Progression-free Survival In Stage Research Articles

EP08.01-03 Lymphocyte Count Pre-immunotherapy Predicts Progression-Free Survival in Stage III NSCLC Treated with Chemoradiotherapy and Immunotherapy

EP08.01-03 Lymphocyte Count Pre-immunotherapy Predicts Progression-Free Survival in Stage III NSCLC Treated with Chemoradiotherapy and Immunotherapy

Comparison of Neoadjuvant Chemotherapy Plus Concurrent Chemoradiotherapy vs. Concurrent Chemoradiotherapy Alone in Locally Advanced Cervical Cancer Under 2018FIGO Staging Correction

<h3>Purpose/Objective(s)</h3> According to NCCN guidelines, concurrent chemoradiation (CCRT) is the standard care for locally advanced cervical cancer (LACC) patients, but the benefit of neoadjuvant chemotherapy (NACT) before CCRT for LACC patients is still controversial, especially based on 2018FIGO staging,This study is designed to answer the question by comparing the efficacy and toxicities of neoadjuvant chemotherapy with concurrent chemoradiation (NACT+CCRT) versus concurrent chemoradiation (CCRT) alone in LACC under 2018FIGO staging correction. <h3>Materials/Methods</h3> Patients with stage IB2, IIA2, IIB-IVA (2009 FIGO staging) cervical cancer were retrospectively reviewed from January 2013 to January 2017 in China. All patients were re-staged after 2018FIGO staging correction. All patients were treated with IMRT to 50.4 Gy with concurrent weekly cisplatin 40 mg/m² followed by intra-cavitary brachytherapy. The primary endpoint was progression free survival (PFS), and the secondary endpoints included overall survival (OS), tumor response by RECIST 1.1 criteria, and toxicities. Survivals were calculated with Kaplan-Meier method. The differences between survivals were calculated with Log-rank test. Toxicities were analyzed using the χ2 test. All statistical tests were two-sided. <h3>Results</h3> A total of 432 patients were identified and 406 were eligible for analysis. The 2009FIGO staging of IB2 in 81, stage IA2 and IIB in 119, stage III in 119, stage IV in 87 were corrected into 2018FIGO staging which IB3 in 58, stage IIA2 and IIB in 75, stage III in 186, and stage IV in 87. No patients were down-staged. 201 patients were treated with NACT+CCRT and 205 with CCRT. With a median follow-up of 58.6 months, 5-year PFS was 60.3% in the NACT+CCRT arm, and was 57.6% in the CCRT arm. There was no significant difference in 5-year PFS between two arms (p=0.287). 5-year OS was 68.8% and 65.0% in the NACT+CCRT arm and CCRT+ACT arm, respectively. There was no statistical difference in 5-year OS between two arms (p=0.301). Multivariate analysis showed that pathological type, FIGO stage and pelvic nodes status were associated with OS and PFS. The CR and PR in NACT group was similar to the CCRT group (196/201 versus 193/205, p=0.090). There were higher acute systemic side effects in the NACT+CCRT arm. The result of subgroup analysis showed that PFS in stage III in NACT+CCRT group was significantly higher than that in CCRT group (57.6% vs 45.4%, P=0.048), but OS had no significant difference (71.9% vs 56.3%, P=0.053). In stage III, the curative effect of IIIC1 was better than that of IIIA-B and IIIC2, with 5-year OS of 81.9%, 61.7% and 37.5% (P=0.004), and 5-year PFS of 62.6%, 48.8% and 38.4% (P=0.031), respectively. <h3>Conclusion</h3> For LACC patients with 2018 FIGO correction stage, neoadjuvant chemotherapy plus concurrent cisplatin chemoradiation did not improves RR, PFS and OS. There were more toxicities for the neoadjuvant chemotherapy group. Further research and longer follow up is needed, especially for the staging IIIC1 LACC patients.

Carbon-ion radiotherapy versus radiofrequency ablation as initial treatment for early-stage hepatocellular carcinoma.

Carbon-ion radiotherapy (C-ion RT) has shown potential as a curative treatment for patients with hepatocellular carcinoma (HCC). However, no reports have compared the effectiveness of C-ion RT and radiofrequency ablation (RFA). This study aimed to compare clinical outcomes between C-ion RT and RFA for patients with early-stage HCC. Medical records of consecutive patients with HCC (single lesion ≤5cm or two to three lesions ≤3cm) who received either C-ion RT or RFA as initial treatment were retrospectively reviewed. Propensity score matching (PSM) was used to adjust for clinical factors between both groups. A total of 560 patients were included, among whom 69 and 491 received C-ion RT and RFA, respectively. After PSM (C-ion RT, 54 patients; RFA, 95 patients), both groups were well balanced. Carbon-ion radiotherapy had significantly lower cumulative intrasubsegmental recurrence rate after PSM compared to RFA (p=0.004) (2-year, 12.6% vs. 31.7%; 5-year, 15.5% vs. 49.6%, respectively). However, no significant difference in cumulative local recurrence rate, stage progression-free survival, or overall survival (OS) was observed between both groups. In the RFA group, 6 of 491 patients (1.2%) showed grade 3 adverse events, whereas no grade 3 or higher adverse events were observed in the C-ion RT group. Carbon-ion radiotherapy provided a lower cumulative intrasubsegmental recurrence rate, but a comparable cumulative local recurrence rate, stage progression-free survival, and OS compared to RFA. Thus, C-ion RT appears to be one of the effective treatment options for early-stage HCC when RFA is deemed not indicated.

