Standard Adjuvant Chemotherapy Research Articles

Unfavorable Prognostic Impact of HER2 2+/FISH-Negativity in Older Patients with HER2-Negative and High-Risk Breast Cancer.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer, consisted of carcinomas with HER2 protein 1+ or 2+ without gene amplification, has been considered a biologically heterogeneous disease. Limited research separately investigated the prognostic significance of HER2 2+ without gene amplification, and no evidence can be identified in older patients. In this dedicated cohort of older patients with HER2-negative and high-risk breast cancer, we analyzed the real-world prognosis after standard adjuvant chemotherapy, and investigated the associations of survival with HER2 2+ without gene amplification. From January 2016 to December 2021, older patients (≥65 years) with breast cancer were reviewed, and HER2-negative/high-risk disease receiving standard adjuvant chemotherapy was included. HER2-negativity was defined as immunohistochemistry (IHC) score 0, 1+ or 2+ without gene amplification by fluorescent in situ hybridization (FISH). Cox proportional hazards regression analyses were performed to assess the associations of HER2 2+/FISH-negativity with disease-free survival (DFS), which was estimated by the Kaplan-Meier method and compared by the Log rank test. This cohort consisted of 121 consecutive older patients. With a median follow-up of 46 months, 12 patients had a DFS event. By univariate and multivariate analyses, HER2 2+/FISH-negativity was the only independent predictor for worse DFS (hazard ratio 5.56; P=0.046). Patients with HER2 2+/FISH-negativity had significantly poorer DFS compared with those with HER2 0 or 1+ (Log rank test, P=0.029). In both hormone receptor (HR)-positive (Log rank test, P=0.052) and HR-negative (Log rank test, P=0.125) subgroups, HER2 2+/FISH-negativity showed a marginally significant adverse influence on DFS. In older patients with HER2-negative/high-risk breast cancer undergoing standard adjuvant chemotherapy, our findings suggest that HER2 2+/FISH-negativity has an independent negative impact on prognosis.

Uterine carcinosarcoma: Unraveling the role of epithelial-to-mesenchymal transition in progression and therapeutic potential.

Uterine carcinosarcoma (UCS) is a rare and highly aggressive gynecological malignancy characterized by poor prognosis. Due to its rarity, UCS remains relatively unexplored, and specific treatment guidelines are scarce. Despite standard treatments, including surgery, adjuvant chemotherapy, and radiotherapy, UCS has a high recurrence rate and poor overall prognosis. The aggressive nature of UCS is attributed to the metaplastic transformation of carcinomatous elements into sarcoma. This "biphasic" neoplasm features a mixture of epithelial and mesenchymal/tumor components, which partially share molecular signatures and exhibit a typical epithelial-to-mesenchymal transition (EMT) gene expression profile. Recent scientific advancements have highlighted the pivotal role of EMT in UCS progression and mortality. This review covers the epidemiology of UCS, theories regarding its origin, and the current state of clinical trials with more emphasis on the role of EMT drivers in UCS progression and scope of targeting these molecules. By shedding light on the molecular mechanisms supporting UCS, particularly emphasizing the importance of EMT, we aim to provide a more comprehensive understanding of the disease to support the development of more effective therapeutic strategies.

Sustained lymphocyte decreases after treatment for early breast cancer

The role of adaptive immunity in long-term outcomes in early breast cancer is increasingly recognised. Standard (neo)adjuvant chemotherapy can have adverse effects on immune cells. We conducted a retrospective longitudinal study of full blood counts (FBC) of 200 patients receiving (neo)adjuvant chemotherapy for early breast cancer at a single institution. FBC results at four time points from pre-treatment to 12 months post-chemotherapy were analysed. Flow cytometry was performed for patients with matched pre- and post-chemotherapy peripheral blood mononuclear cell samples. A significant decrease in absolute lymphocyte count at 12 months post-chemotherapy was observed (p < 0.01), most pronounced in pre-menopausal patients (n = 73; p < 0.01), patients receiving dose-dense chemotherapy regimens (n = 60; p < 0.01) and patients receiving adjuvant radiotherapy (n = 147, p < 0.01). In pre-menopausal patients, significant changes in CD4+ T cells subsets post-chemotherapy were observed. Further investigation, including long-term clinical outcomes, is needed to meaningfully improve long-term anti-tumour immunity.

