Lower Progression-free Survival Research Articles

Safety and Efficacy of Stereotactic Body Radiotherapy for Ultra-Central Thoracic Tumors

The utilization of stereotactic body radiotherapy (SBRT) in the management of ultra-central thoracic tumors is increasing. We sought to evaluate toxicity and efficacy of ultra-central thoracic tumors treated with SBRT in our institution.In this institutional research ethics board approved study, patients with primary or metastatic ultra-central thoracic tumors treated with SBRT from 2015 - 2019 were retrospectively reviewed. Ultra-central was defined where the planning target volume (PTV) of a primary tumor and/or thoracic lymph node overlapped or abutted the proximal main bronchus (PMB) and/or esophagus. The primary endpoint was SBRT-related grade 3 toxicities using common terminology criteria for adverse events (CTCAE v.5). Multivariable stepwise regression was performed to determine relevant organs at risk (OAR) dosimetric parameters as predictors of grade 3 toxicity. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Competing risks analysis was used to estimate the cumulative incidence of local recurrence (LR) using death as a competing risk factor. Predictors of OS/PFS, as well as LR were evaluated using univariable Cox regression and Fine & Gray competing risks regression, respectively. Predictors with P < 0.05 on univariable regression were entered into a multivariable regression model.A total of 81 patients were included, and the median follow-up was 16.4 (range, 0.7 - 69.0) months. SBRT doses ranged from 30-60 Gy in 4-5 fractions, and mean biological equivalent dose (BED10) was 84.1Gy. Tumors were most commonly metastatic (n = 62) followed by NSCLC (n = 15) and recurrent NSCLC (n = 4). In 20 patients, SBRT was also prescribed to thoracic lymph nodes. There were 14 (17.3%) episodes of grade 3 toxicity (n = 8 pulmonary, n = 4 PBT, n = 2 esophagus). There were 3 potentially treatment-related deaths (n = 2 pneumonitis, n = 1 bronchus-pleural fistula). On multivariable modelling, there were no significant dosimetric predictors of grade 3 toxicity. The 1-and 2-year LC for the cohort were 81.5% and 71.5%, respectively. Higher BED10 and higher PTV coverage with the prescribed dose were significantly associated with improved LC. The median PFS was 9.9 (range, 7.6 - 12.4) months; and 1-and 2-year PFS were 39.1% and 23.3%, respectively. Larger PTV volume and patients treated for indications other than primary NSCLC were associated with significantly lower PFS. The median OS was 25.3 (range, 17.6 - 31.7) months. The 1-and 2-year OS were 77.2% and 51.4%, respectively.While SBRT for ultra-central thoracic tumors is associated with encouraging rates of LC, attempts to limit major toxicity should be prioritized to optimize the therapeutic ratio.

Retrospective analysis of Schlafen11 (SLFN11) to predict the outcomes to therapies affecting the DNA damage response

BackgroundThe absence of the putative DNA/RNA helicase Schlafen11 (SLFN11) is thought to cause resistance to DNA-damaging agents (DDAs) and PARP inhibitors.MethodsWe developed and validated a clinically applicable SLFN11 immunohistochemistry assay and retrospectively correlated SLFN11 tumour levels to patient outcome to the standard of care therapies and olaparib maintenance.ResultsHigh SLFN11 associated with improved prognosis to the first-line treatment with DDAs platinum-plus-etoposide in SCLC patients, but was not strongly linked to paclitaxel–platinum response in ovarian cancer patients. Multivariate analysis of patients with relapsed platinum-sensitive ovarian cancer from the randomised, placebo-controlled Phase II olaparib maintenance Study19 showed SLFN11 tumour levels associated with sensitivity to olaparib. Study19 patients with high SLFN11 had a lower progression-free survival (PFS) hazard ratio compared to patients with low SLFN11, although both groups had the benefit of olaparib over placebo. Whilst caveated by small sample size, this trend was maintained for PFS, but not overall survival, when adjusting for BRCA status across the olaparib and placebo treatment groups, a key driver of PARP inhibitor sensitivity.ConclusionWe provide clinical evidence supporting the role of SLFN11 as a DDA therapy selection biomarker in SCLC and highlight the need for further clinical investigation into SLFN11 as a PARP inhibitor predictive biomarker.

P24.13 Circulating Tumor Cells Predict Prognosis Following First-Generation EGFR-TKI Treatment in EGFR- and TP53-Mutant Non-Small Cell Lung Cancer

For advanced non-small cell lung cancer (NSCLC) with EGFR mutations, first-generation EGFR-TKIs have become the first-line standard treatment. Co-mutation of EGFR and TP53 may be indicated EGFR-TKI resistance, shorter PFS and OS. This study isolates and quantifies circulating tumor cells (CTCs) and evaluates patient prognosis before and after first-line treatment with EGFR-TKIs in advanced NSCLC with EGFR and TP53 mutation. Patients with advanced NSCLC with EGFR and TP53 mutation were treated with a first-generation EGFR-TKI using a standard daily dose. Continuous blood samples were collected at baseline (CTCs-d0) and 28 days (CTCs-d28), and the isolation by CTCBIOPSY® was used to detect CTCs. The CTCs results were divided into favorable (< 5 CTCs) and unfavorable (≥ 5 CTCs) groups. The median progression-free survival (PFS) of patients in the favorable group was significantly longer at baseline and after 28 days of treatment compared to those in the unfavorable group (p = 0.0055; p = 0.0003). After treatment, the PFS of patients with reduced CTCs was significantly better than those with no significant change in CTCs (p = 0.014). Patients with CTCs-d0 ≥ 5 and CTCs-d28 ≥ 5 had significantly lower PFS when compared to those with CTCs-d0 < 5 and CTCs-d28 < 5, respectively. This study confirmed for the first time that CTC count is closely correlated with prognosis in EGFR- and TP53-mutant advanced NSCLC following first-line treatment with first-generation EGFR-TKIs.