The secretome of highly metastatic cells as a source of biomarkers and metastatic effectors in colorectal cancer patients.

Introduction: Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries, mainly as a consequence of metastatic spread. Secreted proteins are essential to communicate the cancer cells with the tumor- microenvironment, favoring tumor progression and metastasis. The conditioned medium or cellular secretome, including exosomes, has demonstrated to be a rich source of metastatic effectors and biomarkers of metastatization in different tumors. Our goal was to identify proteins altered in the secreted fraction of highly metastatic cells in order to determine altered biological pathways and potential biomarkers of prognosis. Material and methods: A quantitative label-free proteomic analysis was carried out on the secretome of highly and poorly metastatic CRC cell lines from different genetic background. Proteomic results were validated using unbiased transcriptomic analyses. Hazard ratios and long-rank tests for the differentially-secreted proteins were determined in four different external datasets in order to select the proteins with clinical relevance for further analysis. Gene ontology was performed to determine the biological processes altered in highly metastatic cells. Results: 221 differentially-secreted proteins were found to be significantly associated to metastasis. Some corresponding genes were able to predict the overall and progression free survival in stage II and stage III CRC patients. In addition, they showed higher expression in the stem cell-like and CMS4 subtypes of CRC, associated to worse prognosis. These genes were also associated to deficient mismatch repair, CpG-island methylator positive status and BRAF mutation. It is also remarkable that a significant number of altered proteins were involved in cholesterol metabolism, suggesting an enhancement of the LDL uptake and metabolism in highly metastatic cells. Extracellular matrix constituents involved in cell adhesion and migration were also overrepresented in the highly metastatic fraction. Conclusion: Secretome of highly metastatic cells is enriched in proteins involved in essential pathways for metastasis such us adhesion, migration and lipid metabolism. In addition, several proteins with a robust and significant prognosis value were detected howing the value of the fraction as a source of biomarkers.

Treatment patterns after poly-ADP ribose polymerase (PARP) inhibitors in epithelial ovarian cancer patients

ObjectivesThe primary objective of this study was to describe treatment patterns after poly-ADP ribose polymerase (PARP) inhibitor in patients with epithelial ovarian cancer. Secondary objectives were to evaluate duration of...

Chemotherapy Combined With Recombinant Human Endostatin (Endostar) Significantly Improves the Progression-Free Survival of Stage IV Soft Tissue Sarcomas

PurposeOur previously study showed that recombinant human endostatin (Endostar) combined with chemotherapy had significant activity to increase the mPFS in patients with advanced sarcomas with tolerable side effects. However, the small cohort size and short follow-up time made it difficult to screen sensitive sarcoma subtypes and determine whether there is an overall survival benefit. With the largest sarcoma cohort to our knowledge, we try to confirm the efficacy and safety of chemotherapy combined with Endostar in stage IV sarcomas, with the specific purpose of finding out the sensitive sarcoma types for this combined treatment.MethodsAfter the exclusion of ineligible patients, 156 patients with stage IV bone and soft tissue sarcomas were included in this study according to the inclusion criteria.ResultsBy the end of follow-up, the ORR was 10.7% (9/84) vs 1.4% (1/72) (p=0.041), the DCR was 26.2% (22/84) vs 5.6% (4/72) (p=0.001) in the combined group and chemotherapy group, respectively. The mPFS of combined group was significantly longer than the chemotherapy group (10.42 vs 6.87 months, p=0.003). The mOS were 26.84 months and 23.56 months, without significant difference (p= 0.481). In osteogenic sarcoma, there was no statistically significant difference in the mPFS between the two groups (p=0.59), while in the soft tissue sarcoma, the mPFS in the combined group was significantly higher than that of the chemotherapy group (11.27 vs 8.05 months, p=0.004). Specifically, undifferentiated polymorphic sarcoma (UPS) was the possible sarcoma subtypes that benefited from the combined therapy. For the 38 UPS patients (28 patients in the combined group and 10 patients in the chemotherapy group), the mPFS in the combined group was up to 14.88 months, while it was only 7.1 months in the chemotherapy group, with a significant difference (p=0.006). The most common adverse events in the combined group were myelosuppression, gastrointestinal reactions and abnormal liver function, without significant difference in two groups.ConclusionChemotherapy plus Endostar could prolong mPFS and improve ORR and DCR in patients with stage IV soft tissue sarcoma, suggesting that the combined therapy could improve the patient prognosis in soft tissue sarcomas, especially the UPS patients.

