Disease-free Survival In Subgroups Research Articles

Prognosis influence of additional chromosome abnormalities in newly diagnosed acute promyelocytic leukemia with t(15;17)(q24;q21)

ABSTRACT Objectives In patients with acute promyelocytic leukemia (APL), additional chromosomal abnormalities (ACAs) are prognostic indicators. However, the clinical features of ACAs were not systematically reported in Chinese patients. Therefore, we enrolled a large cohort of APLs to demonstrate the clinical characteristics and prognostic value of ACAs. Methods 268 patients with newly diagnosed APL with t(15;17)(q24;q21) were retrospectively enrolled, and their clinical characteristics and the predictive value of ACAs were assessed between patients with the presence and absence of ACAs. Results APL patients with and without ACAs did not differ significantly in their clinical features or treatment response and clinical outcomes like overall survival (OS) and disease-free survival (DFS). It appeared to be substantially associated with worse OS in APL patients with trisomy 8, which was the most common ACA, although DFS was unaffected. Interestingly, the presence of ACAs or trisomy 8 affected OS and DFS in the subgroup of patients aged ≥60 years; by contrast, ACAs had no effect on OS or DFS in any treatment subgroup (ATRA + ATO/RIF or ATRA + ATO/RIF + CH or ATRA + CH), except for the ATRA + ATO/RIF + CH treatment subgroup, where their impact on DFS was less favorable. Conclusions Our results suggested that OS and DFS were unaffected by ACAs. Nonetheless, in the subgroup of patients older than 60, the existence of ACAs or trisomy 8 appeared to impact OS and DFS negatively. Individuals with t(15;17) alone had a higher DFS and were more susceptible to ATRA + ATO/RIF + CH than individuals with t(15;17) ACAs.

Identification of Characteristics and Prognostic Impact of FUS-ERG and AML1-MTG16 Fusion Genes in Adult AML Patients

Background FUS-ERG and AML1-MTG16 are two rare fusion genes in acute myeloid leukemia (AML), characterized by similar karyotypic abnormalities, namely t(16;21)(p11;q22) and t(16;21)(q24;q22), respectively. A previous research has demonstrated that FUS-ERG represents a high-risk subtype associated with an extremely poor prognosis, while AML1-MTG16 has favorable outcomes in pediatric cohort. Despite this valuable insight, a comprehensive systematic review of these fusion genes in the adult population remains absent. Method In this study, we conducted an extensive collection of AML patients with FUS-ERG or AML1-MTG16 fusion genes, who were reported in Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer, PubMed and China national knowledge infrastructure (CNKI) from 1988 to 2023. Patients lacking detailed survival data or those who did not receive treatment were excluded. Additionally, patients diagnosed and treated in our institution between 2018 and 2023 were included if they were identified as carrying FUS-ERG or AML1-MTG16 fusion genes. The reference cohort comprised of 669 adult AML patients (excluding the t(16;21) cases and acute promyelocytic leukemia) admitted to our institution from 2016 to 2021. All patients within the cohort were classified into 3 categories based on the 2022 ELN genetic risk classification, namely favorable (F), intermediate (I) and adverse (A) risk. These patients were then compared with the FUS-ERG and AML1-MTG16 groups to explore their respective clinical features and prognosis. Results A total of 800 patients were included for analysis (Table 1). Patients with FUS-ERG (n=111) exhibited significant distinctions, including a younger onset age (34 years vs. 59 years), lower platelet count (30×10 9/L vs. 51×10 9/L), higher bone marrow blasts proportion (80.0% vs. 60.0%), a higher relapse rate (78.6% vs. 44.7%) and a higher incidence of trisomy 8 (16.4% vs. 9.0%), trisomy 10 (9.1% vs. 0.3%) and complex karyotype (37.8% vs. 11.6%), when compared to the reference cohort (p<0.01). Meanwhile, patients with AML1-MTG16 (n=20) primarily presented as the secondary AML (70.0%), and displayed a higher prevalence of trisomy 8 (40.0%) and complex karyotype (35.0%) than reference cohort (p<0.01). The FUS-ERG patients had a less median overall survival (OS) when compared to the reference cohort (13 vs. 35 months, p<0.001). The median OS in subgroups with ELN 2022 F-risk vs. ELN 2022 I-risk vs. FUS-ERG was not reached (NR) vs. 33.6 months vs. 13.0 months (p<0.001) and the median OS of FUS-ERG group was even inferior to ELN 2022 A-risk group (13.0 vs. 16.8 months, p=0.015). Furthermore, the FUS-ERG patients also displayed a less median disease-free survival (DFS) than the reference cohort (7.5 vs. 20.5 months, p<0.001). The median DFS in subgroups with F-risk vs. I-risk vs. A-risk vs. FUS-ERG was NR vs. 19.8 vs. 13.3 vs. 7.5 months (p<0.001). In contrast, patients with AML1-MTG16 had a median OS of 18.7 months and a median DFS of 16 months, presenting a relatively unfavorable OS trend and indistinctive DFS, when compared to the reference cohort (OS: p=0.083, DFS: p=0.612), F-risk (OS: p<0.001, DFS: p=0.128), I-risk (OS: p=0.162, DFS: p=0.835) and A-risk (OS: p=0.877, DFS: p=0.731). Moreover, the AML1-MTG16 group had a better DFS than the FUS-ERG group (14.0 vs. 7.5 months, p=0.016), but their OS was comparable (16.0 vs. 7.5 months, p=0.219). For adult patients with FUS-ERG (Table 2) multivariate analysis revealed that age >60 years (HR=2.96, 95%CI: 1.14-7.73, p=0.026), WBC >100×10 9/L (HR=2.98, 95%CI: 1.24-7.13, p=0.014) and the presence of monosomy (HR=2.61, 95%CI: 1.21-5.66, p=0.015) were independent risk factors for OS, while monosomy was associated with poor DFS (HR=3.72, 95%CI: 1.69-8.20, p=0.001). However, receiving HSCT could significantly improve both OS (HR=0.22, 95%CI: 0.11-0.42, p<0.001) and DFS (HR=0.31, 95%CI: 0.16-0.57, p<0.001). Pediatric FUS-ERG patients presented similar clinical features, exhibiting a better median OS (19.5 vs.13 months, p=0.014) and a comparable median DFS (9.5 vs. 7.5 months, p=0.496), when compared to the adult population. Conclusion Both FUS-ERG and AML1-MTG16 were identified as high-risk subgroups in adult AML anddiffered from the results in pediatric cohort. Several factors including age, WBC count, HSCT and monosomy influenced the prognosis of adult AML patients with FUS-ERG.