Prognostic Role of Serum Albumin Level in Patients with Lymphoma Undergoing Autologous Stem Cell Transplantation.

BackgroundHigh-dose chemotherapy followed by autologous stem cell transplantation (HDT/ASCT) plays a crucial role in the therapy of patients with lymphoma. This retrospective study aimed to analyze prognostic factors in patients undergoing HDT/ASCT for lymphoma.Material/MethodsWe included patients with lymphoma who underwent HDT/ASCT at our center. Time-to-event outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed with the Kaplan-Meier method and log-rank test. Receiver operating characteristic (ROC) curve analysis and Cox proportional hazard regression analysis were performed to explore the prognostic value of different factors.ResultsA total of 113 patients with lymphoma were included. Patients with low serum albumin levels (<37 g/L) before transplantation had significantly lower PFS and OS (P<0.01). Albumin levels before transplantation significantly predicted early progression (progressed within 1 year) after transplantation (AUC=0.706, P=0.003). Multivariate Cox analysis indicated that low albumin level (hazard ratio [HR] 3.19, 95% confidence interval [CI] 1.54–6.63; P=0.002) and age >60 years (HR 2.92, 95% CI 1.27–6.71; P=0.012) were independent risk factors for PFS. Total protein <60 g/L was an independent risk factor for OS (HR 3.57, 95% CI 1.45–8.78; P=0.006).ConclusionsLow albumin level before transplantation was an independent risk factor in patients with lymphoma undergoing HDT/ASCT. Intense care and effective maintenance therapy after transplantation are required for patients with low albumin levels.

Outcomes after first-line immunochemotherapy for primary mediastinal B-cell lymphoma: a LYSA study

AbstractPrimary mediastinal B-cell lymphoma (PMBL) is a rare type of aggressive lymphoma typically affecting young female patients. The first-line standard of care remains debated. We performed a large multicenter retrospective study in 25 centers in France and Belgium to describe PMBL patient outcomes after first-line treatment in real-life settings. A total of 313 patients were enrolled and received rituximab (R) plus ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone) (n = 180) or CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) delivered every 14 days (R-CHOP14, n = 76) or 21 days (R-CHOP21, n = 57) and consolidation strategies in modalities that varied according to time and institution, mainly guided by positron emission tomography. Consolidation autologous stem cell transplantation was performed for 46 (25.6%), 24 (31.6%), and 1 (1.8%) patient in the R-ACVBP, R-CHOP14, and R-CHOP21 groups, respectively (P < .001); only 17 (5.4%) patients received mediastinal radiotherapy. The end-of-treatment complete metabolic response rates were 86.3%, 86.8%, and 76.6% (P = .23) in the R-ACVBP, R-CHOP14, and R-CHOP21 groups. The median follow-up was 44 months, and the R-ACVBP, R-CHOP14, and R-CHOP21 three-year progression-free survival probabilities were 89.4% (95% confidence interval [CI], 84.8-94.2), 89.4% (95% CI, 82.7-96.6), and 74.7% (95% CI, 64-87.1) (P = .018). A baseline total metabolic tumor volume (TMTV) ≥360 cm3 was associated with a lower progression-free survival (hazard ratio, 2.18; 95% CI, 1.05-4.53). Excess febrile neutropenia (24.4% vs 5.3% vs 5.3%; P < .001) and mucositis (22.8% vs 3.9% vs 1.8%; P < .001) were observed with R-ACVBP compared with the R-CHOP regimens. Patients with PMBL treated with dose-dense immunochemotherapy without radiotherapy have excellent outcomes. R-ACVBP acute toxicity was higher than that of R-CHOP14. Our data confirmed the prognostic importance of baseline TMTV.

Prognostic significance of tumor budding, poorly differentiated cluster, and desmoplastic reaction in endometrioid endometrial carcinomas

The tumor budding (TB); poorly differentiated cluster (PDC); desmoplastic reaction (DR); and microcystic, elongated, and fragmented (MELF) patterns of invasion are pathological findings at the tumor invasion front associated with epithelial-to-mesenchymal transition. This study aimed to clarify the clinical significance of the TB, PDC, DR, and MELF patterns in endometrioid endometrial carcinomas (EEC). Two hundred and eight cases of histologically proven EEC retrieved from the archives of the Department of Pathology, Fukui Prefectural Hospital, and diagnosed between January 2000 and August 2020 were retrospectively analyzed. The TB, PDC, DR, and MELF patterns were identified in 29 (13.9%), 47 (22.6%), 45 (21.6%), and 23 (11.1%) cases, respectively. Kaplan-Meier curve analysis with log-rank test demonstrated that TB, PDC, and DR were associated with a lower progression-free survival (p=0.010, 0.002, and <0.0001, respectively), whereas the MELF pattern did not show any association (p=0.668). In multivariate analyses, only DR was significantly associated with lower progression-free survival (p=0.034). Moreover, only PDC was associated with lower overall survival in univariate analysis (p=0.018), but the association lost significance in multivariate analysis. The present study revealed that the histological confirmation of TB, PDC, and DR at the tumor invasive front predicts poor prognosis in EEC. However, the MELF pattern was not a predictor of poor prognosis in EEC.