Impact of Disease Extent and Distribution on Outcomes in Stage II Follicular Lymphoma Treated with Curative-Intent Radiation Therapy

Impact of Disease Extent and Distribution on Outcomes in Stage II Follicular Lymphoma Treated with Curative-Intent Radiation Therapy

Genomic Instability of Circulating Tumor DNA as a Prognostic Marker for Pancreatic Cancer Survival: A Prospective Cohort Study.

Simple SummaryThis prospective cohort study showed that circulating tumor DNA-genomic instability (ctDNA-GI) I-scores, which was defined as the natural logarithm of the sum of LOESS-normalized Z-scores of sequenced reads in 1 Mb bins, are prognostic of the outcome of either localized or metastatic pancreatic adenocarcinoma. At baseline, 24.1% of patients had high genomic instability with I-score. Multivariable analyses demonstrated I-score was a significant factor for progression-free survival and overall survival.Genomic instability of circulating tumor DNA (ctDNA) as a prognostic biomarker has not been evaluated in pancreatic cancer. We investigated the role of the genomic instability index of ctDNA in pancreatic ductal adenocarcinoma (PDAC). We prospectively enrolled 315 patients newly diagnosed with resectable (n = 110), locally advanced (n = 78), and metastatic (n = 127) PDAC from March 2015 through January 2020. Low-depth whole-genome cell-free DNA sequencing identified genome-wide copy number alterations using instability score (I-score) to reflect genome-wide instability. Plasma cell-free and matched tumor tissue DNA from 15 patients with resectable pancreatic cancer was sequenced to assess the concordance of chromosomal copy number alteration profiles. Associations of I-score with clinical factors or survival were assessed. Seventy-six patients had high genomic instability with I-score > 7.3 in pre-treatment ctDNA; proportions of high I-score were 5.5%, 5.1%, and 52% in resectable, locally advanced, and metastatic stages, respectively. Correlation coefficients between Z-scores of plasma and tissue DNA at segment resolution were high (r2 = 0.82). Univariable analysis showed the association of I-score with progression-free survival in each stage. Multivariable analyses demonstrated that clinical stage-adjusted I-scores were significant factors for progression-free and overall survival. In these patients, ctDNA genomic I-scores provided prognostic information relevant to progression-free survival in each clinical stage.

P-232 Prognostic inflammatory and microRNA biomarkers in stage IV colorectal cancer patients

Colorectal cancer (CRC) is the second leading cause of cancer deaths worldwide. Stage IV CRC patients have poor prognosis with a five-year survival rate of 14%. Systemic inflammation has a key determinant role in clinicopathological outcomes among CRC patients. Furthermore, microRNA (miRNA), small RNA non-coding molecules, have been detected to be dysregulated in tissues, as well as in biological fluids taken from colorectal cancer patients. Consequently, we are interested in investigating the prognostic potential of inflammatory markers and miRNA in Stage IV colorectal cancer patients. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum albumin, fibrinogen, ferritin, haptoglobin, lymphocyte/monocyte ratio, neutrophil/lymphocyte ratio and platelets/lymphocytes ratio, and Glasgow prognostic score were prospectively evaluated pre-chemotherapy in 67 Stage IV CRC patients presenting at the American University of Beirut Medical Center between May 2018 till November 2020. miRNA (miR-21, miR-19a, miR-23a, miR-29a, miR-155, miR-210, miR-145, miR-203, miR-31 and miR-345) expression was determined using reverse transcription real-time PCR in plasma samples collected prechemotherapy. Cutoff values of the biomarkers were determined using ROC curve. Statistical analysis was performed with SPSS version 25. The median overall survival for the 67 patients was not reached and the median progression-free survival was 13 months. Patients with low pre-chemotherapy WBC count (< 9600 /cu.mm), CRP (< 3.1 mg/L) or ESR (< 20.5 mm/hr) experienced significant improvements in progression-free survival (P=0.012, P=0.016, P < 0.05 respectively) compared with patients with high pre-chemotherapy CRP, ESR or WBC count. Patients with low pre-chemotherapy haptoglobin (< 3.1 g/L) had significantly better overall survival (OS) (P < 0.05) compared with patients with high pre-chemotherapy haptoglobin. Low levels of miR-23a and miR-19a were significantly associated with better PFS (P=0.021 and P=0.031 respectively). Elevated levels of miR-345 and miR-210 were correlated with better OS (P=0.029 and P=0.035 respectively). Subsequent Cox regression multivariate analysis showed that high pre-chemotherapy of CRP, WBC count, miR-19a, and miR-23a were independent favorable prognostic factors for PFS with a HR=3.8; 95%CI: 1.149-12.648; HR=2.426; 95%CI: 1.159-5.075, HR= 2.37; 95%CI: 1.092-5.15 and, HR=2.31; 95%CI: 1.029-4.414), respectively. CRP level, WBC count, miR-19a, and miR-23a are potential prognostic biomarkers for progression-free survival in Stage IV colorectal cancer that need further validation in larger cohorts.