IMpower010: Exploratory analysis of disease-free survival by KRAS status in patients with stage II-IIIA NSCLC treated with adjuvant atezolizumab vs best supportive care.

8522 Background: The Phase III IMpower010 trial (NCT02486718) met its primary disease-free survival (DFS) endpoint leading to approval of atezolizumab after adjuvant platinum-based chemotherapy for completely resected PD-L1 TC ≥1% or ≥50% stage II-IIIA NSCLC in the US, EU and other regions. Mutant KRAS (mKRAS) is the most prevalent oncogenic driver in metastatic NSCLC (27% mKRAS [KRAS G12C,11%]; Osta et al, J Thorac Oncol 2019). Here, we report exploratory DFS outcomes by KRAS mutational status in patients from IMpower010. Methods: The study design and primary results of IMpower010 have been reported (Felip et al, Lancet 2021). After complete resection, patients received cisplatin-based doublet chemotherapy (1-4 21-day cycles) and were subsequently randomized to receive atezolizumab 1200 mg q3w (16 cycles) or best supportive care (BSC). This post hoc analysis evaluated DFS in subgroups of patients by KRAS mutational status. KRAS mutational status was assessed retrospectively using whole-exome sequencing (WES) on resected tumor tissue. Analyses were conducted in patients whose tumors harbored any mKRAS type, including G12C. A separate analysis of the KRAS G12C subgroup was not conducted due to limited patient numbers. Results: Of the 1005 patients in the intention-to-treat population (all randomized patients with stage IB-IIIA NSCLC), 603 comprised the WES biomarker-evaluable population (WES-BEP), and of these, 536 had stage II-IIIA NSCLC. Within the stage II-IIIA WES-BEP, the prevalence of mKRAS and KRAS G12C was 22% (n=118) and 10% (n=52), respectively. mKRAS was enriched in White, non-squamous and smoker populations. Atezolizumab showed DFS improvement vs BSC regardless of KRAS status in the stage II-IIIA WES-BEP (Table). In the mKRAS stage II-IIIA WES-BEP, atezolizumab showed DFS improvement vs BSC regardless of PD-L1 status. Conclusions: In IMpower010, the prevalence of mKRAS and KRAS G12C was similar to that seen in metastatic NSCLC. Despite limited patient numbers in this exploratory analysis, DFS appeared to be consistent and in favor of atezolizumab across subgroups regardless of KRAS status. Clinical trial information: NCT02486718 . [Table: see text]

Polymorphisms in AURKA and AURKB are associated with the survival of triple-negative breast cancer patients treated with taxane-based adjuvant chemotherapy.

