts >5% on rBMA had circulating blasts within 5 weeks of rBMA. Neutropenia (ANC <1.5 K/mcl) at 1 year was predictive of relapse (P = .01). Neutropenia and thrombocytopenia (<160 K/mcl) were predictive of disease-free survival (DFS) with inferior DFS for ANC <1.5 K/mcl, P = .001, or platelet count <160 K/mcl (P = .04). These results demonstrate rBMAs after alloHCT assessed for MRD by MFC and/or for level of DC are poor predictors for relapse in pediatric and young adult patients with AL or MDS. Relapse in these patients presents with PB blasts, cytopenias, or EMD. ANC and platelet count at 1-year were highly predictive for DFS.

Does the time interval from neoadjuvant camrelizumab combined with chemotherapy to surgery affect outcomes for locally advanced esophageal squamous cell carcinoma?

BackgroundThere is currently no consensus on the optimal interval time between neoadjuvant therapy and surgery, and whether prolonged time interval from neoadjuvant therapy to surgery results in bad outcomes for locally advanced esophageal squamous cell carcinoma (ESCC). In this study, we aim to evaluate outcomes of time intervals ≤ 8 weeks and > 8 weeks in locally advanced ESCC.MethodsThis retrospective study consecutively included ESCC patients who received esophagectomy after neoadjuvant camrelizumab combined with chemotherapy at the Department of Thoracic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine. The primary endpoints were disease-free survival (DFS) and overall survival (OS), while the secondary endpoints were pathological response, surgical outcomes, and postoperative complications.ResultsFrom 2019 to 2021, a total of 80 patients were included in our study and were divided into two groups according to the time interval from neoadjuvant immunochemotherapy to surgery: ≤ 8 weeks group (n = 44) and > 8 weeks group (n = 36). The rate of MPR in the ≤ 8 weeks group was 25.0% and 27.8% in the > 8 weeks group (P = 0.779). The rate of pCR in the ≤ 8 weeks group was 11.4%, with 16.7% in the > 8 weeks group (P = 0.493). The incidence of postoperative complications in the ≤ 8 weeks group was 27.3% and 19.4% in the > 8 weeks group (P = 0.413). The median DFS in the two groups had not yet reached (hazard ratio [HR], 3.153; 95% confidence interval [CI] 1.383 to 6.851; P = 0.004). The median OS of ≤ 8 weeks group was not achieved (HR, 3.703; 95% CI 1.584 to 8.657; P = 0.0012), with the > 8 weeks group 31.6 months (95% CI 21.1 to 42.1). In multivariable analysis, inferior DFS and OS were observed in patients with interval time > 8 weeks (HR, 2.992; 95% CI 1.306 to 6.851; and HR, 3.478; 95% CI 1.481 to 8.170, respectively).ConclusionsLocally advanced ESCC patients with time interval from neoadjuvant camrelizumab combined with chemotherapy to surgery > 8 weeks were associated with worse long-term survival.

Long-term Outcomes following Resection of Adenocarcinoma Arising from Intraductal Papillary Mucinous Neoplasm (A-IPMN) versus Pancreatic Ductal Adenocarcinoma (PDAC): A Propensity-score Matched Analysis.

The aim of the present study was to compare long-term post-resection oncological outcomes between A-IPMN and PDAC. Knowledge of long term oncological outcomes (e.g recurrence and survival data) comparing between adenocarcinoma arising from intraductal papillary mucinous neoplasms (A-IPMN) and pancreatic ductal adenocarcinoma (PDAC) is scarce. Patients undergoing pancreatic resection (2010-2020) for A-IPMN were identified retrospectively from 18 academic pancreatic centres and compared with PDAC patients from the same time-period. Propensity-score matching (PSM) was performed and survival and recurrence were compared between A-IPMN and PDAC. 459 A-IPMN patients (median age,70; M:F,250:209) were compared with 476 PDAC patients (median age,69; M:F,262:214). A-IPMN patients had lower T-stage, lymphovascular invasion (51.4%vs. 75.6%), perineural invasion (55.8%vs. 71.2%), lymph node positivity (47.3vs. 72.3%) and R1 resection (38.6%vs. 56.3%) compared to PDAC(P<0.001). The median survival and time-to-recurrence for A-IPMN versus PDAC were 39.0 versus19.5months (P<0.001) and 33.1 versus 14.8months (P<0.001), respectively (median follow-up,78 vs.73 months). Ten-year overall survival for A-IPMN was 34.6%(27/78) and PDAC was 9%(6/67). A-IPMN had higher rates of peritoneal (23.0 vs. 9.1%, P<0.001) and lung recurrence (27.8% vs. 15.6%, P<0.001) but lower rates of locoregional recurrence (39.7% vs. 57.8%; P<0.001). Matched analysis demonstrated inferior overall survival (P=0.005), inferior disease-free survival (P=0.003) and higher locoregional recurrence (P<0.001) in PDAC compared to A-IPMN but no significant difference in systemic recurrence rates (P=0.695). PDACs have inferior survival and higher recurrence rates compared to A-IPMN in matched cohorts. Locoregional recurrence is higher in PDAC but systemic recurrence rates are comparable and constituted by their own distinctive site-specific recurrence patterns.