Abstract 897: Association between transforming growth factor beta 1 and progression-free survival in breast cancer

Abstract Transforming growth factor-beta 1 (TGF-β1) has a dual role in cancer progression, with inhibitory functions in early tumor stages and tumor promotion in advanced stages. However, most prior studies have studied survival in either all tumor stages together or a subset of stages. Therefore, this study examined the effect of TGF-β1 before and after radiotherapy (RT) on progression-free survival (PFS) in a racially/ethnically diverse breast cancer patient population and stratified by cancer stage (n=488). Plasma samples were collected on the first (pre-RT) and last day of RT (post-RT), and patients were followed for up to 10 years through electronic medical records. TGF-β1 was assayed with the ELISA kit (R&amp;D Systems, Inc, Minneapolis, MN). PFS was calculated as the time between the date of diagnosis to the first event (death, recurrence, or metastasis) or last follow-up if no event occurred. TGF-β1 was treated as a continuous variable (per 1,000 pg/mL increase). Univariable and multivariable Cox proportional hazards regression models were used to evaluate the association between TGF-β1 and PFS, adjusted for age at diagnosis, clinical tumor stage, and triple-negative breast cancer status in total, stage 0-II, or stage III-IV patients. The study population was comprised of 306 Hispanic white (63%), 102 Black/African American (21%), 64 non-Hispanic white (13%), and 16 other patients (3%). In univariable analyses, stage 0-II patients had 12% and 11% higher risk for event for every 1,000 pg/mL increase in pre-RT (HR=1.12, 95%CI=1.05-1.19, p&amp;lt;0.001) and post-RT (HR=1.11, 95%CI=1.01-1.23, p=0.034) TGF-β1, respectively. In multivariable models, increases in pre-RT (HR=1.11, 95%CI=1.04-1.19, p&amp;lt;0.001) and post-RT TGF-β1 (HR=1.12, 95%CI=1.01-1.24, p=0.031) remained significantly associated with worse PFS in stage 0-II patients, and post-RT TGF-β1 became significantly associated with worse PFS in all patients (HR=1.10, 95%CI=1.00-1.20, p=0.048). In a subset of 107 patients, there was a significant drop of TGF-β1 levels from baseline before any treatment to pre-RT (mean±SD: 6269±3296 to 3787±2810, p&amp;lt;0.001). The implication is that other treatment(s) before RT reduced the tumor burden that may contribute to decreasing circulating TGF-β1 levels. However, TGF-β1 levels were not different between pre- and post-RT. In summary, our current data suggest that higher pre- and post-RT TGF-β1 levels were associated with worse PFS in early-stage patients. Although plasma TGF-β1 levels may not represent the amount of TGF-β1 in tumor, it may still serve as a surrogate prognostic marker and a potential target in cancer therapy. Future larger studies are warranted to validate our findings that circulating TGF-β1 may predict progression-free survival of breast cancer, especially in patients with early stage tumors. Citation Format: George Ruochen Yang, Cristiane Takita, Jean L. Wright, Isildinha M. Reis, Eunkyung Lee, Jennifer J. Hu. Association between transforming growth factor beta 1 and progression-free survival in breast 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 897.

Clinical Features, Molecular Alterations and Prognosis of Colorectal Adenocarcinoma With Mucinous Component in Chinese Patients.

Mucinous adenocarcinoma (MAC) is conventionally diagnosed by WHO definition when the extracellular mucin is >50% of the tumor area, while tumors with <50% mucin are designated as having a mucinous component. The study is aimed at analyzing the clinicopathologic characteristics, mutation spectrum, and prognosis of colorectal adenocarcinoma with mucinous component (CAWMC). Mutation analyses for exon 2 to 4 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing. Expression of DNA mismatch repairs and P53 proteins were evaluated by immunohistochemistry. Density of tumor-infiltrating lymphocyte (TIL) status was scored. We also evaluated the percentage of glands producing mucin and the morphology of the different tumor cell types in mucin pools. We retrospectively analyzed the prognosis of 43 patients with stage II/III. The overall frequencies of KRAS and BRAF mutations were 36% and 8%, respectively. Patients with MAC exhibiting high levels of mucin were related to the increase of tumor diameter (P=0.038) but were not associated with any of the other clinicopathologic parameters. The proportion or variable morphology of mucinous component did not stratify progression-free survival in stage II/III cases. TIL was the most significant predictor of progression-free survival among stage II/III CAWMC. It is interesting to note that signet ring cell carcinoma does not portend a worse prognosis for patients with high TIL levels. Combining use the grade of TIL status with the WHO grade of the entire tumor can help identify patients with a high risk of recurrence more accurately.