Algorithmically Deduced FREM2 Molecular Pathway Is a Potent Grade and Survival Biomarker of Human Gliomas.

Simple SummaryGliomas are the most common malignant brain tumors with high mortality rates. Recently the role of the FREM2 gene has been shown in glioblastoma progression. Here we reconstructed the FREM2 molecular pathway. We assessed the biomarker capacity of FREM2 expression and its pathway as the overall survival (OS) and progression-free survival (PFS) biomarkers. We used 566 glioblastomas (GBM) and 1097 low-grade gliomas (LGG) to test these biomarkers. FREM2 molecular pathway was a better biomarker than FREM2 gene expression. It could robustly discriminate between GBM and LGG. High FREM2 pathway activation level was associated with poor overall survival (OS) in LGG, and low progression-free survival in LGG and GBM. FREM2 pathway activation level was also a poor prognosis biomarker for OS and PFS in LGG with IDH mutation, for PFS in LGG with wild type IDH and mutant IDH with 1p/19q codeletion, in GBM with unmethylated MGMT, and in GBM with wild type IDH.Gliomas are the most common malignant brain tumors with high mortality rates. Recently we showed that the FREM2 gene has a role in glioblastoma progression. Here we reconstructed the FREM2 molecular pathway using the human interactome model. We assessed the biomarker capacity of FREM2 expression and its pathway as the overall survival (OS) and progression-free survival (PFS) biomarkers. To this end, we used three literature and one experimental RNA sequencing datasets collectively covering 566 glioblastomas (GBM) and 1097 low-grade gliomas (LGG). The activation level of deduced FREM2 pathway showed strong biomarker characteristics and significantly outperformed the FREM2 expression level itself. For all relevant datasets, it could robustly discriminate GBM and LGG (p < 1.63 × 10−13, AUC > 0.74). High FREM2 pathway activation level was associated with poor OS in LGG (p < 0.001), and low PFS in LGG (p < 0.001) and GBM (p < 0.05). FREM2 pathway activation level was poor prognosis biomarker for OS (p < 0.05) and PFS (p < 0.05) in LGG with IDH mutation, for PFS in LGG with wild type IDH (p < 0.001) and mutant IDH with 1p/19q codeletion(p < 0.05), in GBM with unmethylated MGMT (p < 0.05), and in GBM with wild type IDH (p < 0.05). Thus, we conclude that the activation level of the FREM2 pathway is a potent new-generation diagnostic and prognostic biomarker for multiple molecular subtypes of GBM and LGG.

A Multi-institutional, Retrospective Analysis of Patients with Metastatic Renal Cell Carcinoma to Bone Treated with Combination Ipilimumab and Nivolumab.

Bone metastases (BM) in renal cell carcinoma (RCC) patients are associated with poor outcomes. There are limited published data on outcomes in these patients with immunotherapy agents. We present a multi-institutional, retrospective analysis of metastatic RCC patients with BM treated with ipilimumab and nivolumab (I + N). Patient, tumor, and treatment-related variables were retrospectively collected from electronic medical records of patients with a histologically confirmed diagnosis of RCC and at least one radiographically confirmed BM prior to initiation of I + N. Best objective response was assessed by clinical chart review, imaging reports, and treating physician evaluation; progression-free survival (PFS) and overall survival (OS) were recorded as of 31 December 2020. Descriptive statistics were used to summarize patient characteristics and BM-related variables. Kaplan-Meier method and Mantel-Haenszel log-rank test were used to compare survival among groups. Cox regression univariable and multivariable models were used to correlate patient- and treatment-related variables to outcomes. Eighty patients with RCC and BM treated with I + N were identified. Patients were predominantly male and Caucasian presenting primarily with IMDC intermediate or poor-risk clear-cell RCC. Best response to I + N was progressive disease (46%), stable disease (28%), partial response (21%), and not evaluable (5%). Median PFS was 6.1 months (95% CI 3.8-8.9 months) with the majority of patients (65%) discontinuing I + N due to disease progression. Median OS was 25.6 months (95% CI 14.9-NA) with median follow-up of 25.2 months. A multivariable regression model for PFS showed several variables to be significantly associated with worse PFS including female gender [p = 0.02; hazard ratio (HR) 2.16; 95% CI 1.14-4.12], metastases to other sites (p = 0.006; HR 2.12; 95% CI 1.24-3.62) and presence of BM to ribs (p = 0.0007; HR 2.61; 95% CI 1.50-4.52). A multivariable Cox model of OS showed no prior radiation therapy to BM (p = 0.02; HR 2.17; 95% CI 1.13-4.17) and presence of liver metastases (p = 0.0006; HR 3.19; 95% CI 1.65-6.19) to be significantly associated with worse OS. RCC patients with ≥ 1 BM who received I + N therapy had a relatively low response rate, PFS, and OS. Strategies to improve outcomes in this subset of patients are needed.

Gankyrin as Potential Biomarker for Colorectal Cancer With Occult Liver Metastases.