Tailored Dose-Dense Versus Standard Adjuvant Chemotherapy for High-Risk Early Breast Cancer: End-of-Study Results of the Randomized PANTHER Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Although dose-dense adjuvant chemotherapy administered once every 2 weeks leads to superior outcomes compared with standard regimens once every 3 weeks, the observed improvement is largely limited to studies using the suboptimal paclitaxel schedule once every 3 weeks as control. PANTHER is an international phase III trial which compared sequential epirubicin/cyclophosphamide and docetaxel administered either once every 2 or once every 3 weeks, with tailored dosing at the dose-dense schedule according to hematologic toxicity. In this end-of-study analysis, the median follow-up was 10.3 years. Compared with standard adjuvant chemotherapy, dose-dense treatment improved breast cancer recurrence-free survival (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.98]; P = .030), event-free survival (HR, 0.78 [95% CI, 0.65 to 0.94]; P = .009), and distant disease-free survival (HR, 0.79 [95% CI, 0.64 to 0.98]; P = .030) while the improvement in overall survival was not statistically significant (HR, 0.82 [95% CI, 0.65 to 1.04]; P = .109). To our knowledge, this is the first trial that confirms the benefit of a dose-dense regimen over a control regimen containing docetaxel once every 3 weeks.

Feasibility and predictive factors on the completion of docetaxel plus S‐1 adjuvant chemotherapy in pathological stage III gastric cancer

AbstractBackgroundThe standard adjuvant chemotherapy regimen for stage III gastric cancer is docetaxel plus S‐1 (DS) based on the results of the START‐II trials. However, in clinical practice some patients could not continue this intensive doublet chemotherapy because of limited tolerability. This study aimed to assess the practical feasibility of DS and elucidate the predictive factors for the completion of adjuvant DS therapy.MethodsData from consecutive patients who underwent radical gastrectomy between 2018 and 2021 and were diagnosed with histopathologically confirmed stage III gastric cancer were retrospectively collected. First, the completion rate and adverse effects of DS were assessed. Second, the association between DS incompletion and patient backgrounds including body weight, skeletal muscle index (SMI), and intramuscular adipose content (IMAC) were examined.ResultsOf 87 patients, 59 patients (67.8%) completed DS and dose reduction was required in 18 patients (20.6%). Neutropenia of grade 3 or higher was the most common hematological toxicity observed (17.2%). The most frequent nonhematological toxicity of grade 3 or higher was fatigue (6.9%), followed by diarrhea (5.7%), nausea (4.5%), and anorexia (4.5%). In a multivariate analysis, low SMI (p = 0.005) and high IMAC (p = 0.004) were significant risk factors for DS incompletion.ConclusionsDS adjuvant chemotherapy after radical gastrectomy for pathological stage III gastric cancer is acceptable, even in clinical practice, with respect to completion and toxicity. Additionally, the body composition factors such as SMI and IMAC might be useful in predicting incompletion of DS. These findings will help us to preoperatively select patients for DS.

Improved Survival With Adjuvant Cyclooxygenase 2 Inhibition in PIK3CA-Activated Stage III Colon Cancer: CALGB/SWOG 80702 (Alliance).

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Observational studies have associated aspirin or cyclooxygenase 2 (COX-2) inhibitor usage either before or after colorectal cancer diagnosis with lower risk of recurrence and suggest that PIK3CA mutational status is predictive of better response to COX-2 inhibition. To prospectively test whether adding the COX-2 inhibitor celecoxib to standard adjuvant chemotherapy reduces the risk of recurrence and improves survival, the National Cancer Institute sponsored the CALGB/SWOG 80702 trial (ClinicalTrials.gov identifier: NCT01150045) for patients with stage III resected colon cancer. Although the primary hypothesis for all patients did not show a statistically significant improvement in disease-free survival (DFS) with celecoxib, subgroup analysis by PIK3CA mutational status was a preplanned study. PIK3CA gain-of-function mutations were detected in 259 of 1,197 tumors with available whole-exome sequencing data. When stratified by PIK3CA status, patients with PIK3CA gain-of-function mutations treated with celecoxib exhibited improved DFS (adjusted hazard ratio [HR], 0.56 [95% CI, 0.33 to 0.96]) compared with PIK3CA wildtype patients (adjusted HR, 0.89 [95% CI, 0.70 to 1.14]), although the interaction test was nonsignificant (Pinteraction = .13). Overall survival was similarly improved for patients with PIK3CA gain-of-function mutations (adjusted HR, 0.44 [95% CI, 0.22 to 0.85]) compared with PIK3CA wildtype patients (adjusted HR, 0.94 [95% CI, 0.68 to 1.30]; Pinteraction = .04). Although the test for heterogeneity in DFS did not reach statistical significance, the results suggest potential utility of PIK3CA to consider selective usage of COX-2 inhibitors in addition to standard treatment for stage III colon cancer.