Novel imaging biomarkers predict progression-free survival in stage 3 NSCLC treated with chemoradiation and durvalumab.

3054 Background: The current management of stage III non-small cell lung cancer (NSCLC) is chemoradiation followed by durvalumab consolidation. There are no robust biomarkers that predict benefit from this regimen. We evaluated the utility of novel imaging biomarkers (radiomics) to distinguish patients with stage III NSCLC who will benefit from treatment from those likely to progress despite therapy. Methods: Patients with stage III NSCLC treated at our center with chemoradiation and durvalumab from July 2017 - July 2019 were identified. We collected patient clinical outcomes, subtype of NSCLC, and PD-L1 expression as well as pre-treatment CT images. Images were split into training and test sets. Lung tumors were contoured on 3D-Slicer software and 1542 radiomic features capturing both intra- and peritumoral texture patterns were extracted. The primary endpoint of this study was progression-free survival (PFS), and the secondary objective was difference in PFS within high PD-L1 (≥50%) and low PDL1 (&lt;50%) groups. We used the least absolute shrinkage and selection operator (LASSO) Cox regression model to build the radiomic signature for PFS. A risk score was computed according to a linear combination of selected features and their corresponding coefficients. High- and low-risk groups were defined based on median radiomics risk score. Multivariable Cox regression analysis was performed to evaluate the effect of each factor on PFS. We performed Kaplan–Meier survival analysis and log-rank tests to assess prognostic ability of the features. Results: We identified 118 patients who fit our criteria with available CT images and randomly divided them into a training (n=59) and a test set (n=59). The radiomic risk score was calculated using a linear combination of the top six selected features with corresponding coefficients. In a multivariable analysis using clinicopathologic and radiomic signatures, the radiomics risk-score and PD-L1 expression were found to be significantly associated with PFS in training (risk-score: HR = 2.3, 95% CI: [1.46 – 3.63], P = 0.0003; PD-L1: HR = 0.31, 95% CI: [0.081 – 0.96], P = 0.038) and test sets (risk-score: HR= 2.56, 95% CI: [1.75 – 4], P = 8.7e-05; PD-L1: HR = 0.27, 95% CI: [0.048 – 0.58], P = 0.005). Kaplan-Meier analyses showed a significantly shorter PFS in the high-risk radiomics group versus the low-risk group (P &lt; 0.0001). The radiomics risk scores were also predictive of significant differences in PFS within both the low (p=0.0005) and high (p=0.0007) PD-L1 groups. Conclusions: Radiomic biomarkers from pre-treatment CT images in stage III NSCLC patients were predictive of PFS to chemoradiation followed by durvalumab and could predict outcomes regardless of PD-L1 level. Pre-treatment radiomics may allow early prediction of benefit and expedite more aggressive treatment for high-risk patients. Additional validation of these imaging biomarkers is warranted.

Characteristics and outcomes for fecal occult blood test (FOBT) screen detected (SD) versus non-screen detected (NSD) colorectal cancer (CRC).

42 Background: FOBT based screening for CRC has been shown in multiple studies to reduce CRC mortality. Beyond the well described earlier stage at diagnosis, other characteristics of SD cancers have not been well studied. Since 2006 Australians aged 50-74 have regularly been mailed an immunochemical FOBT via the National Bowel Cancer Screening Program (NBCSP), with participation rate stable around 40%. Methods: To explore patient (pt), tumour, treatment and outcome data for SD compared to NSD, we examined a multi-site CRC database where prospectively collected data includes method of detection. Categories include SD via the NBCSP, cases that were symptomatic or incidentally found on imaging (NSD), and cases detected by screening outside the NBCSP (OSD). High risk features for Australian Clinicopathological Staging System (ACPS) Stage B included emergency presentation, T4, lymphovascular invasion and &lt;12 lymph nodes examined. Results: Of 6969 registry pts diagnosed 06/2006–06/2020, 4107 (59%) were aged 50-74, including 473 (12%) SD, 3228 (79%) NSD and 406 (10%) OSD. SD versus NSD pts were younger (mean 62.4 v 64.2 years), had better ASA score (ASA 1-2: 79% v 66%, Odds Ratio [OR] 1.9, p&lt;0.001), earlier stage at diagnosis (ACPS A/B/C/D = 38%/21%/28%/5% v 17%/29%/26%/21%, p&lt;0.001), were more often left-sided (41% v 33%, OR 1.44, p&lt;0.001) but less frequently located in the rectum (28% v 36% OR 0.70, p=0.001). There was no difference by gender. SD tumors were more often well/moderately differentiated (76% v 66%, OR 1.65, p&lt;0.001) and less often mucinous (16% v 20%, OR 0.66, p=0.002). SD stage A tumours were more often T1 (66% v 43%, OR 0.36, p&lt;0.001). SD stage B tumours were more often T3 (92% v 85%, OR 0.43, p=0.033), and had fewer high risk features (60% v 49%, OR 0.64, p=0.036). SD stage C pts had a similar rate of N2 disease (25% v 31%, p=0.20), but more often received adjuvant chemotherapy (96% v 86%, OR 3.6, p=0.002). De novo stage D and relapsed SD pts more often underwent metastatic resection (46% v 25%, OR 2.6, p&lt;0.001). Relapse free survival (RFS) in stage A-C, progression free survival in stage D (PFS), and overall survival (OS) was superior for SD and is in Table. Conclusions: We show for the first time to our knowledge that SD CRCs have many distinct and favourable prognostic features that appear to be driving favourable stage based outcomes when compared to NSD patients. This prognostic data could inform adjuvant therapy decision making and surveillance strategies for SD CRC. [Table: see text]