The majority of occult liver metastases cannot be detected by computed tomography (CT), magnetic resonance imaging (MRI) or other traditionally morphological imaging approaches since the lesions are too small or they have not yet formed cancer nodules. Gankyrin is a small molecular protein composed of seven ankyrin domains. In this study, the expression of Gankyrin in colorectal cancer (CRC) patients with liver metastases was investigated to determine its prognosis value. Gankyrin expression in CRC patients was initially analyzed using data from The Cancer Genome Atlas (TCGA) database and bioinformatics tools. RT-qPCR, western blotting, immunohistochemistry (IHC) and transwell migration and invasion assays were then performed to verify the expression and function of Gankyrin in CRC cell line, CRC tissues and matched non-tumor tissues of clinical patients. General clinicopathological information including TNM stage as well as preoperative and postoperative imaging results were collected. The main outcome indicator was overall survival (OS), referring to the length of time from surgery to either death or the last visit. Statistical analyses included chi-squared tests, Cox analyses, progression free survival (PFS) rates and OS rates. Elevated Gankyrin expression was confirmed in CRC patients. The upregulated Gankyrin expression was positively correlated with the progression of disease and liver metastasis in CRC patients. OS analysis revealed that prognosis was worse in CRC patients with high Gankyrin expression compared to those with low expression. CRC patients with higher Gankyrin expression also had a higher risk of occult liver metastases and a lower PFS rate. Therefore, Gankyrin can be used as a potential biomarker for early diagnosis of CRC with occult liver metastasis.

Influence of IL1B (rs16944) and IL1R2 (rs4141134) polymorphisms on aggressiveness and prognosis of cutaneous melanoma.

Cutaneous melanoma is the most aggressive skin cancer with high mortality. Proinflammatory cytokines can modulate the proliferation and survival of cutaneous melanoma cells. Higher levels of interleukin-1β (IL1B) were associated with tumor cell proliferation, invasion, and migration, and the IL-1 type II receptor (IL1R2) serves as an endogenous inhibitor of IL1B signaling. Single-nucleotide variations (SNVs) in these genes (IL1B rs16944 and IL1R2 rs4141134) can modulate cytokine production and binding; however, their role in cutaneous melanoma is still unknown. Thus, we investigated the influence of the above SNVs in clinicopathological aspects and cutaneous melanoma patients' survival. In the present study, we analyzed 193 patients with cutaneous melanoma for IL1B c.-598T>C (rs16944) and IL1R2 c.-2009G>A (rs4141134) genotypes with TaqMan assays. Differences between groups were calculated using χ2 or Fisher's exact test and multiple logistic regression. Progression-free survival (PFS) and melanoma-specific survival were calculated by Kaplan-Meier and Cox methods. The prognostic value of IL1R2 was also analyzed by the online consensus survival webserver for skin cutaneous melanoma (OSskcm). We found that IL1R2 rs4141134 GG genotype was more common in patients with nodular subtype (49.1% vs. 29.8%, P = 0.01) and the frequency of IL1R2 rs4141134 GG or GA was higher in patients with Clark levels III-V (87.4% vs. 75.8%, P = 0.04). Patients with IL1R2 rs4141134 GG or GA genotypes presented lower PFS (hazard ratio: 3.12, 95% confidence interval, 1.10-8.79, P = 0.03) when compared with AA genotype, supported by OSskcm results. Thus, our study presented for the first time preliminary evidence that IL1R2 rs4141134 SNV may modulate cutaneous melanoma clinicopathological aspects and survival possible by allowing IL1B signaling.

Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib

BackgroundBRAF and MEK inhibitors combination, including dabrafenib (D) and trametinib (T) have transformed the treatment of BRAF V600-mutant advanced melanoma patients, including patients with brain metastasis (BM). In a large phase IIIb, single-arm, open-label, multicenter French study, we assessed safety, response to treatment, progression-free survival (PFS) and factors associated with progression, and stratified the population into risk groups. MethodsPatients with unresectable, advanced, BRAF V600-mutant melanoma were included, including those with the presence of BM, Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2, elevated lactate dehydrogenase (LDH) or previous melanoma treatments. Responses were determined locally, without central review. PFS was estimated using the Kaplan–Meier analysis and modelled with multivariate Cox model. Risk subgroups were identified using a regression tree analysis. ResultsBetween March 2015 and November 2016, 856 patients received at least one D + T dose. Overall, 92% had stage IV melanoma, 38% ECOG PS ≥1, 32% BM and 37.5% elevated LDH. Median PFS was 8.02 months (95% confidence interval [CI] 7.33–8.77). Significant factors associated with lower PFS were ECOG PS ≥1, elevated LDH, ≥3 metastatic sites and presence of BM. Patients with <3 metastatic sites, ECOG = 0 and no BM had the highest probability of PFS at 6 months (83%, 95% CI 76–87) and 12 months (56%, 95% CI 47–64), respectively. ConclusionsThis is the largest prospective study in advanced BRAF V600-mutant melanoma patients treated with D + T, conducted in conditions close to ‘real-world practice’. We confirm previous findings that LDH, ECOG PS and ≥3 metastatic sites are associated with shorter PFS, but the real-world setting introduces BM as a major prognostic factor.

Abstract 2526: PMEPA1 gene isoforms indicated aggressive disease progression in non-prostate solid tumors