Critical appraisal of surgical margins according to KRAS status in liver resection for colorectal liver metastases: Should surgical strategy be influenced by tumor biology?

BackgroundKRAS mutation is a negative prognostic factor for colorectal liver metastases. Several studies have investigated the resection margins according to KRAS status, with conflicting results. The aim of the study was to assess the oncologic outcomes of R0 and R1 resections for colorectal liver metastases according to KRAS status. MethodsAll patients who underwent resection for colorectal liver metastases between 2010 and 2015 with available KRAS status were enrolled in this multicentric international cohort study. Logistic regression models were used to investigate the outcomes of R0 and R1 colorectal liver metastases resections according to KRAS status: wild type versus mutated. The primary outcomes were overall survival and disease-free survival. ResultsThe analysis included 593 patients. KRAS mutation was associated with shorter overall survival (40 vs 60 months; P = .0012) and disease-free survival (15 vs 21 months; P = .003). In KRAS-mutated tumors, the resection margin did not influence oncologic outcomes. In multivariable analysis, the only predictor of disease-free survival and overall survival was primary tumor location (P = .03 and P = .03, respectively). In KRAS wild-type tumors, R0 resection was associated with prolonged overall survival (74 vs 45 months, P < .001) and disease-free survival (30 vs 17 months, P < .001). The multivariable model confirmed that R0 resection margin was associated with prolonged overall survival (hazard ratio = 1.43, 95% confidence interval: 1.01–2.03) and disease-free survival (hazard ratio = 1.42; 95% confidence interval: 1.06–1.91). ConclusionsKRAS-mutated colorectal liver metastases showed more aggressive tumor biology with inferior overall survival and disease-free survival after liver resection. Although R0 resection was not associated with improved oncologic outcomes in the KRAS-mutated tumors group, it seems to be of paramount importance for achieving prolonged long-term survival in KRAS wild-type tumors.

Who benefit from adjuvant chemotherapy in stage I lung adenocarcinoma? A multi-dimensional model for candidate selection

BackgroundDespite promising overall survival of stage I lung adenocarcinoma (LUAD) patients, 10-25 % of them still went through recurrence after surgery. [1] While it is still disputable whether adjuvant chemotherapy is necessary for stage I patients. [2] IASLC grading system for non-mucinous LUAD shows that minor high-grade patterns are significant indicator of poor prognosis. [3] Other risk factors, such as, pleura invasion, lympho-vascular invasion, STAS, etc. are also related to poor prognosis. [4-6] There still lack evidence whether IASLC grade itself or together with other risk factors can guide the use of adjuvant therapy in stage I patients. In this article, we tried to establish a multi-variable recurrence prediction model for stage I LUAD patients that is able to identify candidates of adjuvant chemotherapy. MethodsWe retrospectively collected patients who underwent lung surgery from 2018.8.1 to 2018.12.31 at our institution and diagnosed with lung adenocarcinoma pT1-2aN0M0 (stage I). Clinical data, manifestation on CT scan, pathologic features, driver gene mutations and follow-up information were collected. Cox proportional hazards regression analyses were performed utilizing the non-adjuvant cohort to predict disease free survival (DFS) and a nomogram was constructed and applied to the total cohort. Kaplan-Meier method was used to compare DFS between groups. Statistical analysis was conducted by R version 3.6.3. FindingsA total of 913 stage I LUAD patients were included in this study. Median follow-up time is 48.1 months.4-year and 5-year DFS are 92.9 % and 89.6 % for the total cohort. 65 patient experienced recurrence or death. 4-year DFS are 97.0 %,94.6 % and 76.2 %, and 5-year DFS are 95.5 %, 90.0 % and 74.1 % in IASLC Grade1, 2 and 3, respectively(p < 0.0001). High-risk patients defined by single risk factors, such as, IASLC grade 3, pleura invasion, STAS, less LN resected could not benefit from adjuvant therapy. A LASSO-COX regression model was built and patients are divided into high-risk and low-risk groups. In the high-risk group, patients underwent adjuvant chemotherapy have longer DFS than those who did not (p = 0.024), while in the low-risk group, patients underwent adjuvant chemotherapy have inferior DFS than those who did not (p < 0.001). InterpretationIASLC grading is a significant indicator of DFS, however it could not guide adjuvant therapy in our stage I LUAD cohort. Growth patterns and T indicators together with other risk factors could identify high-risk patients that are potential candidate of adjuvant therapy, including some stage IA LUAD patients.

Current analysis of the survival implications for minimally invasive surgery in the treatment of early-stage cervix cancer.