CTLA4 promoter methylation predicts response and progression-free survival in stage IV melanoma treated with anti-CTLA-4 immunotherapy (ipilimumab)

Anti-CTLA-4-antibodies can induce long-lasting tumor remissions. However, only a few patients respond, necessitating the development of predictive companion biomarkers. Increasing evidence suggests a major role of epigenetics, including DNA methylation, in immunology and resistance to immune checkpoint blockade. Here, we tested CTLA4 promoter methylation and CTLA-4 protein expression as predictive biomarkers for response to anti-CTLA-4 immunotherapy. We identified retrospectively N = 30 stage IV melanoma patients treated with single-agent anti-CTLA-4 immunotherapy (ipilimumab). We used quantitative methylation-specific PCR and immunohistochemistry to quantify CTLA4 methylation and protein expression in pre-treatment samples. CTLA4 methylation was significantly higher in progressive as compared to responding tumors and significantly associated with progression-free survival. A subset of infiltrating lymphocytes and tumor cells highly expressed CTLA-4. However, CTLA-4 protein expression did not predict response to treatment. We conclude that CTLA4 methylation is a predictive biomarker for response to anti-CTLA-4 immunotherapy.

The prognostic value of the lysyl oxidase family in ovarian cancer.

BackgroundOur study intended to evaluate the prognostic value of lysyl oxidase (LOX) and its four relevant members, the lysyl oxidase–like genes (LOXL1‐4), in ovarian cancer (OC) patients.Material and MethodsThe Kaplan‐Meier plotter (KM plotter) database was used to investigate the prognostic power of the LOX family for OC patients. Overall survival (OS) and progression‐free survival (PFS) were the clinical endpoints. The prognostic roles of the LOX family in OC patients were also analyzed according to various clinicopathological characteristics, including histological subtypes, clinical stages, pathological grades, and chemotherapeutic treatments.ResultsOverexpression of LOX, LOXL1, LOXL2, and LOXL3 mRNA indicated poor OS and PFS in OC patients, particularly in serous and grade II + III OC patients. Overexpression of LOXL4 mRNA resulted in worse PFS in OC patients. Overexpression of LOX and LOXL1 mRNA showed worse OS and PFS in stage III + IV OC patients, and overexpression of LOXL3 mRNA indicated worse OS and PFS in stage I + II OC patients. Overexpression of LOX, LOXL3, and LOXL4 mRNA indicated worse OS and PFS among OC patients who received platinum, taxol, and taxol + platinum chemotherapy. Overexpression of LOXL1 and LOXL2 mRNA was related to lower OS and PFS in OC patients who received platinum chemotherapy.ConclusionLOX, LOXL1, LOXL2, and LOXL3 may become potential predictive markers for negative outcomes in OC patients. Moreover, the LOX family can serve as new molecular predictors for the efficiency of platinum‐based chemotherapy in OC patients.

Value of interim 18F-FDG PET/CT for predicting progression-free survival in stage ⅢB/IV EGFR-mutant non–small-cell lung cancer patients with EGFR-TKI therapy