Abstract Introduction: Abnormal activation of androgen and TGF-β signaling play important roles in tumorigenesis of various solid tumors including prostate, lung and colon cancers. As an androgen and TGF-β responsive gene, PMEPA1 has been defined to regulate androgen and TGF-β signaling via negative feed-back loops. Our lab recently established that PMEPA1 distinct isoforms (isoforms a, b, c, d and e) with disparities within N-terminus protein sequences navigated different regulations of androgen/TGF-β signaling. In this study, the expressions and the correlations to disease progression of PMEPA1 isoforms were investigated in prostate, breast, lung and colon cancers. Methods: RNA seq data from total 2479 solid tumor samples in the TCGA dataset were used to study the correlation between expressions of PMEPA1 isoforms and disease progression including Gleason score, pathology stages, progression free survival rate (PFS) and overall survival rate (OS). The cohort is composed of 482 prostate, 1049 breast, 499 lung and 449 colon cancer patients. Results: In prostate cancer, TCGA data analysis showed that lower transcript level of PMEPA1-b isoform associated with higher Gleason scores and lower progression free survival rate (PFS) (P=0.014) and worse overall survival rate (OS) (P&amp;lt;0.01). The ratio of mRNA levels of PMEPA1-a versus PMEPA-b indicated higher Gleason score, lower PFS rate (P=0.0063) and worse OS rate (P=0.0042). In contrast, higher expression of both PMEPA1-a and PMEPA1-b associated with lower PFS (P=0.023 and 0.028, respectively) in breast cancer. And the enhanced ratio of PMEPA1-a/b was also found to indicate lower PFS (P=0.016) and worse OS (P=0.016) in breast cancer. Similarly, the increased transcript levels of PMEPA1-a and PMEPA1-b isoforms significantly associated with lower PFS and worse OS rates in lung and colon cancer. The expressions of PMEPA1 isoforms were not found to associate with pathology stages of non-prostate tumors. Interestingly, our data further showed that the expressions of both PMEPA1-a and PMEPA1-b isoforms were positively correlated to TGF-β responsive genes including COL1A and THBS1 in breast cancer, lung adenocarcinoma, lung square cancer and colon cancers, which may indicate non-androgen regulation mechanism of PMEPA1-b isoform in non-prostate context. Conclusions: Our data establish the biomarker potential of PMEPA1 isoforms (a and b) indicating more aggressive disease progressions in 4 solid tumors, further underscoring the PMEPA1 isoform specific biological functions to differentiate regulation of androgen and TGF-β signaling in various organ specific contexts. Citation Format: Shashwat Sharad, Zsófia M. Sztupinszki, Zoltan Szallasi, Shiv Srivastava, Alagarsamy Srinivasan, Albert Dobi, Hua Li. PMEPA1 gene isoforms indicated aggressive disease progression in non-prostate solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2526.

Unscheduled Treatment Breaks During Radical Radiotherapy for Head and Neck Cancers

Aims: The aim of this article was to audit radical radiotherapy practice in head and neck cancer to assess unscheduled treatment breaks and their reasons thereof. Materials and Methods: Records of all patients of head and neck squamous cell carcinomas registered in the year preceding the pandemic were analyzed. A total of 287 patients treated with radical intent with doses equivalent to 66 Gy in 33 fractions were eligible for final analysis. Results: More than half (148/287) of our patients suffered from treatment breaks during their radiotherapy treatment with primary cause being treatment-related toxicities. Radiotherapy dose of 66 Gy and above (P &lt; 0.001), primary in the oral cavity (P = 0.009), and preceding surgery and concurrent chemotherapy (P = 0.032) were found to be significantly associated with treatment breaks as well as breaks lasting for 15 days or more. Patients having a break in their treatment were also found to have a significantly low progression-free survival (25.8 vs. 12.7 months; P = 0.012). Conclusion: It is in the interest of the patients that stringent patients’ selection criteria identify the ideal candidates for treatment intensification.

Abstract 766: Expression of HER-2 statue and PD-L1 is associated with prognosis in gastric cancer

Abstract Background PD-L1 and HER-2 as routine biomarkers in gastric cancer (GC). However, little research has been done to investigate the correlation among PD-L1, HER-2, and clinical features in GC. Methods Between Jan. 2013 and May 2020, a total of 120 GC patients treated with chemotherapy were admitted to Henan Tumor Hospital. We retrospectively identified PD-L1, HER-2 level before chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between PD-L1/HER-2 levels and progression-free survival (PFS). Results We retrospectively analyzed 120 patients with gastric cancer, including 17 patients with HER-2 positive and 103 patients with HER-2 negative GC. The results showed that the expression of PD-L1 was closely correlated with HER-2 gene status, with statistical significance (P =0.015). Patients with PD-L1/HER-2 positive obtained lower PFS compared to PD-L1/HER-2 negative (mPFS: 6.4 vs. 11.1 months, P=0.014, mPFS: 5.3 vs. 11.1 months, P=0.002). And the PD-L1 negative and HER-2 negative had the best PFS than other groups (P=0.0008). In a multivariate model, PD-L1 statue, HER-2 statue, tumor location and tumor differentiation remained independent prognostic indicators for PFS (P&amp;lt;0.05). Conclusion HER-2 status could predict the efficacy of immune checkpoint inhibitors, and HER-2 status combined with PD-L1 level could predict the prognosis of GC patients. Citation Format: Huifang Lv, Keran Sun, Caiyun Nie, Beibei Chen, Jianzheng Wang, Weifeng Xu, Saiqi Wang, Yingjun Liu, Junling Zhang, Shiqing Chen, Xiaobing Chen. Expression of HER-2 statue and PD-L1 is associated with prognosis in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 766.