Early-stage cervical cancer (ESCC) is managed with radical hysterectomy, a procedure that can be performed either via open surgery or minimally invasive surgery (MIS), the latter of which is accomplished via traditional laparoscopy or robotic-assisted surgery. Previously, MIS was routinely incorporated into the management of ESCC due to the approach's reduced operative morbidity and truncated hospital stay duration, but more recent clinical evidence has since impugned the efficacy of MIS because of the reportedly inferior disease-free survival and overall survival outcomes compared to open surgery. However, additional studies have documented equivalent outcomes among the various surgical modalities, suggesting further exploration of clinical factors as we endeavor to conclusively determine the standard of care for patients diagnosed with ESCC.

Prognostic factors of gallbladder cancer (GBC) in patients diagnosed over a period of 20 years: A Canadian province experience.

437 Background: GBC is an uncommon but often fatal gastrointestinal cancer. The poor prognosis of GBC may in part be due to lack of effective screening tools and a delay in diagnosis that leads to presentation in the latter stages of the disease. The current study aims to determine outcomes of patients with GBC in relation to contextual, demographic and clinical factors in a Canadian province over a span of 20 years. Methods: In this population-based retrospective cohort study patients with GBC diagnosed in Saskatchewan, Canada from 2000-2019 were evaluated. Cox proportional multivariate regression analyses was performed to determine factor correlated with inferior outcomes. Results: 331 patients with median age of 74 yrs and M:F of 1:2 were identified. 92% had a pathological diagnosis of GBC &amp; 80% had adenocarcinoma. 49% were diagnosed &gt;year 2010. 217 (66%) of those diagnosed with GBC were rural residents. 149 (45%) patients were referred to a cancer center. In patients with documented stage, 64% had stage IV disease &amp; &gt;90% were symptomatic with a median time from the onset of symptoms to the diagnosis of 7 months. Rural residents have a significantly high rate of smoking history whereas urban residents have significantly high rates of pathological diagnosis, low serum albumin and elevated platelet count. Median overall survival (OS) of patients with stage I-III GBC was 20 months (95% CI:10.9-29.1) vs. 4.0 months (3.0-5.0) with stage IV GBC (&lt;0.001). No significant differences were noted in OS in relation to residence and time-period of diagnosis. Patients who were not referred for a cancer center had a median OS of 3 months (1.98-4.0) vs. 13 months (9.9-16.1), p&lt;0.001. Median disease-free survival (DFS) of patients with stage I-III GBC was 20 months (95%CI: 10-30.1) with 5-year DFS of 36%. Patients with stage I-III GBC who received adjuvant chemotherapy had 5-yr DFS of 43% vs. 33% without adjuvant chemotherapy (p=0.73). 5-year DFS of urban patients was 25% vs. 42% of rural patients (p=0.016). On multivariate analysis for patients with Stage I-III GBC, stage III disease, HR (hazard ratio), 2.63 (1.09-6.34) and urban residence, HR, 2.20 (1.1-4.39) were correlated with inferior DFS whereas for all patients, stage IV disease, HR, 3.02 (1.85-4.94); no referral to cancer center, HR, 2.64 (1.51-4.62); lack of surgery, HR, 1.63 (1.03-2.57); neutrophil:lymphocyte of &gt;3.2, HR, 1.57 (1.05-2.36); and age ≥70, HR, 1.51 (1.04-2.19) were correlated with inferior OS. Conclusions: In a real-world setting, most patients with GBC are diagnosed with late-stage disease and were not referred to cancer center. For early-stage GBC, urban residence and stage III disease were correlated with inferior outcome, whereas for all stage GBC, stage IV disease, old age, lack of surgery, lack of referral to cancer center, and high neutrophil to lymphocyte ratio were correlated with inferior survival.

Circulating tumor DNA (ctDNA) for informing adjuvant chemotherapy (ACT) in stage II/III colorectal cancer (CRC): Interim analysis of BESPOKE CRC study.