PurposeTriple-negative breast cancer (TNBC) is more than a single disease. Identifying biomarkers to further subdivide TNBC patients with distinct outcome is of great importance. It has been reported that single-nucleotide polymorphisms (SNPs) in Aurora kinase A (AURKA) or Aurora kinase B (AURKB) are associated with the risk and survival of several cancers. But till now, there is no research about these polymorphisms in TNBC patients.Materials and methodsIn this study, we investigated the association between polymorphisms in AURKA or AURKB gene and prognosis of TNBC patients treated with taxane-based adjuvant chemotherapy. A total of 273 TNBC patients were enrolled. Haploview 4.2 software was used to identify Tag SNPs. Genotyping was conducted using the MassARRAY MALDI-TOF system.ResultsWe found that AURKA rs6099128 GG genotype carriers had significantly worse overall survival (OS) than TT+ TG genotype carriers (P = 0.003, HR = 12.499, 95% CI = 2.357–66.298). AURKB rs11651993 TT genotype carriers had better disease-free survival (DFS) than TC + CC genotype carriers (P = 0.018, HR = 1.876, 95% CI = 1.116–3.154). AURKB rs2289590 CC genotype carriers had worse DFS than CA + AA genotype carriers (P = 0.021, HR = 0.536, 95% CI = 0.315–0.912). After subgroup analysis, rs11651993 TC + CC genotype predicted worse DFS in subgroups of age ≤ 50, post-menopausal, grade unknown (UK), tumor size >2 cm, and lymph node negative. Rs2289590 CA + AA genotype could predict favorable DFS in pre-menopausal, grade 3 and lymph node-positive patients.ConclusionWe first demonstrated that polymorphisms in AURKA or AURKB gene might predict the OS or DFS of TNBC patients treated with taxane-based adjuvant chemotherapy.

Meta-analysis of prognostic value of inflammation parameter in breast cancer.

Recently, increasing studies investigated the association between inflammation parameter such as neutrophil to lymphocyte ratio (NLR) and the prognosis of cancers. However, the clinical and prognostic significance of NLR in breast cancer remains controversial. This meta-analysis was conducted to establish the overall accuracy of the NLR test in the diagnosis of breast cancer. A comprehensive search of the literature was conducted using PubMed and Web of Science. Six studies dating up to July 2014 with 2267 patients were enrolled in the present study. STATA 11.0 software (STATA Corporation, College Station, TX, USA) was selected for data analysis. In order to evaluate the association between NLR and overall survival (OS), disease-free survival (DFS), recurrence-free survival or cancer-specific survival, the hazard ratios (HRs), and their 95% confidence intervals (CIs) were extracted. Subgroup analyses showed that NLR was a strong prognostic factor for OS in multivariate analysis (HR = 2.81, 95% CI = 2.13-3.71, PH = 0.992) and without metastasis (HR = 1.45, 95% CI = 0.37-5.66, PH < 0.001). Elevated NLR was associated with a high risk for DFS in subgroups of multivariate analysis (HR = 2.16, 95% CI = 1.67-2.80, PH = 0.977) and mixed metastasis (HR = 2.13, 95% CI = 1.38-3.30, PH = 0.84). In summary, NLR may be considered as a predictive factor for patients with breast cancer.

Radiofrequency ablation versus hepatic resection as an initial treatment for solitary small-sized hepatocellular carcinoma.