The Prognostic Impact of Minimal Residual Disease on Risk of Progression and Progression Free Survival in Acute Myeloid Leukemia

Assessment of minimal residual disease (MRD) in patients with complete remission CR) defined as <5% bone marrow blast count at allogeneic stem cell transplantation (HSCT) provides powerful independent prognostic information in acute myeloid leukemia and defines risk groups for transplant outcomes. Previous studies showed that transplant outcomes for AML patients with morphologically detectable disease (active disease) are comparable to those for CR patients with MRD (CR-MRDpos).We aimed to compare the outcomes of 458 AML patients who underwent HSCT after 2012 at our institution based on the status of morphologically detectable disease and MRD by 8 color flow cytometry at HSCT in addition to cytogenetic and molecular risk classification by European LeukemiaNet. The primary outcomes were disease progression and progression free survival (PFS) and analyses were stratified by ELN risk classification as favorable and intermediate (n=295) and adverse (n=163).Patients were categorized as active disease (n=81) vs. CR-MRDneg (n=191) and CR-MRDpos (n=52) vs. primary induction failure with marrow aplasia (PIF)-MRD (n=25) and PIF-MRDpos (n=74) vs. relapsed refractory with marrow aplasia (RR)-MRDneg (n=19) and RR-MRDpos (n=16). Median age of cohort was 56 (range, 3-80). Conditioning intensity was either myeloablative (n=260) or reduced intensity (n=198).The median follow-up of survivors was 18 months. For disease progression in favorable/intermediate risk by ELN, the only prognostic factors were the morphological disease status and MRD as shown in Figure 1. Active disease patients had the highest incidence of progression at 2-year with 53% which was similar to 43% observed in RR patients (HR=0.6, p=0.3). In comparison to active disease, CR-MRDpos and PIF-MRDpos patients had lower incidence of progression with 29% and 32% at 2-yr (HR=0.5, p=0.08 and HR=0.5, p=0.06). Among adverse risk patients, CR patients had significantly lower risk of disease progression independent of their MRD status when compared with active disease patients (HR=0.4, p=0.002 for CR-MRDneg and HR=0.4, p=0.02 for CRMRDpos).For PFS at 2 year, not only morphological disease status and MRD but also older age and hematopoietic comorbidity index (HCT-CI) were prognostic. In patients with favorable/intermediate ELN risk, Classification and Regression Tree multivariate analysis revealed 3 potential PFS groups: high PFS group included CR-MRDneg patients aged <60 who had the best 2-yr PFS estimated at 81%, and CR-MRDneg but aged ≥60 who had an estimated 2-yr PFS of 61%. In contrast, low PFS group included not CR-MRDneg patients with HCT-CI ≥4 in combination with either RR-marrow aplasia (2-yr PFS 0%) or age >60 (2-yr PFS 10%). In the absence of RR-marrow aplasia and older age, not CR-MRDneg patients with HCT-CI ≥4 had an intermediate 2-yr PFS (30%) which was comparable to the PFS (43%) in not CR-MRDneg patient with HCT-CI <4, irrespective of age.For adverse ELN risk group, PFS was the best in patients with CR (independent of the MRD status) and HCT-CI <4 with 2 year PFS of 59%. All other adverse risk patients had similarly low PFS with estimates of 17%-23%.In conclusion, we observed a lower progression incidence in CRMRDpos patients compared with active disease in both intermediate and adverse risk ELN groups after HSCT. However, PFS is a more complex endpoint with not only morphological disease status and MRD but also ELN risk classification, older age and HCT-CI determining the outcome expectations. These factors need to be taken into account when planning treatment for HSCT and thereafter. [Display omitted] DisclosuresOran:Celgene: Research Funding; AROG: Research Funding; Astex: Research Funding.

Outcomes of Cord Blood Transplantation for Adult Patients with Hodgkin Lymphoma, a Eurocord and EBMT Lymphoma Working Party Study

Allogeneic stem cell transplantation represents an alternative for relapsed or refractory patients (pts) with Hodgkin Lymphoma (HL). In this setting, only limited data on unrelated umbilical cord blood transplantation (UCBT) are available. We analyzed 133 adult pts with HL who underwent UCBT in EBMT centers. Histological subtype was nodular sclerosis in 65% of the pts. Median age at UCBT was 29 (18-65) years. Median follow-up was 37 (2-119) months and median year of UCBT was 2010 (2003-2015). Ninety pts had received a previous autologous transplantation (ASCT), while 19 had received 2 ASCT before UCBT; median time from ASCT to UCBT was 15 (2-281) months. Disease status at UCBT was complete remission (CR) in 45%, partial remission (PR) in 28% and relapse or refractory disease in 27% of the pts. Sixty percent of pts were male and 54% had a positive cytomegalovirus serology. Fifty-one percent (n=68) received a single UCBT and 49% (n=65) a double UCBT; 58% of pts received a graft with 2 or more HLA mismatch. The majority of the pts (n=104, 77%) underwent a reduced intensity conditioning regimen, the most frequent conditioning regimen (n=69) being Cyclophosphamide + Fludarabine + Total Body Irradiation (TBI) (2 Gy). Forty percent (n=46) of pts received anti-thymocyte globulin and Cyclosporine A + mycophenolate mofetil prophylaxis was given to 60% (n=80) of the pts. Median total nucleated cell (TNC) dose at cryopreservation was 3.99 (1.5-12.2) x107/Kg.The cumulative incidence (CI) of neutrophil engraftment at 60 days was 87% (81%-93%). The 100-day CI of acute grade II-IV GVHD was 26% (19%-35%). At 3 years, chronic GVHD was 30% (21%-41%). Relapse incidence (RI) and non-relapse mortality (NRM) were 40% (32%-50%) and 30% (23%-40%) at 3 years, respectively. The overall survival (OS) was 48% (39%-57%) and progression free survival (PFS) was 28% (21%-37%) at 3 years. Sixty-nine patients died: 27 of relapse and 39 of transplant related causes (infections, n=13, GVHD, n=7, idiopathic pneumonia syndrome n=6, EBV-PTLD n=2, VOD n=2 and others causes, n=9). According to disease status at UCBT, OS at 3 years was 68% (55%-79%) for pts in CR, 31% (18%-50%) for pts in PR and 26% (14%-44%) for pts in relapsed or refractory disease.In multivariate analysis, adjusted for median year of UCBT, Cyclophosphamide + Fludarabine + low dose TBI conditioning regimen, disease status at UCBT, conditioning intensity and type of UCBT, none of these factors were found to be associated with acute or chronic GVHD. 3-year RI and NRM were higher for pts in relapse or refractory disease at UCBT compared to pts in CR (HR=2.62, 95%CI 1.12-6.11, p=0.03 and HR=3.66, 95%CI 1.52-8.80, p=0.004, respectively). The use of Cyclophosphamide + Fludarabine + low dose TBI conditioning regimen was associated with a lower risk of NRM (HR=0.38, 95%CI 0.15-0.95, p=0.04) and also with a better OS (HR=0.37, 95%CI 0.18-0.76, p=0.006). OS was significantly worse for pts who underwent UCBT in PR (HR=1.97, 95%CI 1.02-3.80, p=0.04) and for those in relapse or refractory disease at transplant (HR=2.86, 95%CI 1.41-5.81, p=0.004). Pts transplanted in relapse or refractory disease have also a lower PFS (HR=3.12, 95%CI 1.71-5.71, p<0.001).In conclusion, UCBT is feasible in heavily pretreated pts with HL, if there are no other alternative donors. Conditioning with Cyclophosphamide + Fludarabine + low dose TBI is associated with a better OS and NRM. However, outcomes are poor for patients not in CR at the time of UCBT and one might consider the use of new therapeutic agents earlier before UCBT in this setting. DisclosuresZuckerman:BioSight Ltd.: Consultancy. Snowden:Sanofi: Honoraria. Robinson:Gilead: Honoraria, Other: Travel Grants; Takeda: Consultancy, Honoraria, Other: Travel Grants; Roche: Honoraria, Other: Travel Grants; Riemser: Consultancy.