9 Background: ctDNA-based post-surgical detection of molecular residual disease (MRD) is known to be predictive of a high risk of recurrence. Here, we report the first results of BESPOKE CRC, a multicenter, prospective, observational study evaluating the ability of a tumor-informed ctDNA assay to inform ACT treatment decisions in stage II/III CRC patients (pts). Methods: Of the 1792 pts enrolled between 2020-07-02 and 2022-08-25, plasma samples from the first 350 pts with stage II-III CRC were analyzed. ctDNA was detected and quantified using a personalized, tumor-informed assay (Signatera, Natera, Inc.). Following curative resection, 232 pts received ACT and 118 underwent observation. Results: The cohort included 154 stage II and 196 stage III CRC pts; the median follow-up was 24.8 months. ctDNA results at the post-op MRD time point (tp) were available for 295 pts; 15.6% (46/295; stage II: 9/130=6.9%; stage III: 37/165=22.4%) of pts were ctDNA positive (ctDNA+) at MRD tp (MRD+). MRD-positivity was significantly associated with inferior disease-free survival (DFS) in stages II-III combined (HR=20.8, 95% CI: 10.0-43.4, p&lt;0.0001) and in stage-stratified subgroups (stage II: HR=25.7, 95% CI 6.8-96.7; stage III: HR=18.1, 95% CI 7.3-45.1). Within the MRD+ group, pts receiving ACT had longer DFS compared to those in the observation group (median DFS: 18.7 vs 6.7 months; HR=3.9, 95% CI: 1.3-11.5, p=0.01). In contrast, no benefit of ACT was observed in MRD- pts (HR=1.1, 95% CI: 0.3-3.9, p=0.89). Of the MRD+ pts, 39.1% (18/46) had ctDNA clearance at 12-weeks post-surgery tp. Pts with ctDNA clearance had longer DFS compared to those who remained positive (median DFS: 24.2 vs 13.8 months; HR=0.4, 95% CI 0.1-1.0, p=0.045), however, had worse DFS than pts who were ctDNA- at both 4- and 12-weeks (HR=22.5, 95% CI: 6.8-75.0, p&lt;0.0001). Notably, 44.4% (8/18) pts with ctDNA clearance recurred; all 8 turned back ctDNA+ before radiological detection of relapse. ctDNA results during surveillance were available for 339 pts, of whom 8.3% (58/339) were ctDNA+ and had significantly worse DFS compared to serially ctDNA- pts (HR=124.3, 95% CI: 29.8-518.7, p&lt;0.0001). Conclusions: ctDNA-based MRD detection of MRD was highly prognostic of recurrence in an early representative subset of BESPOKE CRC cohort. Data from the expanded cohort will be presented at the meeting. ctDNA MRD results were also predictive: significant benefit from ACT was observed in MRD+ but not in MRD- pts. Additionally, early ctDNA clearance in response to adjuvant therapy and ctDNA status during surveillance were prognostic of pt outcomes. Our results highlight the potential utility of ctDNA-guided adjuvant therapy in pts with stage II/III CRC. The results of BESPOKE CRC herein, as one of the first ctDNA-based prospective studies, will be further validated by ongoing ctDNA-directed randomized clinical trials. Clinical trial information: NCT04264702 .

CD301 and LSECtin glycan-binding receptors of innate immune cells serve as prognostic markers and potential predictors of immune response in breast cancer subtypes.

Glycosylation is a prominent posttranslational modification, and alterations in glycosylation are a hallmark of cancer. Glycan-binding receptors, primarily expressed on immune cells, play a central role in glycan recognition and immune response. Here, we used the recombinant C-type glycan-binding receptors CD301, Langerin, SRCL, LSECtin, and DC-SIGNR to recognize their ligands on tissue microarrays (TMA) of a large cohort (n=1859) of invasive breast cancer of different histopathological types to systematically determine the relevance of altered glycosylation in breast cancer. Staining frequencies of cancer cells were quantified in an unbiased manner by a computer-based algorithm. CD301 showed the highest overall staining frequency (40%), followed by LSECtin (16%), Langerin (4%) and DC-SIGNR (0.5%). By Kaplan-Meier analyses, we identified LSECtin and CD301 as prognostic markers in different breast cancer subtypes. Positivity for LSECtin was associated with inferior disease-free survival in all cases, particularly in estrogen receptor positive (ER+) breast cancer of higher histological grade. In triple negative breast cancer, positivity for CD301 correlated with a worse prognosis. Based on public RNA single-cell sequencing data of human breast cancer infiltrating immune cells, we found CLEC10A (CD301) and CLEC4G (LSECtin) exclusively expressed in distinct subpopulations, particularly in dendritic cells and macrophages, indicating that specific changes in glycosylation may play a significant role in breast cancer immune response and progression.

Reclassification of RAS/BRAF allele mutations predicts the survival benefit of triplet chemotherapy in metastatic colorectal cancer.