Epidemiological investigation of neuroendocrine differentiation in carcinomas: Focus on pancreatic and cholangiocarcinoma cohorts.

e16375 Background: Neuroendocrine differentiated (NED) occurs in various non-neuroendocrine organs and is associated with unique clinical profiles, disease progression, and poorer prognosis. However, global research on NED is scarce. To address this, our study utilized standardized detection methods to explore NED's prevalence in several solid tumors. This research aims to clarify NED pathological characteristics and prognostic significance, enhancing diagnostic and treatment approaches in clinical practice. Methods: Patients (18-75 years) with cancers including pancreatic, cholangiocarcinoma, gastric, colorectal, lung, breast, and prostate, were analyzed post-surgery at our hospital (January 2017- June 2018). Criteria for inclusion were normal organ function and no pre-surgery neoadjuvant therapy. Tumors were staged postoperatively using AJCC 8th criteria (stages I-III), followed by standard adjuvant chemotherapy. NED markers like Chromogranin A, Synaptophysin, and CD56 were detected in tumors via immunohistochemical staining. Results: Between January 2017 and June 2018, over 450 cases were enrolled. Initial analysis included 46 pancreatic cancer and 49 cholangiocarcinoma samples. NED markers were found in 11 (23.9%) of the pancreatic cancer patients, comprising 5 Syno (+), 10 ChrA (+), and 1 CD56 (+) cases. In cholangiocarcinoma patients, 12 (24.5%) expressed NED markers, including 4 Syno (+) and 11 ChrA (+) cases. Conclusions: This study reveals a significant occurrence of neuroendocrine differentiation in pancreatic cancer and cholangiocarcinoma. The notable prevalence of NED underscores its potential as a reference for tailoring clinical treatments. The association between NED and patient prognosis warrants further investigation.

Non-basal subtype defined by FOXC1 expression as an independent predictor of capecitabine efficacy in the triple negative breast cancer GEICAM/2003-11_CIBOMA/2004-01 trial.

516 Background: In a prespecified correlative analysis of the GEICAM/2003-11_CIBOMA/2004-01 phase III clinical trial (CIBOMA trial), PAM50 non-basal status identified triple-negative breast cancer (TNBC) patients (pts) most likely to benefit from adjuvant capecitabine (cap). FOXC1 cell plasticity/metastasis transcriptional driver assessment by standardized Veresca FOXC1 Immunohistochemistry (IHC) BC test (Veresca) has shown rigorous capacity to identify basal-like breast cancer (BLBC) subtype throughout TNBC cohorts. We sought to explore the concordance of BLBC identification by FOXC1 with PAM50 molecular subtyping and its prognostic/predictive value in the CIBOMA trial (NCT00130533). Methods: We analyzed FOXC1 expression (Veresca, Onconostic Technologies) and the Ki-67 Antigen MIB-1 (Dako) by IHC on tumors from 705 TNBC pts randomized to maintenance with cap (357, 51%) vs observation (obs) (348, 49%) after standard (neo)adjuvant chemotherapy (CT). Veresca score (VFOXC1) was defined as % of tumor cells with positive nuclear staining (Proportion Score 0-5) plus staining intensity (Intensity Score 0-3). BLBC subtyping by Veresca (cutoff ≥4) and PAM50 signature (Nanostring) were compared using ROC analysis and Kappa index (KI). Ki67 ≥20% cutoff was applied. Cox regression models were assessed to predict DRFS (primary endpoint), DFS and OS (secondary endpoints). Results: VFOXC1≥4 identified 460 (65%) BLBC pts in this CIBOMA trial cohort (229 (49.8%) treated with cap, and 231 (50.2%) in obs). VFOXC1 detection was not associated with any clinicopathological characteristic. VFOXC1 expression significantly correlated with PAM50 BLBC subtyping (ROC analysis AUC 0.874, KI 0.43) but moderately with IHC subtyping (AUC 0.548). VFOXC1 BLBC subtype was not associated with DRFS (HR=0.94; 95%CI 0.68-1.30; p=0.713) in the entire cohort. However, VFOXC1 non-BLBC subtype was a strong independent predictor of cap benefit for DRFS (univariate analysis, interaction p-value p=0.117; HR=0.53; 95%CI 0.31-0.90; p=0.019; multivariate analysis, HR=0.44; 95%CI 0.25–0.76; p=0.003). This predictive effect of VFOXC1 non-BLBC on cap benefit was also confirmed at DFS (HR=0.47; 95%CI 0.28–0.78; p=0.003) and OS (HR=0.48; 95%CI 0.24–0.96; p=0.038), and was independent of Ki67 proliferation status (multivariate DRFS; Ki67&lt;20%, HR=0.41; 95%CI 0.20-0.82; p=0.012; Ki67≥20%, HR=0.31; 95%CI 0.10-0.97; p=0.045). VFOXC1 non-BLBC subtype had no association with clinical outcome in obs arm. Conclusions: In the CIBOMA TNBC trial, the non-BLBC definition by a single biomarker (FOXC1 Veresca) provided prognostic and predictive value of cap benefit after (neo)adjuvant CT, corroborating our previous findings by PAM50 and IHC non-BLBC subtyping. This is a pragmatic option to effectively apply findings from this trial in the real-world setting. Clinical trial information: NCT00130533 .