ObjectivesWe retrospectively investigated the prognostic value of FDG-PET performed for patients with Stage ⅢB/IV EGFR-mutant non–small-cell lung cancer (NSCLC) receiving EGFR tyrosine kinase inhibitor (TKI) therapy. MethodsA total of 78 patients newly diagnosed with Stage ⅢB/IV EGFR-mutant NSCLC who received baseline and interim PET/CT examination and were treated with EGFR-TKI therapy were included. Interim PET was performed after 4–6 weeks of treatment. Cox proportional hazards regression analysis was used to assess the association between quantitative 18F-FDG PET/CT parameters, other clinicopathological factors and progression-free survival (PFS), non-durable clinical benefit (non-DCB). Five interim PET variables were analyzed in this study in the prediction of non-DCB. ResultsThe one-year and two-year progression-free survival rates of the patients were 33.9% (28.6–39.2%) and 20.7% (16.1–25.3%), respectively. Multivariable analysis indicated that interim PET relevant factors ΔSUVmax (p = 0.002, p = 0.014) and ΔSUVmean (p = 0.000, p = 0.030) were independent risk factors for predicting the PFS or non-DCB of patients receiving EGFR-TKI treatment. The optimal cutoff values of the parameters in the tumor survival analyses were 56.74% for ΔSUVmax (p = 0.002) and 36.48% for ΔSUVmean (p = 0.001). ΔSUVmax had the highest diagnostic value in the prediction of non-DCB. The one-year progression-free survival rates (95% confidence intervals) of patients with ΔSUVmax ≥ 56.74% and ΔSUVmax <56.74% were 59.5% (44.2–74.8%) and 5.7% (0.0–13.3%), respectively (p = 0.000). ConclusionAn early PET scan after 4–6 weeks can effectively predict the PFS and non-DCB of patients with Stage ⅢB/IV EGFR-mutant NSCLC receiving EGFR-TKI therapy.

PET/MRI in Cervical Cancer: Associations Between Imaging Biomarkers and Tumor Stage, Disease Progression, and Overall Survival.

Positron emission tomography (PET)/MRI biomarkers have been shown to have prognostic significance in patients with cervical cancer. Their associations with progression-free survival (PFS) and overall survival (OS) merit further investigation. To evaluate the association between PET/MRI biomarkers and tumor stage, PFS, and OS in patients with cervical cancer. Prospective cohort study. In all, 54 patients with newly diagnosed cervical cancer and measurable tumors (>1 cm) were included in the image analysis. 3.0T integrated PET/MRI including diffusion-weighted echo-planar imaging (b = 50 and 1000 s/mm2 ) and [18F]fluorodeoxyglucose PET. Two radiologists measured the minimum and mean apparent diffusion coefficient (ADCmin and ADCmean ), maximum standardized uptake value (SUVmax ), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of the primary tumors. A Mann-Whitney U-test was used to evaluate the association between the imaging biomarkers and tumor stage. A Cox proportional hazards model was used to assess the relationships between the imaging biomarkers and survival. In advanced tumors (T ≥ 1b2, M1, stage ≥ IB3), ADCmin was significantly lower and MTV, TLG, MTV/ADCmin , and TLG/ADCmin were significantly higher (P values between <0.001 and 0.036). In N1 tumors, ADCmin was significantly lower and MTV and MTV/ADCmin were significantly higher (P values between 0.005 and 0.016). In survival analysis, SUVmax was an independent predictor of PFS (hazard ratio [HR] = 4.57, P < 0.05), and ADCmin was an independent predictor of OS (HR = 0.02, P < 0.05). In subgroup analysis of patients with different stages, MTV/ADCmin was a predictor of PFS in stage I disease (P = 0.003), ADCmin (P = 0.038), and MTV (P = 0.020) in stage II, SUVmax (P = 0.006), and TLG (P = 0.006) in stage IV; and ADCmin was a predictor of OS in stage III disease (P = 0.008). PET/MRI biomarkers of cervical cancer are associated with tumor stage and survival. SUVmax and ADCmin are independent predictors of PFS and OS, respectively. 1 TECHNICAL EFFICACY: 3.

A combined FAK, c-MET, and MST1R three-protein panel risk-stratifies colorectal cancer patients.

Focal adhesion kinase (FAK) is a key tyrosine kinase downstream of c-MET (or hepatocyte growth factor receptor, HGFR) and MST1R (macrophage-stimulating protein receptor or recepteur d'origine Nantais, RON) membrane receptors. The pathway plays an important role in cancer survival and invasion. In this study, we examined the protein expression of FAK, c-MET, and MST1R levels in a well-annotated cohort of 330 colorectal cancer patients. We found FAK to be overexpressed in colorectal adenocarcinomas (p = 0.0002), and FAK levels correlated positively with phospho-FAK levels (R2 = 0.81). In comparison, MST1R levels were not significantly different, and c-MET levels were slightly higher in the normal samples. We then developed a combined 3-protein panel of FAK, c-MET, and MST1R expression signatures that can robustly risk-stratify colorectal cancer across all stages into three clusters that differ in progression-free survival. The colorectal cancer subgroup with high FAK, low c-MET, and low MST1R protein levels showed the worst progression-free survival with particularly early progression of disease (p = 0.0053). Combined FAK, c-MET, and MST1R were independently prognostic for progression-free survival in stage II colorectal cancers in a multivariate model. The 3-protein panel provides a potentially clinically attractive method for risk-stratification and adjuvant therapy guidance, especially in stage II disease.