Different RAS/BRAF allele mutations imply distinct biological properties in various solid tumors. Recently, several studies have focused on the predictive and prognostic roles of various RAS/BRAF allele mutations in colorectal cancer (CRC) but the results remain controversial. Between March 2017 and September 2022, the patients diagnosed as stages I-IV CRC with detailed medical records including next-generation sequencing (NGS) data and clinicopathological follow-up information available at our center were enrolled. Survival data were estimated using the Kaplan-Meier method, and the difference was tested in a log-rank test. Multivariate tests were carried out using Cox models. A total of 1029 CRC patients were included, and the incidence of RAS/BRAF mutation was 58.4%. The hypermutated cohort was defined as patients with microsatellite instability-H or POLE/D mutation. In the non-hypermutational cohort, only KRAS G13D mutation was associated with a higher incidence and inferior disease-free survival in patients with stage I-III CRC. In the cohort of patients with non-hypermutated metastatic colorectal cancer (mCRC), we assessed the risk of various RAS/BRAF allele mutations and subsequently reclassified patients into four groups based on first-line median progression-free survival: wild type (group 1), low-risk RAS/BRAF mutation (group 2, RAS/BRAF mutations other than KRAS G13D/G12V/G12C or BRAF V600E), high-risk RAS mutation (group 3, KRAS G13D/G12V/G12C), and BRAF V600E mutation (group 4). mCRC patients with high-risk RAS mutation could significantly benefit from intensive triplet chemotherapy (hazard ratio, 2.54; 95% confidence interval, 1.36-5.12; p = 0.0091). In the non-hypermutated CRC cohort, the prognostic risk of various RAS/BRAF allele mutations varied between local and metastatic CRC. KRAS G13D mutation tended to be the only prognostic marker for stages I-III CRC; however, KRAS G13D/G12V/G12C mutations collectively defined a high-risk subgroup of mCRC patients with poor prognosis, who would benefit from intensive triplet chemotherapy.

Developmental trajectories and cooperating genomic events define molecular subtypes of BCR::ABL1-positive ALL

AbstractDistinct diagnostic entities within BCR::ABL1-positive acute lymphoblastic leukemia (ALL) are currently defined by the International Consensus Classification of myeloid neoplasms and acute leukemias (ICC): “lymphoid only”, with BCR::ABL1 observed exclusively in lymphatic precursors, vs “multilineage”, where BCR::ABL1 is also present in other hematopoietic lineages. Here, we analyzed transcriptomes of 327 BCR::ABL1-positive patients with ALL (age, 2-84 years; median, 46 years) and identified 2 main gene expression clusters reproducible across 4 independent patient cohorts. Fluorescence in situ hybridization analysis of fluorescence-activated cell-sorted hematopoietic compartments showed distinct BCR::ABL1 involvement in myeloid cells for these clusters (n = 18/18 vs n = 3/16 patients; P < .001), indicating that a multilineage or lymphoid BCR::ABL1 subtype can be inferred from gene expression. Further subclusters grouped samples according to cooperating genomic events (multilineage: HBS1L deletion or monosomy 7; lymphoid: IKZF1-/- or CDKN2A/PAX5 deletions/hyperdiploidy). A novel HSB1L transcript was highly specific for BCR::ABL1 multilineage cases independent of HBS1L genomic aberrations. Treatment on current German Multicenter Study Group for Adult ALL (GMALL) protocols resulted in comparable disease-free survival (DFS) for multilineage vs lymphoid cluster patients (3-year DFS: 70% vs 61%; P = .530; n = 91). However, the IKZF1-/- enriched lymphoid subcluster was associated with inferior DFS, whereas hyperdiploid cases showed a superior outcome. Thus, gene expression clusters define underlying developmental trajectories and distinct patterns of cooperating events in BCR::ABL1-positive ALL with prognostic relevance.

KRAS-related miR-143 expression is associated with lymph node involvement and correlates with outcome in pancreatic adenocarcinoma patients.

Pancreatic adenocarcinoma (PC) is one of the most lethal malignancies; even after resection the patients' 5-year disease-free survival (DFS) is lower than 26%. The genetic mutational landscape of PC is dominated by activating KRAS mutations, that have been reported in approximately 90% of cases; however, beyond KRAS - direct mutations, several KRAS-targeting miRNAs appear to be downregulated, strengthening the already activated RAS signaling. In addition, the interplay between miRNAs and RAS includes poorly investigated downstream miRNAs. The aim of this study was to determine the prognostic value of some of these candidate KRAS-related miRNAs. Between 2015 and 2022, 44 patients with pathologically confirmed PC, who received surgery and were enrolled by the Clinical Oncology Unit, Careggi University Hospital, Florence (Italy). PC Total RNA was extracted from FFPE sections, retro-transcribed and the resulting cDNA was then used for qPCR analysis. A panel of KRAS-related miRNA (miR-155, miR-206 and miR-143) was analyzed. In this observational study patients sex distribution was unequal with 34.1% being male and 65.9% female. The most frequent tumor localization was the head of the pancreas (65.9%) and the pathological stages were pT1-2 (45.5%), pT3 (54.5%), pN0 (22.7%), pN+ (77.3%). Adjuvant therapy was administered to 63.6% of patients; disease recurrence was observed in 69% of cases. Twenty-three patients, whose RNA was of adequate quality, were used in the mRNAs expression studies. When comparing the miRNA expression between PC and a pool of healthy tissues, miR-155 was overexpressed and miR-206 downregulated in PC, while miR-143 expression was unchanged. However, when categorized in low- and high- miR-143 expressing PC (according to the median value), high miR-143 was associated with nodal involvement (pN+) (p=0.029), who in turn was linked with shorter DFS (p=0.009) and overall survival (OS) (p=0.021) compared to pN0. A trend toward inferior DFS was observed for higher expression of miR-206 (p=0.095) and miR-143 (p=0.092). Finally, responders to a first-line treatment for advanced disease had miR-155 overexpressed (p=0.048). miRNAs are involved in PC tumorigenesis and metastatic spread. In light of miR-143 association with lymphatic spread and poor prognosis, a comprehensive analysis of miRNA interplay with KRAS deserves further investigation.