290 Background: Nowadays Radiofrequency ablation (RFA) is a popular method and demonstrates favorable results for the treatment of small-sized hepatocellular carcinoma (HCC). However, whether RFA is as effective as hepatic resection (HR) for long-term outcomes remains controversial. The aim of this study is to compare HR and RFA with regard to survival and recurrence for the establishment of treatment strategy of small-sized HCC. Methods: A total of 183 patients with solitary small-sized (≤3cm) HCC were enrolled in this study: 101 patients underwent HR and 82 underwent RFA as an initial treatment. Overall survival (OS) and disease-free survival (DFS) were compared between the two groups and in subgroup analyses. Results: Patients who underwent RFA had less platelet count (HR: 15.3±7.0, RFA: 9.8±3.6, P&lt;0.01), and more advancer Child-Pugh class (A/B = HR: 97/4, RFA: 61/22, P&lt;0.01). The 5-year OS and DFS were significantly higher in the HR group compared with the RFA group (OS: 90% vs 59%, P&lt;0.01, DFS: 45% vs 27%, P&lt;0.01, respectively). In multivariate analyses, treatment modality (HR or RFA) and gender were indipendent predicting factors for DFS (RR: 1.85, P=0.05, and RR: 2.15, P=0.01, respectively). In subgroup analyses of HCC &lt;2cm, there was no significant difference in OS and DFS between the two group (5-year OS: 90% vs 74%, P=0.40, 5-year DFS: 43% vs 28%, P=0.24, respectively), despite the differences in liver functional reserve. However, HR was superior to RFA for OS and DFS in subgroup ≥2cm (5-year OS: 85% vs 32%, P&lt;0.01, 5-year DFS: 40% vs 23%, P&lt;0.01). In the subgroup analyses treated by RFA, GPT &gt;35mIU/ml and tumor ≥2cm were significant predicting factors for DFS (RR: 2.34, P=0.01, and RR: 2.09, P=0.02, respectively). For OS, tumor ≥2cm was the only prognostic factor (RR: 2.9, P=0.04). Conclusions: RFA might be as effective as HR for the treatment of solitary HCC &lt;2cm. However, in the patients with HCC ≥2cm, HR provides a better OS and DFS than RFA.

Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial

BackgroundTrastuzumab (Herceptin®) improves disease-free survival (DFS) and overall survival for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess the magnitude of its clinical benefit for subpopulations defined by nodal and steroid hormone receptor status using data from the Herceptin Adjuvant (HERA) study. Patients and methodsHERA is an international multicenter randomized trial comparing 1 or 2 years of trastuzumab treatment with observation after standard chemotherapy in women with HER2-positive breast cancer. In total, 1703 women randomized to 1-year trastuzumab and 1698 women randomized to observation were included in these analyses. Median follow-up was 23.5 months. The primary endpoint was DFS. ResultsThe overall hazard ratio (HR) for trastuzumab versus observation was 0.64 [95% confidence interval (CI) 0.54–0.76; P < 0.0001], ranging from 0.46 to 0.82 for subgroups. Estimated improvement in 3-year DFS in subgroups ranged from +11.3% to +0.6%. Patients with the best prognosis (those with node-negative disease and tumors 1.1–2.0 cm) had benefit similar to the overall cohort (HR 0.53, 95% CI 0.26–1.07; 3-year DFS improvement +4.6%, 95% CI -4.0% to 13.2%). ConclusionsAdjuvant trastuzumab therapy reduces the risk of relapse similarly across subgroups defined by nodal status and steroid hormone receptor status, even those at relatively low risk for relapse.

Genetic alterations predicting the response of high risk breast cancer patients to Taxol-based adjuvant chemotherapy

9574 Objectives: In an effort to identify predictive markers that may have the potential to identify patients who are likely to respond to paclitaxel in a dose-dense sequential chemotherapy regimen we analyzed DNA alterations in fixed tumor tissues obtained from the adjuvant breast cancer trial HE 10/97. This is a two-arm trial (E-CMF vs. E-T-CMF) investigating postoperative dose-dense sequential chemotherapy with epirubicin (E) followed by CMF with or without paclitaxel (T). Disease -free survival (DFS) was the primary study endpoint. Methods: DNA from fixed tumor tissues was isolated employing an experimental method based on magnetic beads from Bayer HealthCare Diagnostics. The amplification of genes with putative relevance to breast cancer was verified by TaqMan™ PCR analyses. The amplification status of candidate genes was then used to identify differences in DFS in subgroups of patients. Results: By analyzing fixed tumor tissues from 270 patients, we found that amplification of genomic DNA frequently occurred as an overexpression of multiple (10–180) neighboring genes. We therefore named these genomic regions ARCHEONs (“Amplified Regions of Chromosomal Expression Observed in Neoplasia”). Notably, patients with ARCHEONs on chromosome 2q 33–34 or 4q34.1–3 that were treated with paclitaxel had a DFS rate of 84% at 48 months, which was significantly higher (p=0,006) than the 70% DFS rate observed in patients that had the ARCHEONs but were not treated with paclitaxel, or a rate of 68% seen in patients that were treated with paclitaxel but did not have the ARCHEONs. Conclusion: The described ARCHEONs appear therefore to influence the response of high-risk breast cancer patients to dose-dense sequential chemotherapy and to have predictive value in identifying patients that can benefit from paclitaxel. Identification of such ARCHEONs prior to the initiation of chemotherapy could help physicians determine whether to add paclitaxel to an adjuvant anthracyclin-based treatment. No significant financial relationships to disclose.