Survival analysis in pT1-3 and paracolic lymph-node invasion colorectal cancer: the prognostic role of positive paracolic lymph-node ratio for adjuvant chemotherapy.

Several studies have observed that some stage III colorectal cancer (CRC) patients cannot benefit from standard adjuvant chemotherapy. However, there is no unified screening standard to date. Consecutive patients with pathologically confirmed colon adenocarcinoma treated in 3 centers between January 2016 and December 2018 were included. Patients were divided into four groups according to different stages and positive paracolic lymph-node ratio (P-LNR) [Cohort 1: pT1-3N0M0, Cohort 2: pT1-3N + (P-LNR ≤ 0.15)M0, Cohort 3: pT4N0M0, Cohort 4: stage III patients except for pT1-3N + (P-LNR ≤ 0.15)M0], and further overall survival was compared by Kaplan-Meier method. The univariate and multivariate analyses were employed for cox proportional hazards model. We retrospectively reviewed 5581 consecutive CRC patients with, and 2861 eligible patients were enrolled for further analysis. The optimal cut-off value of P-LNR in our study was 0.15. There was no significant difference in OS (91.36 vs. 93.74%) and DFS (87.65 vs. 90.96%) between stage III patients with pT1-3N + (P-LNR ≤ 0.15)M0 and those with pT1-3N0M0. Further analysis demonstrated that CRC patients with pT1-3N + (P-LNR ≤ 0.15)M0 were less likely to benefit from 8 cycles of CAPOX or FOLFOX chemotherapy and suffered fewer adverse events from declining chemotherapy. Comparing with 0-4 cycles versus 8 cycles, the overall survival rates were 91.35 versus 90.19% (P = 0.79), and with a DFS of 87.50 versus 88.24% (P = 0.49), the duration of adjuvant chemotherapy was not an independent risk factor for patients with pT1-3N + (P-LNR ≤ 0.15)M0 (HR: 0.70, 95% CI 0.90-1.30, P = 0.42). The concept of P-LNR we proposed might have a high clinical application value and accurately enable clinicians to screen out specific CRC patients who decline or prefer limited chemotherapy. The clinical trial registration number: ChiCTR2300076883.

Machine learning reveals diverse cell death patterns in lung adenocarcinoma prognosis and therapy

Cancer cell growth, metastasis, and drug resistance pose significant challenges in the management of lung adenocarcinoma (LUAD). However, there is a deficiency in optimal predictive models capable of accurately forecasting patient prognoses and guiding the selection of targeted treatments. Programmed cell death (PCD) pathways play a pivotal role in the development and progression of various cancers, offering potential as prognostic indicators and drug sensitivity markers for LUAD patients. The development and validation of predictive models were conducted by integrating 13 PCD patterns with comprehensive analysis of bulk RNA, single-cell RNA transcriptomics, and pertinent clinicopathological details derived from TCGA-LUAD and six GEO datasets. Utilizing the machine learning algorithms, we identified ten critical differentially expressed genes associated with PCD in LUAD, namely CHEK2, KRT18, RRM2, GAPDH, MMP1, CHRNA5, TMPRSS4, ITGB4, CD79A, and CTLA4. Subsequently, we conducted a programmed cell death index (PCDI) based on these genes across the aforementioned cohorts and integrated this index with relevant clinical features to develop several prognostic nomograms. Furthermore, we observed a significant correlation between the PCDI and immune features in LUAD, including immune cell infiltration and the expression of immune checkpoint molecules. Additionally, we found that patients with a high PCDI score may exhibit resistance to immunotherapy and standard adjuvant chemotherapy regimens; however, they may benefit from other FDA-supported drugs such as docetaxel and dasatinib. In conclusion, the PCDI holds potential as a prognostic signature and can facilitate personalized treatment for LUAD patients.

Prediction of Benefit From Adjuvant Pertuzumab by 80-Gene Signature in the APHINITY (BIG 4-11) Trial.