Longitudinal post-radiotherapy plasma Epstein-Barr virus DNA trends inform on optimal risk stratification in endemic nasopharyngeal carcinoma

ObjectivesTo characterize longitudinal changes in Epstein-Barr virus (EBV) DNA post-radiotherapy in nasopharyngeal carcinoma (NPC) patients, and investigate whether an early (0–2 weeks) or delayed (8–12 weeks) EBV DNA result better predicts for disease-free survival (DFS). Materials and MethodsHistologically-confirmed NPC patients with ≥1 EBV DNA test quantified using the harmonized BamHI-W polymerase chain reaction-based assay at 0–2 and 8–12 weeks post-radiotherapy were included. ResultsWe identified 302 patients with EBV DNA measured at 0–2 weeks post-radiotherapy; of which, 110 (36.4 %) underwent a repeat test at 8–12 weeks post-treatment. Patients harboring a detectable EBV DNA at 0–2 weeks experienced an inferior DFS (adjusted HR1-264 copies 1.72 [95 %CI: 1.05–2.83], P = 0.031; AHR≥265 copies 4.39 [95 %CI: 1.68–11.44], P = 0.002 relative to 0 copies/mL). At 8–12 weeks, we observed substantial shifts in EBV DNA readings from 0 to 2 weeks; 76/110 (69.1 %) and 34/110 (30.9 %) patients at 0–2 weeks versus 90/110 (81.8 %) and 20/110 (18.2 %) at 8–12 weeks recorded undetectable and detectable EBV DNA, respectively. Positive EBV DNA at 8–12 weeks was strongly associated with relapse (73.3 % [11/15] for 1–264; 80.0 % [4/5] for ≥265 subgroups had relapses versus 15.6 % [14/90] for 0 copies/mL). Area under receiver operating curve values for 2-year relapse rates were 0.817 (95 %CI: 0.725–0.909) for stage + EBV DNA8-12w versus 0.654 (95 %CI: 0.542–0.765) for stage + EBV DNA0-2w. ConclusionEBV DNA is dynamic post-radiotherapy, and delayed EBV DNA testing better enriched for higher-risk NPC patients. This implicates trials investigating adjuvant chemotherapy intensification based on early EBV DNA testing.

Robotic Vaginal Cuff Closure During Radical Hysterectomy for Early-Stage Cervical Cancer: The Bruges Method.

The only randomized trial (LACC trial, Laparoscopic Approach to Cervical Cancer), published in 2018, comparing the oncologic outcomes of minimally invasive and open surgery in early-stage cervical cancer, has shown inferior disease-free and overall survival for minimally invasive surgery. Subsequent large retrospective cohort studies of centers with long-standing experience in minimally invasive surgery and large nationwide cohort studies have shown that both the laparoscopic and robotic approaches have similar survival outcomes as the open surgery group in the LACC trial. Important protective measures to avoid tumor spillage in the peritoneal cavity during colpotomy were the closure of the vaginal cuff and avoiding the use of a uterine manipulator. Several methods have been described to close the vaginal cuff, mainly by a vaginal approach. Here we describe with a video a new technique of vaginal cuff closure during a robotic-assisted radical hysterectomy. During the robotic procedure, a purse string barbed suture is placed through the vaginal walls in order to close the vagina prior to colpotomy. The technique is a feasible, relatively fast, and easy-to-learn addition to the robotic radical hysterectomy procedure in early-stage cervical cancer.

High Exposure of Rabbit Anti-Thymocyte Globulin (ATG) Is Strongly Associated with Inferior DFS in Pediatric Patients with Malignancy Undergoing Alpha-Beta T-Cell Depleted Haploidentical HCT