Prognostic value of p53 protein expression in breast cancer; an immunohistochemical analysis of frozen sections in 514 Japanese women.

Although the prognostic value of p53 protein has been extensively studied in breast cancer, there have so far been few immunohistochemical studies of p53 protein using frozen sections in a large series of Japanese women with breast cancer. Immunohistochemical staining for p53 protein was performed on frozen sections from 514 Japanese patients with breast cancer with a mean follow-up duration of 31 months. Two hundred and eight (40.5%) of 514 cases showed nuclear accumulation of p53 protein. There was a significant inverse correlation between p53 protein and estrogen receptor (ER) status. The patients who were positive for p53 protein had a significantly worse outcome in terms of both disease free survival (DFS) (p<0.0001) and overall survival (OS) (p=0.0411) than those negative for p53 protein. The same effect on DFS was seen in subgroups divided either by nodal status or ER status. Multivariate analyses indicated that nodal status, ER and p53 protein were all independent prognostic factors for DFS. The nodal status, ER and tumor size were independent prognostic factors for OS, and p53 protein status was still an independent prognostic factor for DFS in subgroups divided either by nodal status or ER status. Our findings demonstrated the prognostic value of p53 protein expression for the early recurrence of breast cancer, and the prognostic value of p53 protein expression was independent from that of both the nodal status and ER status in breast cancer.

Biological and prognostic significance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomas.

The biological significance of the differential expression of cytokeratin (CK) polypeptides in breast carcinomas is unclear. We examined the CK profiles of 101 primary infiltrating ductal breast carcinomas using monoclonal antibodies directed against 11 different CKs and against vimentin. Two major CK phenotypes were distinguished: first, a phenotype expressing only the simple-epithelial CKs 7 (variably), 8, 18 and 19, and secondly, a bimodal phenotype co-expressing significant amounts of one or more of the stratified-epithelial CKs 4, 14 and 17. The vast majority of G1 and G2 carcinomas had the simple-epithelium phenotype, as did a subgroup of G3 carcinomas. Interestingly, the majority (62%) of G3 carcinomas exhibited the bimodal phenotype, with the expression of CKs 4, 14 and 17 being statistically correlated with poor histological differentiation and absence of steroid hormone receptors. The distribution of vimentin only partially overlapped with that of these stratified-epithelial CKs. Prognostic analyses suggested that the presence of CKs 4, 14 and/or 17 was associated with short overall and disease-free survival in subgroups comprising G3, oestrogen-receptor-negative and vimentin-negative tumours. In node-positive tumours the correlation between these CKs and a shorter disease-free interval attained statistical significance (log rank, 0.0096). Thus, abnormal CK profiles in ductal breast carcinomas appear to reflect disturbed regulation of differentiation-related gene expression programmes and may prove to be of clinical value.

Variable effects of post-operative radiotherapy on disease-free survival in subgroups of patients with node-negative breast carcinoma

We report in this paper a retrospective cohort study of the effect of post-operative radiotherapy on 5-yr disease-free survival in 433 patients with carcinoma of the breast registered at two clinics of the Ontario Cancer Treatment and Research Foundation between 1961 and 1970. All patients had had surgical removal of the breast and axillary tissue and were free of axillary spread of their disease. The contribution of radiotherapy to survival was assessed with possible confounding by known prognostic factors controlled using the multivariate stratification method recently described by Miettinen. In addition, to give a quantitative indication of radiotherapy's relationship with survival, logistic function modelling, accounting for both confounding and effect-modification of the prognostic factors, was employed. In each of the analyses, it was found that radiotherapy was associated in one subgroup with better than expected survival and in another with poorer outcome. In general, the subgroups identified by the different techniques were similar. These results suggest that, in considering the role of post-operative radiotherapy in the management of patients with carcinoma of the breast, the possibility that this treatment has variable effects that can be predicted by commonly recorded prognostic factors should be taken into account.