At the primary analysis, the APHINITY trial reported a statistically significant but modest benefit of adding pertuzumab to standard adjuvant chemotherapy plus trastuzumab in patients with histologically confirmed human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer. This study evaluated whether the 80-gene molecular subtyping signature (80-GS) could identify patients within the APHINITY population who derive the most benefit from dual anti-HER2 therapy. In a nested case-control study design of 1,023 patients (matched event to control ratio of 3:1), the 80-GS classified breast tumors into functional luminal type, HER2 type, or basal type. Additionally, 80-GS distinguished tumor subtypes that exhibited a single-dominant functional pathway versus tumors with multiple activated pathways. The primary end point was invasive disease-free survival (IDFS). Hazard ratios (HRs) were evaluated by Cox regression. After excluding patients without appropriate consent and those with missing data, 964 patients were included. The 80-GS classified 50% (n = 479) of tumors as luminal type, 28% (n = 275) as HER2 type, and 22% (n = 209) as basal type. Most luminal-type tumors (86%) displayed a single-activated pathway, whereas 49% of HER2-type and 42% of basal-type tumors were dual activated. There was no significant difference in IDFS among different conventional 80-GS subtypes (single- and dual-activated subtypes combined). However, basal single-subtype tumors were significantly more likely to have an IDFS event (hazard ratio, 1.69 [95% CI, 1.12 to 2.54]) compared with other subtypes. HER2 single-subtype tumors displayed a trend toward greater beneficial effect on the addition of pertuzumab (hazard ratio, 0.56 [95% CI, 0.27 to 1.16]) compared with all other subtypes. The 80-GS identified subgroups of histologically confirmed HER2-positive tumors with distinct biological characteristics. Basal single-subtype tumors exhibit an inferior prognosis compared with other subgroups and may be candidates for additional therapeutic strategies. Preliminary results suggest patients with HER2-positive, genomically HER2 single-subtype tumors may particularly benefit from added pertuzumab, which warrants further investigation.

Multiplexed high-throughput immune cell imaging in patients with high-risk triple negative early breast cancer: Analysis from the International Breast Cancer Study Group (IBCSG) Trial 22-00

BackgroundTriple-negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype, with dismal prognosis and limited option in advanced settings, yet stromal tumor infiltrating lymphocytes (sTILs) in this subtype has a predictive role. Patients and methods: The International Breast Cancer Study Group (IBCSG) Trial 22–00 is a randomized phase III clinical trial testing the efficacy of low-dose metronomic oral Cyclophosphamide-Methotrexate (CM) maintenance following standard adjuvant chemotherapy treatment for early-stage hormone receptor-negative breast cancer patients. A case-cohort sampling was used. We characterized immune cells infiltrates in patients with TNBC by 6 plex immunofluorescence (IF) staining for CD4, FOXP3, CD3, cytokeratine and CD8 ResultsWe confirmed that high immune CD3+ T cells as well as stromal and intra-epithelial Tregs (CD4+Foxp3+ T cells) infiltrates were associated with a better Distant Recurrence-Free Interval (DRFI), especially in LN+ patient, regardless of the treatment. More importantly, we showed that the spatial distribution of immune cells at baseline is crucial, as CM maintenance was detrimental for T cells excluded LN+ TNBC patients. Conclusionsimmune spatial classification on immune cells infiltrates seems crucial and could help patients’ selection in clinical trial and greatly improve responses to specific therapies.

Influence of MRI Follow-Up on Treatment Decisions during Standard Concomitant and Adjuvant Chemotherapy in Patients with Glioblastoma: Is Less More?

MRI is the gold standard for treatment response assessments for glioblastoma. However, there is no consensus regarding the optimal interval for MRI follow-up during standard treatment. Moreover, a reliable assessment of treatment response is hindered by the occurrence of pseudoprogression. It is unknown if a radiological follow-up strategy at 2-3 month intervals actually benefits patients and how it influences clinical decision making about the continuation or discontinuation of treatment. This study assessed the consequences of scheduled follow-up scans post-chemoradiotherapy (post-CCRT), after three cycles of adjuvant chemotherapy [TMZ3/6], and after the completion of treatment [TMZ6/6]), and of unscheduled scans on treatment decisions during standard concomitant and adjuvant treatment in glioblastoma patients. Additionally, we evaluated how often follow-up scans resulted in diagnostic uncertainty (tumor progression versus pseudoprogression), and whether perfusion MRI improved clinical decision making. Scheduled follow-up scans during standard treatment in glioblastoma patients rarely resulted in an early termination of treatment (2.3% post-CCRT, 3.2% TMZ3/6, and 7.8% TMZ6/6), but introduced diagnostic uncertainty in 27.7% of cases. Unscheduled scans resulted in more major treatment consequences (30%; p < 0.001). Perfusion MRI caused less diagnostic uncertainty (p = 0.021) but did not influence treatment consequences (p = 0.871). This study does not support the current pragmatic follow-up strategy and suggests a more tailored follow-up approach.