The PTCTC ONC1401 trial reported a 75% 2-year disease-free survival (DFS) for pediatric patients with acute leukemia or MDS undergoing AB-TCR/CD19 depleted (AB-TCD) haploidentical HCT. Patients ≥10 years had significantly worse DFS. Conditioning for AB-TCD HCT typically includes rATG (Thymoglobulin®) 3 mg/kg/day on days -12 to -10. Models of rATG pharmacokinetics (PK) show slower clearance in older children. We hypothesized worse DFS seen in older patients may be due to excessive in vivo T-cell depletion by residual rATG post HCT. Patients undergoing first AB-TCD haploidentical HCT with rATG as the sole serotherapy agent for treatment of malignancy from Dec 2015 to Jan 2023 were included. Patients were treated on PTCTC ONC1401 or institutional prospective trials of AB-TCD. Minimal residual disease (MRD) was determined by the best-available method (multi-parameter flow or next-generation sequencing) for each patient. Predicted pre- and post-HCT AUC of rATG (in AU*day/mL) were retrospectively determined using the software platform InsightRx© (InsightRx, Inc., San Francisco, CA) and a validated PK model for rATG clearance. Quadratic regression was used to identify optimal target windows of rATG exposure for cumulative incidence and Kaplan-Meier estimations. Multivariate analysis (MVA) Cox regression models were built using all covariates with a univariate p-value &amp;lt;0.2. The dataset included 134 patients ( Table 1); median (range) follow-up of survivors was 3.4 years (0.5-7.6). The median age at HCT was 12.3 years (0.4-27.4), and median donor age was 32 years (5-61). The median infused cell doses for CD34 and AB-T-cells were 15.2 (2.5-45.8) x10^6/kg and 7.0 (0.1-27.6) x10^4/kg. The 100-day incidence of rejection was 11.3% (5.8-16.8) with a 3-year EFS of 59% (50.2-67.8). The 3-year incidence of non-relapse mortality (NRM) and relapse were 13.8% (6.9-20.7) and 21.4% (13.8-29). The 100-day incidence of grades 2-4 and 3-4 aGVHD were 24.4% (16.2-32.6) and 8.5% (3.4-13.6), while 3-year incidence of cGVHD was 16.7% (9.1-24.3). The 3-year DFS and OS were 67.6% (59.2-76) and 73.8% (64-83.6). Increased 3-year NRM was seen in patients ≥10 years: 19.9% (10.6-31.4) vs. 5.6% (0.1-13.4) ( p=0.03); in those with sibling vs. parent donors: 27.3% (12.4-42.2) vs. 8.5% (1.6-15.4) (p=0.008); and CMV mismatched donors: 25.5% (9.1-41.3) vs. 10.4% (3.3-17.5) ( p=0.03). There was no difference in relapse between MRD-techniques, so these were combined for subsequent analyses. Lower 3-year relapse was seen in patients who were MRD-negative: 12.6% (5.5-19.7) vs. 45.7% (26.7-64.7) ( p&amp;lt;0.001); and who received targeted small-molecule therapy post-HCT: 0% (0-19.8) vs. 24.1% (15.5-32.7) ( p=0.04). The median predicted pre-HCT AUC of rATG was 63.7 AU*day/mL (16.4-109). A pre-HCT exposure of ≥40 AU*day/mL was associated with decreased rejection: 8.1% (3-13.2) vs. 27.3% (8.8-45.9; p=0.008). A pre-HCT exposure of &amp;lt;80 AU*day/mL was associated with lower 3-year TRM: 8% (1.7-14.3) vs. 33.4% (14.8-52; p&amp;lt;0.001). The 3-year EFS for patients with a pre-HCT AUC of 40-79.9 AU*day/mL was 69.7% (58.7-80.7) vs. 45.4% (31.9-58.9) for those not in goal range ( p=0.004). The median post-HCT AUC of rATG was 9.5 AU*day/mL (1-42.5). There was no different in grade 2-4 (p=0.61) or grade 3-4 (p=0.25) aGVHD or cGVHD (p=0.9) between those with low (&amp;lt;13 AU*day/mL) vs. high (≥13 AU*day/mL) exposure. A low post-HCT AUC was associated with both lower 3-year NRM: 7.2% (0.9-13.5) vs. 28.1% (11.6-44.6) ( p=0.002), and lower 3-year relapse incidence: 15.5% (7-23.7) vs. 34.3% (18.6-50) ( p=0.01). In MRD-negative patients, low vs. high post-HCT rATG AUC was associated with a 3-year DFS of 81.2% (71-91.4) vs. 60.2% (42-78.4) ( p=0.03); in MRD-positive patients, low vs. high post-HCT rATG AUC was associated with a 3-year DFS of 69.3% (47.9-90.7) vs. 17.9% (0.1-39.5) ( p&amp;lt;0.001). MVA showed that high post-HCT rATG exposure, MRD-positivity, and CMV-mismatched donors were associated with worse 3-year DFS ( Table 2). We identified optimal windows for rATG exposure - pre-HCT of 40-79.9 AU*day/mL, post-HCT &amp;lt;13 AU*day/mL - associated with lower rates of rejection, NRM, relapse, and improved DFS. Validation with prospective drug levels and an independent cohort would strengthen these conclusions. Our data indicates that model-based dosing of rATG to target pre- and post-HCT exposure may be superior to weight-based dosing in patients undergoing AB-TCD HCT.