Conditional Long-Term Survival Among Diffuse Large B-Cell Lymphoma (DLBCL) Patients Treated with Autologous Hematopoietic Cell Transplantation (AHCT)

Introduction: AHCT is standard therapy for chemosensitive relapsed DLBCL and survival from the time of AHCT has been well described in large patient cohorts. Outcomes have not been well described for patients who survive a certain time period after transplantation, when the risks of relapse have diminished. We performed a retrospective cohort study to delineate conditional survival in patients with DLBCL who survived 1, 2, and 5 yrs after AHCT. We also compare survival for these cohorts to their general population controls.Methods: We included 371 consecutive adult (≥18 yrs) patients with DLBCL who received AHCT at our institution from 2000-2014. 10-year overall survival (OS), progression-free survival (PFS), relapse mortality (RM) and non-relapse mortality (NRM) from AHCT were determined for three cohorts: 1-yr survivors (N=272), 2-yr survivors (N=232), and 5-yr survivors (N=157). Outcomes were estimated with Kaplan-Meier (OS, PFS) or cumulative incidence (RM, NRM). Cox regression analyses were performed to evaluate prognostic factors for OS and PFS. In addition, standardized mortality ratio (SMR) compared to the age-, gender- and race-matched healthy population was estimated for each survivor cohort.Results: Median age for 1-yr cohort was 56 yrs (19-78 yrs). 61% were male, 78% were stage III/IV and 45% had B-symptoms at diagnosis, 28% had received prior radiation and 81% had received prior rituximab. 77% patients received chemotherapy mobilization and Bu/Cy/VP was conditioning regimen for 97% patients. Median followup for this 1 yr cohort was 8 yrs (1.3-16.5 yrs). OS, PFS, RM and NRM at 10 yrs after AHCT are described in Table 1. OS and PFS improved with increasing survival after transplantation. Relapse was the primary cause of death in 1- and 2-yr survivors; cumulative incidence of RM and NRM was low but similar in 5-yr survivors. As expected, in multivariable analyses, lymphoma relapse prior to landmark time was associated with significantly worse OS and PFS for 1-, 2- and 5-yr survivors. Among other patient and disease characteristics evaluated in risk factor analysis, age and duration of AHCT hospitalization were the only factors associated with OS and PFS. Older age (10 yr increments) was associated with greater mortality risk among 1- and 2-yr but not 5-yr survivors. Older age at AHCT was associated with worse PFS in all three survivor cohorts. Prolonged hospital stay, as a surrogate for early post-transplant complications, was also associated with lower OS for all three cohorts, and lower PFS for 2-yr and 5-yr survivors. Survival was lower compared to the general population, although it improved and approached that of healthy peers with increasing post-transplant survival (SMR 4.0, 3.0 and 1.8 among 1-, 2- and 5-yr survivors, respectively, Figure 1).Conclusions: Conditional OS and PFS for DLBCL patients treated with AHCT improves with increasing survival post-transplantation. Relapse is the primary driver of poor survival, although the probability of death due to relapse decreases over time. NRM continues to be an important cause of treatment failure even among patients surviving 5-years after AHCT. Our data provide personalized survivorship information for DLBCL AHCT recipients and identify risk factors for poor survival. Our study also underscores the need for continued research on decreasing relapse risk and for surveillance for prevention and management of late-complications in this population. [Display omitted] DisclosuresKharfan-Dabaja:Incyte: Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau; Seattle Genetics: Speakers Bureau. Majhail:Anthem, Inc.: Consultancy; Sanofi: Honoraria.

STAT3 activation in thymic epithelial tumors: correlation with cyclin D1, JAK3, and clinical behavior.