P11.60.A RACTAC TRIAL: PHASE II MULTICENTRIC ITALIAN TRIAL ON REPOSITIONING OF THE ANTIPSYCHOTIC DRUG CHLORPROMAZINE AND ITS COMBINATION WITH TEMOZOLOMIDE IN MGMT UNMETHYLATED GLIOBLASTOMA PATIENTS

Abstract BACKGROUND The poor prognosis of patients affected by glioblastoma (GBM) prompts the search for new and more effective therapies, particularly for GBMs with unmethylated MGMT. In this regard, drug repurposing, can represent a safe and inexpensive way to bring novel pharmacological approaches from bench to bedside. Chlorpromazine, a medication in use since six decades for the therapy of psychiatric disorders, shows in vitro features that make it eligible for repositioning in GBM therapy. In our experimentation on six GBM cell lines, chlorpromazine inhibited cell viability in an apoptosis-independent way, induced polyploidy, reduced cloning efficiency as well as neurosphere formation and downregulated the expression of stemness genes. Notably, we found that chlorpromazine synergized with temozolomide, in reducing cell viability and strongly cooperated in reducing cloning efficiency and inducing cell death in vitro for all the GBM cell lines assayed. MATERIAL AND METHODS With these assumptions, we started a multicentric Phase II clinical trial on newly diagnosed GBM patients with unmethylated MGMT by adding chlorpromazine to temozolomide in the adjuvant phase of the standard first-line therapeutic protocol. The experimental procedure involves the combination of CPZ with standard treatment with TMZ in the adjuvant phase of the Stupp protocol. CPZ was administered orally at a dose of 50 mg/day - GG 1-28 - of every cycle of the adjuvant treatment with TMZ. . Efficacy outcomes were evaluated using Kaplan-Meier methodology. OS was measured from diagnosis to death; PFS was determined from radiotherapy to the first sign of PD or death due to any cause. RESULTS The trial was closed on December 2022. 53 patients have been enrolled, 39 male, 14 female. 21 patients completed 6 cycles of treatment, without relevant toxicity.The results shows a median PFS of 7 months (St.Dev. 5,7) and a median OS of 15 months (St.Dev. 6,9). 23 patients are still alive (43%) CONCLUSION The addition of Chlorpromazine to the standard adjuvant chemotherapy with temozolomide was well tolerated in newly diagnosed Glioblastoma unmethylated patients, with promising impact on outcome measures. On the basis of the RACTAC trial RESULTS , a phase II multicentric trial evaluating Chlorpromazine added to standard treatment (RT+TMZ+adj TMZx 6 cycles plus CPZ) in newly diagnosed Glioblastoma patients is in preparation

Coq10 for preventing cardiotoxicity in breast cancer patients treated with trastuzumab.

Trastuzumab is a successful treatment option for HER2-positive breast cancer, but a decline in left ventricular ejection fraction (LVEF) and an increase in inflammatory and cardiac enzyme biomarkers can lead to cessation and termination of therapy. This study aimed to investigate the ability of Coenzyme Q10 (Coq10) to avoid these adverse effects. The study included 100 female patients with HER2+ (HER2+3 or amplified gene) breast cancer. All patients underwent standard adjuvant chemotherapy regimens, which involved a four-cycle treatment of Adriamycin, Cyclophosphamide, Docetaxel, and an initial 8 mg/kg loading dose of trastuzumab, followed by a year of 6 mg/kg maintenance doses every three weeks. One group of 50 patients received trastuzumab and a placebo, while the other 50 were given trastuzumab and CoQ10 for a full year. The CoQ10-treated group exhibited a statistically significant decrease in levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL6), soluble toll-like receptor 4 (sTLR4), and cardiac troponin I (cTnI) compared to the control group (p<0.05). However, there was no significant difference in the mean F2-isoprostane levels between the treated and the control groups at any data collection point. Furthermore, the CoQ10-treated group experienced a significant reduction in the decline of EF levels compared to the control group at all stages except for baseline. According to our findings, Coenzyme Q10 protected patients with HER2+3 breast cancer from the cardiotoxicity of trastuzumab by increasing ejection fraction and decreasing inflammatory biomarkers and cardiac enzyme levels.

Neoadjuvant Versus Adjuvant Systemic Therapy for Early-Stage Non-Small Cell Lung Cancer: The Changing Landscape Due to Immunotherapy.

Non-small cell lung cancer (NSCLC) remains a major cause of morbidity and mortality worldwide. One-third of NSCLC patients present with surgically resectable, non-metastatic disease; however, many of these patients will recur despite curative surgery and adjuvant therapy. The recent publication of randomized trials incorporating immune check-point inhibitors (ICI) to the standard neo-adjuvant and adjuvant treatment regimens has reported improved survival with manageable toxicity profiles. The IMpower 010 studied the use of adjuvant atezolizumab after standard surgery and adjuvant chemotherapy. They demonstrated an improvement in 3-year disease-free survival (DFS) prompting a change in treatment guidelines. The Checkmate 816 and NADIM II studies evaluated the addition of pembrolizumab and nivolumab, respectively, to standard neo-adjuvant chemotherapy. The results from both trials showed an improvement in 2-year event-free survival (EFS) and 2-year PFS (PFS), respectively. In this review, we summarize the prior data regarding adjuvant and neo-adjuvant chemotherapy in NSCLC and elaborate on results from the newer trials incorporating ICIs. We briefly discuss the pros and cons of each treatment approach along with areas that need further clarity to inform clinical practice and future directions for research in this disease.