Adverse Prognostic Role of Copy Number Alterations and Mutations in Adults with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Background: The impact of copy number alterations (CNAs) or mutations on outcomes has been broadly analyzed in pediatric acute lymphoblastic leukemia (ALL). However, the magnitude of the effect was often marginal, frequently restricted to specific genetic subtypes and rarely replicated across independent cohorts in adult ALL. Aim: We tried to analyze the prognostic relevance of genetic copy number alterations and gene mutations in patients with Ph-negative ALL who were treated with modified hyper-CVAD based chemotherapy followed by allogeneic hematopoietic cell transplantation (alllo-HCT). Methods: We investigated the role of CNAs or mutations to refine risk stratification in 128 adults with newly diagnosed Philadelphia chromosome (Ph)-negative B-cell precursor ALL treated with intensive chemotherapy followed by allo-HCT for post-remission therapy. We performed multiplex ligation-dependent probe amplification (MLPA) to detect deletions of 11 genes ( IKZF1, CDKN2A/B, EBF1, ETV6, PAX5, BTG1, JAK2, RB1, PAR1, ZFY) and high throughput sequencing (HTS) of 70 gene mutations. Results: MLPA analysis showed that IKZF1 and CDKN2A/B deletions were observed in 54 (42.2%) and 52 (40.6%) patients, respectively. The remaining gene deletions were: PAX5 in 29 (22.6%), ETV6 in 22 (17.2%), BTG1 in 15 (11.7%), EBF1 in 14 (10.9%), RB1 in 13 (10.1%), JAK2 in 8 (6.2%), and PAR1 in 4 (3.1%). By HTS, NRAS (n=21, 16.4%), KRAS (n=11, 8.6%), TP53 (n=14, 10.9%), and PTPN11 (n=12, 9.4%) mutations were frequently detected. Overall, multivariate analysis for disease-free survival (DFS) and cumulative incidence of relapse (Table 1) showed that TP53 mutations (HR 5.04, 95%CI 2.29-11.30, P&amp;lt;0.001) and CDKN2A/B deletions (HR 1.88, 95%CI 1.10-3.31, P=0.026) were significantly associated with a poorer DFS. Patients with TP53 mutations (HR 5.64, 95%CI 1.95-16.20, P&amp;lt;0.001) and IKZF1 deletions (HR 1.91, 95%CI 1.09-3.31, P=0.022) had a higher relapse risk. To better define the prognostic role of CNAs, further analyses were restricted to patients excluding 14 TP53 mutations (n=114). Here, we classified patients into 4 subgroups; (1) No deletions (n=45, 39.5%), (2) IKZF1 deletion-alone (n=11, 9.6%), (3) IKZF1plus (n=40, 35.1%), and (4) CDKN2A/B±other deletions without IKZF1 deletions (n=18, 15.8%). Patients with IKZF1plus or CDKN2A/B±other deletions had an inferior DFS ( P=0.023) and higher relapse incidence ( P=0.002) than patients having no deletions. The results were similarly reproduced in patients receiving allo-HCT in first complete remission. Conclusions: Our data showed that IKZF1 or CDKN2A/B deletions and TP53 mutations may confer a poor prognosis for adult Ph-negative B-cell precursor ALL in the setting of intensive chemotherapy and allo-HCT. The combination of genomic abnormalities and minimal residual disease response may further refine risk stratification and better select patients who could benefit from novel therapeutic approaches.

Comparison of adjuvant capecitabine plus oxaliplatin (CAPOX) versus S-1 after gastrectomy: a population-based cohort study using a nationwide claims database

Although both capecitabine plus oxaliplatin (CAPOX) and S-1 are accepted as adjuvant chemotherapy following gastrectomy for gastric cancer, the better option between the two is still controversial. We conducted a retrospective nationwide cohort study using data from the National Health Insurance Service of Korea. We included patients who underwent gastrectomy for a primary diagnosis of gastric cancer between January 1, 2013, and December 31, 2018. The study compared the survival outcomes of patients who received postoperative chemotherapy based on S-1 (Arm S) vs. CAPOX (Arm C), as well as other relevant clinical variables such as comorbidity and completion of planned treatment. A total of 6602 patients were included in the analysis, with 4199 in Arm S and 2403 in Arm C. After propensity score matching, the final study population consisted of 2067 patients in each arm. Arm C showed statistically inferior 5-year overall survival (OS) and disease-free survival (DFS) rates compared to Arm S (84.0% vs. 90.0%; p < 0.0001; and 78.4% vs. 86.1%; p < 0.0001). Age (65 ≥ vs. < 65) and the incomplete planned treatment also had a significant negative effect on both OS and DFS. In the multivariable analysis, Arm C still showed worse OS (hazard ratio [HR], 1.609; 95% confidence intervals [CI], 1.339–1.934; p < 0.0001) and DFS (HR, 1.552; 95% CI 1.333–1.807; p < 0.0001) than Arm S. Both S-1 and CAPOX showed excellent efficacy, but this nationwide cohort study suggests that S-1 may be a better option in certain clinical situations.