Thymic epithelial tumors are the most common adult mediastinal tumors; however, their growth mechanism remains relatively unknown. Among the JAK/STAT pathway-related proteins, which control various intracellular events, STAT3 is deeply involved in cell proliferation. Constitutive activation of STAT3 and the resulting overexpression of cyclin D1 have been confirmed in various tumors, but have not been thoroughly investigated in thymic epithelial tumors. In this study, we immunohistochemically examined STAT3 activation, cyclin D1 expression, and JAK3 activation in thymic epithelial tumors and statistically analyzed their correlation with clinicopathological features. Formalin-fixed paraffin-embedded specimens of 94 thymic epithelial tumors surgically resected at Kyorin University Hospital between 2005 and 2018 were included in this study. pSTAT3, cyclin D1, and pJAK3 were immunohistochemically examined, and the correlation with histology, Masaoka stage, and survival time was statistically analyzed. Cyclin D1 was found to be significantly overexpressed in the STAT3-activated group. This phenomenon was associated with histology and Masaoka stage. JAK3 was also activated in thymic epithelial tumors; however, JAK3 and STAT3 activation were not always correlated. Using survival time analysis, the STAT3-activated group, cyclin D1-expressed group, and JAK3-activated group had significantly lower progression-free survival times than those for both the non-activated and non-expressed groups. STAT3 activation may promote cyclin D1 overexpression in thymic epithelial tumors, and intracellular signaling pathways other than JAK3 may be involved in STAT3 activation. STAT3 activation, cyclin D1 overexpression, and JAK3 activation are biomarker candidates that indicate clinically poor prognosis.

Outcomes of patients with multiple myeloma treated at a regional Australian center compared to a metropolitan Australian center.

e20003 Background: A number of studies have demonstrated poorer outcomes for patients with cancer who live in rural/regional areas compared to metropolitan areas. There is conflicting information on the effect of rurality on outcomes of patients with multiple myeloma, and limited information regarding the cause of this discrepancy. Methods: Retrospective analysis of demographic, treatment and outcomes of 238 patients newly diagnosed with multiple myeloma between 2002-2019 in the Illawara Shoalhaven Local Health District. Results: Patients being treated in a regional cancer care centre had lower overall survival compared to those treated at a metropolitan cancer care centre (median OS = 63.6 months vs. 43.8 months, p=0.004), and a trend towards lower progression-free survival (median PFS = 24.7 months vs. 19.8 months, p=0.228) despite treatment by the same group of hematologists. There was a lower rate of autologous transplantation for patients treated at a regional cancer care centre compared to a metropolitan cancer care centre (36% vs. 18%, p=0.007). Conclusions: Survival differences between patients with multiple myeloma living in regional areas compared to metropolitan areas may be due to lower rates of autologous transplantation.

BRAF and NRAS mutation status and response to checkpoint inhibition in advanced melanoma.

9558 Background: The ability to analyze tumor mutation profiles has altered the oncology treatment landscape over the past decades. However, little is known about the effect of specific gene mutations on the response to immune checkpoint inhibitors (ICIs) in patients with advanced melanoma. Methods: All unresectable stage IIIc and IV patients with BRAF V600, NRAS mutations and BRAF and NRAS wild-type patients treated with anti-PD-1 or ipilimumab-nivolumab between 2012 and 2020 were included from the Dutch Melanoma Treatment Registry, a nationwide population-based registry. Outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). A Cox model was used to analyze the association of possible prognostic factors with PFS and OS. Results: In total 1358 first-line patients treated with anti-PD-1 and 524 treated with ipilimumab-nivolumab were included. Median follow-up was 25.6 months for anti-PD-1 treated patients and 16.3 months for ipilimumab-nivolumab treated patients. The highest ORR, in first-line, to anti-PD-1 was in patients who were BRAF and NRAS wildtype (50.2%), compared to BRAF V600 (43.8%) and NRAS mutated patients (49.8%). ORR to ipilimumab-nivolumab was highest in NRAS mutated patients (44.9%), while ORR was 39.5% for BRAF mutated patients and 40.3% for wild-type patients. Median PFS in the anti-PD-1 treatment regimen was significantly higher (p = 0.049) for double wild-type patients (16.7 months) patients than for BRAF mutated patients (9.9 months) and NRAS mutated patients (11.3 months). PFS was not significantly different (p = 0.11) in the ipilimumab-nivolumab treatment cohort, with a median PFS of 6.5 months for the wild-type group, 10.8 months for the BRAF group, and 9.1 months for the NRAS group. In the anti-PD-1 treated patients, median OS was significantly higher (p &lt; 0.001) for BRAF mutated patients (32.8 months) compared to NRAS (21.0 months) and wild-type patients (23.0 months). For ipilimumab-nivolumab treated patients, median OS was also significantly higher (p &lt; 0.001) for BRAF mutated patients (36.5 months) than for NRAS mutated patients (11.8 months) and wild-type patients (16.1 months). After adjustment for potential confounders, the presence of a BRAF mutation remained associated with lower PFS in the anti-PD-1 treatment cohort and better OS in both treatment cohorts. Higher age, higher ECOG score, elevated LDH levels, liver metastases and brain metastases were associated with worse survival. Conclusions: PFS in first-line PD-1 was significantly higher for double wild-type patients than for BRAF mutant and NRAS mutant patients. PFS in ipilimumab-nivolumab treated patients did not significantly differ between BRAF mutant, NRAS mutant and double wild-type patients. OS was significantly higher for BRAF mutant patients in both treatment strata, which is probably the result of the subsequent BRAF/MEK-inhibition treatment option in this group.