Biomarker For Progression-free Survival Research Articles

T-antigen as a biomarker of progression-free survival in patients with glioblastoma.

Glioblastoma (GBM) is one of the most aggressive brain tumors and often leads to poor outcomes. Studies have indicated that glycan levels are significantly correlated with the pathogenesis and development of cancers. However, whether glycan levels can serve as diagnostic or prognostic biomarkers in GBM remains unclear. We obtained glycomic profiles in tissue and serum samples from 55 individuals with GBM using a well-established lectin biochip platform probing with 11 specific lectins. Our univariate analysis showed that 5 out of the 11 lectin-probed glycans (LPGs) were significantly higher in GBM tissues than in peri-tumoral tissues. After logistic regression analyses, only the Jacalin-probed T-antigen difference between the two groups remained significant (p = 0.037). Moreover, survival-related analyses showed that the level of Jacalin-probed T-antigen was significantly associated with the progression-free survival (p = 0.038) of patients. However, none of the LPG levels were correlated with the overall survival or the chemosensitivity to temozolomide therapy. The correlation coefficient analysis showed a moderate-to-strong correlation in the Jacalin-probed T-antigen levels between GBM tissues and serum samples, indicating its potential usefulness as a non-invasive GBM progression biomarker. Glycomics analyses can be helpful in the prediction of GBM recurrences and may provide information useful for GBM glycan-based target therapies or vaccine development.

Loss of hematopoietic progenitors heterogeneity is an adverse prognostic factor in lower-risk myelodysplastic neoplasms

Myelodysplastic neoplasms (MDS) are characterized by clonal evolution starting from the compartment of hematopoietic stem and progenitors cells (HSPCs), leading in some cases to leukemic transformation. We hypothesized that deciphering the diversity of the HSPCs compartment may allow for the early detection of an emergent sub-clone that drives disease progression. Deep analysis of HSPCs repartition by multiparametric flow cytometry revealed a strong disorder of the hematopoietic branching system in most patients at diagnosis with different phenotypic signatures closely related to specific MDS features. In two independent cohorts of 131 and 584 MDS, the HSPCs heterogeneity quantified through entropy calculation was decreased in 47% and 46% of cases, reflecting a more advanced state of the disease with deeper cytopenias, higher IPSS-R risk and accumulation of somatic mutations. We demonstrated that patients with lower-risk MDS and low CD34 + CD38+HSPCs entropy had an adverse outcome and that this parameter is as an independent predictive biomarker for progression free survival, leukemia free survival and overall survival. Analysis of HSPCs repartition at diagnosis represents therefore a very powerful tool to identify lower-risk MDS patients with a worse outcome and valuable for clinical decision-making, which could be fully integrated in the MDS diagnostic workflow.

Pre-treatment 18F-FDG-PET/CT parameters as biomarkers for progression free survival, best overall response and overall survival in metastatic melanoma patients undergoing first-line immunotherapy.

Checkpoint inhibitors have drastically improved the therapy of patients with advanced melanoma. 18F-FDG-PET/CT parameters might act as biomarkers for response and survival and thus can identify patients that do not benefit from immunotherapy. However, little literature exists on the association of baseline 18F-FDG-PET/CT parameters with progression free survival (PFS), best overall response (BOR), and overall survival (OS). Using a whole tumor volume segmentation approach, we investigated in a retrospective registry study (n = 50) whether pre-treatment 18F-FDG-PET/CT parameters of three subgroups (tumor burden, tumor glucose uptake and non-tumoral hematopoietic tissue metabolism), can act as biomarkers for the primary endpoints PFS and BOR as well as for the secondary endpoint OS. Compared to the sole use of clinical parameters, baseline 18F-FDG-PET/CT parameters did not significantly improve a Cox proportional-hazard model for PFS (C-index/AIC: 0.70/225.17 and 0.68/223.54, respectively; p = 0.14). A binomial logistic regression analysis for BOR was not statistically significant (χ2(15) = 16.44, p = 0.35), with a low amount of explained variance (Nagelkerke's R2 = 0.38). Mean FDG uptake of the spleen contributed significantly to a Cox proportional-hazard model for OS (HR 3.55, p = 0.04). The present study could not confirm the capability of the pre-treatment 18F-FDG-PET/CT parameters tumor burden, tumor glucose uptake and non-tumoral hematopoietic tissue metabolism to act as biomarkers for PFS and BOR in metastatic melanoma patients receiving first-line immunotherapy. The documented potential of 18F-FDG uptake by immune-mediating tissues such as the spleen to act as a biomarker for OS has been reproduced.