Chemotherapy response score as a prognostic tool in advanced-stage endometrial cancer patients treated with neoadjuvant chemotherapy.

e18095 Background: Chemotherapy response score (CRS) applied to omental metastases obtained at the time of interval debulking surgery (IDS) has been used to quantify response to neoadjuvant chemotherapy (NACT) in advanced stage ovarian cancer patients. The score has been correlated with both progression free survival (PFS) and overall survival (OS). This CRS score has not been studied in advanced stage endometrial cancer. The aim of the current study is 1) to apply the CRS to omental and adnexal metastases obtained at IDS of advanced stage endometrial cancer patients and 2) to investigate the association between the CRS score and surgical outcome, PFS and OS. Methods: Patients with clinical stage III-IV endometrial cancer (endometrioid, serous, clear cell, carcinosarcoma) were identified through the endometrial cancer database, billing data and tumor board notes (2003-2019) from the University of Chicago. Patients were included if they received NACT followed by IDS (R0 no gross residual, optimal &lt; 1 cm residual or suboptimal ≥ 1 cm residual disease). Patients who received pre-operative radiotherapy were excluded. Pathology specimens from primary and metastatic sites were reviewed by the study pathologist blinded to clinical outcome. Histologic specimens from the omental and adnexal metastases were assigned a single quantitative score of 1 (no/minimal tumor response), 2 (appreciable tumor response with viable tumor) or 3 (complete/near complete response) using the CRS system as previously described by Bohm et al (JCO 2015; 33:2457-63). Results: A total of 40 patients were available for analysis. Median age 63.5, median BMI 32 kg/m2. There is a significant association between omental CRS and optimal IDS (p = 0.029) but no significant association between the adnexal CRS and optimal IDS (p = 0.145). Cox regression analysis identified CRS omentum [2: HR = 0.095, p = 0.001; 3 HR = 0.088, p = 0.004] and CRS adnexa [2: HR = 0.24, p = 0.007] predictive of PFS. There was not enough evidence to comment on any association between CRS with OS. Conclusions: Omental CRS2, CRS3 are associated with optimal IDS. Omental CRS2, CRS3 and adnexal CRS2 are prognostic for improved PFS in stage III – IV endometrial cancer patients after neoadjuvant chemotherapy. [Table: see text]

Gastric-type adenocarcinoma of the cervix: Genomic drivers and clinical outcomes.

6030 Background: Cervical Gastric-type adenocarcinoma (CGA) is a non-HPV-associated adenocarcinoma, comprising 10% of all cervical adenocarcinomas (Park et al, 2019). The optimal management approach is unclear, given that most data in advanced cervical cancer is driven by HPV-positive disease. We summarize our experience with this rare tumor type at a large cancer center. Methods: A retrospective review was performed for all women diagnosed with CGA 6/1/2002- 7/1/2019. Patients who did not follow up after a single visit were excluded. Kaplan-Meier survival analysis was performed to determine progression-free survival (PFS) and overall survival (OS) from date of diagnosis. Tumors from a subset of patients were subjected to MSK-IMPACT targeted sequencing and analysis (Zehir et al, 2017). Results: A total of 68 women were identified; 47 met inclusion criteria. The median age at diagnosis was 52 years (range 27-83). The majority of patients were white (70%), an additional 19% were Asian. The majority of patients (60%, n=28) presented with advanced disease (FIGO 2018, stage II-IV), while 40% (n=19) were Stage I. Of note, 26% (n=12) had positive pelvic lymph nodes and 13% (n=6) had ovarian metastases at time of surgical resection. For upfront treatment: 13% (n=6) had surgery alone of whom 83% had stage 1 disease, 36% (n=17) had surgery followed by adjuvant therapy, 30% (n =14) received definitive chemo-radiation (CRT). All patients with stage IV disease 15% (n=7) received chemotherapy alone. At completion of primary treatment, 19% (n=9) of patients had persistent disease. In patients who received CCRT, 65% (n=22) recurred, the majority (64%) within 12 months of completion of upfront therapy. Pelvic recurrence was the most common site (n=14, 64%). With a median follow up time of 30 months (range 1-159), the median PFS for Stage I was 34.4 months, compared to 17.5 months in patients with Stage II-IV disease (p= 0.29). Of the 24 patients that had MSK-IMPACT, the most common mutation was TP53 (n=16, 64%) followed by mutations in the RAS pathway (n=8, 33%), PIK3CA (n=3, 12.5%), STK11 (n=3, 12.5%), and ERBB2 alterations (n=2, 8.3 %). 2 (8.3%) women enrolled on a clinical trial based on their NGS results, one targeting ERBB2 and one targeting PIK3CA. Conclusions: Consistent with prior published literature, CGA is an aggressive form of cervical cancer with poor median OS in the advanced setting. With universal HPV vaccination, HPV negative cervical cancer will represent a larger percentage of newly diagnosed cancers and further research is needed to identify the optimal management approach.