ATTRACTION-5: A phase 3 study of nivolumab plus chemotherapy as postoperative adjuvant treatment for pathological stage III (pStage III) gastric or gastroesophageal junction (G/GEJ) cancer.

4000 Background: Nivolumab plus chemotherapy (N+C) in the first-line treatment and nivolumab monotherapy in the third- or later-line have shown survival benefit in patients with unresectable advanced or recurrent G/GEJ cancer. Adjuvant chemotherapy after D2 or more extended gastrectomy is a widely used standard of care for pStage III G/GEJ cancer in Asia. However, standard adjuvant chemotherapy has shown limited efficacy for pStage III G/GEJ cancer. ATTRACTION-5 is the first phase 3 study to evaluate an immune checkpoint inhibitor in combination with adjuvant chemotherapy for pStage III G/GEJ cancer. Here, we report the first confirmatory results of N+C as postoperative adjuvant treatment. Methods: The ATTRACTION-5 study is a multicenter, double-blind, randomized study conducted in Japan, Korea, Taiwan, and China. We enrolled patients with pStage III G/GEJ cancer who had undergone D2 or more extended gastrectomy. Investigators selected an appropriate adjuvant chemotherapy (tegafur/gimeracil/oteracil [S-1] therapy or capecitabine plus oxaliplatin [CapeOX] therapy) for each patient, and thereafter patients were randomly assigned (1:1) to the N+C or placebo plus chemotherapy (P+C) arm, using the allocation factors of country and disease stage. The primary endpoint was centrally-assessed relapse-free survival (RFS). The sample size was calculated, based on the results of the ACTS-GC study and the CLASSIC study (The assumed hazard ratio [HR], 0.67; the assumed 3-year RFS, 71% vs 60%). Secondary endpoints were investigator-assessed RFS, overall survival (OS), and 3-year RFS and OS rates. Results: A total of 755 patients underwent randomization from February 2017 to August 2019: 377 were assigned to the N+C arm and 378 to the P+C arm. The final analysis of RFS was performed based on the clinical data cutoff of August 2022, with the minimum follow-up of 36 months after the last patient was randomized. The primary efficacy endpoint of centrally-assessed RFS was not met (HR, 0.90; 95.72% CI, 0.69–1.18; P=0.4363), with the 3-year RFS rates of 68.4% (95% CI, 63.0–73.2) in the N+C arm and 65.3% (95% CI, 59.9–70.2) in the P+C arm. The completion rate of the planned postoperative adjuvant treatment was 61.5% in the N+C arm and 71.4% in the P+C arm. Incidences of grade≥3 TRAEs, serious TRAEs, and TRAEs leading to discontinuation were 54.4%, 25.3%, and 9.2%, respectively, in the N+C arm and 46.8%, 10.7%, and 3.5% in the P+C arm. Conclusions: The ATTRACTION-5 study of N+C vs P+C in patients with pStage III G/GEJ cancer after D2 or more extended gastrectomy did not meet the primary endpoint of RFS. The safety profile in the ATTRACTION-5 study was consistent with its known safety profile. Clinical trial information: NCT03006705 .

PACE: A phase III trial of CAPOX versus anti-PD-1 inhibitor as adjuvant therapy for patients with dMMR/MSI-H stage III colon cancer.

TPS3637 Background: Approximately 12% of stage III colon cancer are deficient mismatch repair (dMMR), leading to high levels of microsatellite instability (MSI-H). In the KEYNOTE-177 study, the anti–PD-1 inhibitor Pembrolizumab alone significantly improved progression free survival (PFS) versus chemotherapy as first-line therapy for metastatic colorectal cancer (mCRC) patients with MSI-H/dMMR. We are conducting a phase III randomised trial to determine whether anti-PD-1 inhibitor Sintilimab monotherapy can improve disease free survival (DFS) compared with standard adjuvant chemotherapy in stage III colon cancer patients with dMMR. Methods: This is an open-label, multicentre, randomised phase III study. Patients aged ≥ 18 years with completely resected, stage III colon cancer confirmed to have dMMR/MSI-H and ECOG performance status 0-1 are eligible. Approximately 323 patients will be randomly assigned 1:1 to either Sintilimab monotherapy (200 mg IV every 3 weeks for 8 cycles) or CAPOX regimen (capecitabine, oxaliplatin for 4 or 8 cycles according to current standard practice). Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Primary endpoint is 3-year DFS. The study was estimated to provide approximately 80% power to detect a hazard ratio of 0.56 for DFS at a two-sided alpha of 0.05. Secondary endpoints include OS, safety profile, toxicity, and quality of life. Archived tumor tissue and blood samples will be collected for correlative studies. Study enrollment is ongoing. Clinical trial information: NCT05236972 .