Artificial intelligence-based pathology as a biomarker of sensitivity to atezolizumab–bevacizumab in patients with hepatocellular carcinoma: a multicentre retrospective study

Clinical benefits of atezolizumab plus bevacizumab (atezolizumab-bevacizumab) are observed only in a subset of patients with hepatocellular carcinoma and the development of biomarkers is needed to improve therapeutic strategies. The atezolizumab-bevacizumab response signature (ABRS), assessed by molecular biology profiling techniques, has been shown to be associated with progression-free survival after treatment initiation. The primary objective of our study was to develop an artificial intelligence (AI) model able to estimate ABRS expression directly from histological slides, and to evaluate if model predictions were associated with progression-free survival. In this multicentre retrospective study, we developed a model (ABRS-prediction; ABRS-P), which was derived from the previously published clustering-constrained attention multiple instance learning (or CLAM) pipeline. We trained the model fit for regression analysis using a multicentre dataset from The Cancer Genome Atlas (patients treated by surgical resection, n=336). The ABRS-P model was externally validated on two independent series of samples from patients with hepatocellular carcinoma (a surgical resection series, n=225; and a biopsy series, n=157). The predictive value of the model was further tested in a series of biopsy samples from a multicentre cohort of patients with hepatocellular carcinoma treated with atezolizumab-bevacizumab (n=122). All samples in the study were from adults (aged ≥18 years). The validation sets were sampled between Jan 1, 2008, to Jan 1, 2023. For the multicentre validation set, the primary objective was to assess the association of high versus low ABRS-P values, defined relative to cross-validation median split thresholds in the first biopsy series, with progression-free survival after treatment initiation. Finally, we performed spatial transcriptomics and matched prediction heatmaps with in situ expression profiles. Of the 840 patients sampled, 641 (76%) were male and 199 (24%) were female. Across the development and validation datasets, hepatocellular carcinoma risk factors included alcohol intake, hepatitis B and C virus infections, and non-alcoholic steatohepatitis. Using cross-validation in the development series, the mean Pearson's correlation between ABRS-P values and ABRS score (mean expression of ABRS genes) was r=0·62 (SD 0·09; mean p<0·0001, SD<0·0001). The ABRS-P generalised well on the external validation series (surgical resection series, r=0·60 [95% CI 0·51-0·68], p<0·0001; biopsy series, r=0·53 [0·40-0·63], p<0·0001). In the 122 patients treated with atezolizumab-bevacizumab, those with ABRS-P-high tumours (n=74) showed significantly longer median progression-free survival than those with ABRS-P-low tumours (n=48) after treatment initiation (12 months [95% CI 7-not reached] vs 7 months [4-9]; p=0·014). Spatial transcriptomics showed significantly higher ABRS score, along with upregulation of various other immune effectors, in tumour areas with high ABRS-P values versus areas with low ABRS-P values. Our study indicates that AI applied on hepatocellular carcinoma digital slides is able to serve as a biomarker for progression-free survival in patients treated with atezolizumab-bevacizumab. This approach could be used in the development of inexpensive and fast biomarkers for targeted therapies. The combination of AI heatmaps with spatial transcriptomics provides insight on the molecular features associated with predictions. This methodology could be applied to other cancers or diseases and improve understanding of the biological mechanisms that drive responses to treatments. Institut National du Cancer, Fondation ARC, China Scholarship Council, Ligue Contre le Cancer du Val de Marne, Fondation de l'Avenir, Ipsen, and Fondation Bristol Myers Squibb Pour la Recherche en Immuno-Oncologie.

Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR) and hemoglobin (Hb) predict immunotherapy outcomes in patients with advanced or metastatic gastric cancer.

e16075 Background: This study aimed to confirm the prognostic role of pretreatment neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), hemoglobin (Hb) levels as effective and convenient biomarkers for patients with advanced or metastatic gastric cancer (AGC or MGC) receiving immunotherapy. Methods: patients with AGC and MGC who received anti-PD-1 treatment at the Chinese PLA General Hospital between January 2016 and November 2020 were reviewed. The receiver operating characteristic analyses for predicting 6 months PFS by the NLR, PLR was used to identify an appropriate cut-off value. The study analyzed the association of NLR, PLR, Hb and overall survival (OS) or progression-free survival (PFS) and anti-tumor response rate with immunotherapy respectively. Results: 137 patients were included in the final analysis. 71 patients were administered immunotherapy in the first line and the rest of the patients in the second or further line. 92 patients had received immunotherapy combined with chemotherapy, whereas 45 patients had undertaken immunotherapy monotherapy or with anti-angiogenesis. The best cut-off value for NLR was 3.23 and for PLR was 816.43. NLR &lt;3.23 was associated with longer OS (HR = 0.38, 95% CI, 0.26-0.57, p &lt; 0.001) and PFS (HR = 0.42, 95% CI, 0.29-0.62, p &lt; 0.001) in patients with AGC or MGC. Patients in PLR&lt;816.43 group had prolonged PFS (7.9m vs 4.3m, p&lt;0.001) and OS (11.1m vs9.2m, p&lt;0.001) than in PLR&gt;=816.43 group. The median PFS was 7.8m in the normal Hb level group (Hb&gt;=110g/L) and 4.3m in the decreased Hb group (Hb&lt;110g/L) (HR=0.5, 95% CI 0.31, 0.81, P=0.004). The OS was 14.4m with normal Hb level as compared with 8.2m with decreased Hb level( HR=0.59, 95% CI 0.37, 0.94, P=0.024). No significant difference was observed in objective response rate (ORR) and disease control rate (DCR) in the different NLR, PLR, Hb group, respectively. Univariate and multivariate analysis found that NLR, PLR, Hb were independent prognostic biomarkers for PFS and OS (p&lt;0.05). Conclusions: pre-treatment NLR, PLR, Hb was significantly associated with PFS and OS in patients with AGC and MGC who received immunotherapy. Clinicians need to consider patients with elevated NLR and PLR or decreased Hb level for decisions on immunotherapy strategy.