Targeting minimal residual disease (MRD) in resected RAS mutated pancreatic cancer with vaccine TG01/QS-21 +/- PD-1 inhibitor, balstilimab: A randomized phase II study (TESLA).

TPS4205 Background: MRD detected by presence of circulating tumor DNA (ctDNA) after intended curative treatment is associated with high risk of relapse in pancreatic cancer. Early treatment of patients with presence of ctDNA after completion of surgery +/- adjuvant therapy may offer an opportunity to clear ctDNA and improve outcomes. TG01 is a RAS-neoantigen peptide vaccine adjuvanted by QS-21 (Stimulon) targeting the seven most frequent codon 12-13 RAS mutations. TG01 has previously demonstrated ability to activate mutant RAS specific CD4+ and CD8+ T-cell responses in vaccinated patients and repeated TG01 dosing in resected pancreatic cancer was found to be well tolerated and associated with a median OS of 33.4 months (95% CI 24.0, 45.8)1,2. Checkpoint inhibitors as single agents have not shown anti-tumor activity in pancreatic cancer, suggesting that a priming agent inducing tumor-specific T-cells may be required to support efficacy. Balstilimab is a human monoclonal antibody targeting programmed cell death protein 1 (PD-1) which is intended to reverse the immunosuppressive effects of this signaling pathway in the context of tumor immuno-surveillance by T-cells. Methods: Design: A two-arm, open-label, phase II randomized trial of TG01/QS-21 vaccine or TG01/QS-21 vaccine plus balstilimab (n=12 per arm, N=24) with surgically resected Stage 1-3 RAS mutant PDAC who are MRD+ following completion of standard adjuvant chemotherapy. Assay: MRD is detected by a commercially available ctDNA assay (Signatera, Natera). Somatic variants are identified by whole–exome sequencing of the primary tumor and the matched normal (whole blood) sample and a bespoke assay of up to 16 clonal, somatic variants are generated for each patient. This “tumor signature” will be monitored in plasma throughout the study. Treatment schedule: A priming phase of six vaccine administrations once every two weeks followed by a maintenance phase of administrations once every 8 weeks for up to 51 weeks. Balstilimab will be administered every 2 weeks for up to 51 weeks beginning at week 3. Imaging assessment will be done every 12 weeks. Eligibility: Surgically resected pancreatic adenocarcinoma with pathogenic RAS mutation, and no evidence of recurrent disease on baseline imaging. Inclusion criteria also include ECOG PS 0-1, and positive Signatera ctDNA MRD. Objectives: The primary objective is to assess the 6-month molecular disease control rate as defined by ctDNA stable, decreased or cleared. Secondary objectives include safety of TG01/QS-21 with or without balstilimab, 6 and 12-month DFS rate in each cohort, as well as correlation between the depth of molecular response and DFS. Exploratory: changes in clonality of RAS mutations and assess immune response. Enrollment is ongoing. 1) Gjertsen MK et al. Int J Cancer 1997, 72(5) 784-90. 2) Palmer DH et al. Br J Cancer 2020 122:971-77. Clinical trial information: NCT05638698 .

Current progress in perioperative chemotherapy for biliary tract cancer.

Biliary tract cancer (BTCs) is a heterogeneous malignancy divided into cholangiocarcinoma, gallbladder cancer, and ampullary cancer. Due to little or no symptoms, most patients with BTCs are diagnosed with unresectable or metastatic disease. Only 20%-30% of all BTCs are suitable for potentially resectable diseases. Although radical resection with a negative surgical margin is the only potentially curative method for BTCs, most patients develop postoperative recurrence, which is associated with poor prognosis. Therefore, perioperative treatment is necessary to improve survival. There are very few randomized phase III clinical trials of perioperative chemotherapy due to the relative rarity of BTCs. Adjuvant chemotherapy with S-1 for patients with resected BTC significantly increased overall survival compared with upfront surgery in a recent ASCOT trial. In East Asia, S-1 is currently considered the standard adjuvant chemotherapy, while capecitabine may still be used in other areas. Since then, our phase III trial (KHBO1401), gemcitabine and cisplatin plus S-1 (GCS) has become the standard chemotherapy for advanced BTCs. GCS not only improved overall survival but demonstrated a high response rate. The efficacy of GCS as a preoperative neoadjuvant chemotherapy for resectable BTCs has been investigated in a randomized phase III trial (JCOG1920) in Japan. In this review, we summarize the current and ongoing clinical trials focusing on adjuvant and neoadjuvant chemotherapy for BTCs.