Tumor growth rate in pancreatic neuroendocrine tumor patients undergoing PRRT with 177Lu-DOTATATE.

BackgroundMonitoring of pancreatic neuroendocrine tumors (PanNET) undergoing peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE depends on changes in tumor size, which often occur late. Tumor growth rate (TGR) allows for quantitative assessment of the tumor kinetics expressed as %/month. We explored how TGR changes before and during/after PRRT and evaluated TGR as a biomarker for progression-free survival (PFS).MethodsIn PanNET patients undergoing PRRT with 177Lu-DOTATATE from 2006 to 2018, contrast-enhanced CT or MRI was performed before and during the therapy. Patients with at least one hypervascular liver metastasis were included. TGR was calculated for the period preceding treatment and for two intervals during/after PRRT. Cox regression was used for the survival analysis.ResultsSixty-seven patients (43 men, 24 women), median age 60 years (range 29–77), median Ki-67 10% (range 1–30) were included. TGR before baseline (n = 57) (TGR0) was mean (s.d.) 6.0%/month (s.d. = 8.7). TGR at 4.5 months (n = 56) (TGR4) from baseline was −3.4 (s.d. = 4.2) %/month. TGR at 9.9 months (n = 57) (TGR10) from baseline was −3.0 (s.d. = 2.9) %/month. TGR4 and TGR10 were lower than TGR0 (TGR4 vs TGR0, P < 0.001 and TGR10 vs TGR0, P < 0.001). In the survival analysis, patients with TGR10 ≥ 0.5%/month (vs <0.5%/month) had shorter PFS (median = 16.0 months vs 31.5 months, hazard ratio 2.82; 95% CI 1.05–7.57, P = 0.040).DiscussionTGR in PanNET patients decreases considerably during PRRT with 177Lu-DOTATATE. TGR may be useful as a biomarker to identify patients with the shortest PFS.

Abstract 1413: Exploring the prognostic value of microRNAs and drug exposure in patients with metastatic castration resistant prostate cancer treated with abiraterone: a prospective observational study

Abstract Background Abiraterone acetate is registered for treatment of metastatic prostate cancer, including those with castration-resistant disease (mCRPC). Although it improves overall survival and progression free survival (PFS), treatment response differs between patients. Biomarkers to predict treatment response are lacking. Liquid biopsies containing microRNAs (miRNAs) are a promising source of prognostic biomarkers in mCRPC patients. Furthermore, the exposure to abiraterone in plasma is highly variable and subtherapeutic exposure might contribute to the variability in response to therapy. We explored the prognostic value of microRNAs and drug exposure in mCRPC patients treated with abiraterone. Methods In a prospective multi-center observational study, 53 patients with mCRPC were included who started pre-chemotherapy abiraterone treatment. Blood was drawn at baseline, 1, 3 and 6 months after start of treatment. The following predefined miRNAs were selected; miR-21, miR-141, miR-200a, miR-200c, miR-375, miR-3687 and abiraterone concentrations were measured. MiRNA-levels in 30 healthy individuals served as controls. Relative miRNA-levels were calculated by the ΔΔCt method. If the geometric mean of a miRNA was more than 2-fold higher in patients versus healthy controls, they were included for survival analysis. Ctrough levels after 1, 3 and 6 months of therapy were measured. The average Ctrough level per patient was used for further analysis. The prognostic value of miRNAs and drug exposure for PFS (radiographic, biochemical or clinical progression) was analyzed with Kaplan-Meier (KM) analysis and tested with a log-rank test. Cut-off values for miRNAs in KM analysis were calculated using maximally selected rank statistics and for the relation with abiraterone Ctrough the earlier defined threshold of 8.4ng/ml was used. Results Of the miRNAs analyzed, miR-375 was more than 2-fold higher in mCRPC patients versus healthy controls. Patients with more than 2.16 fold higher miR-375 compared to healthy controls showed a trend towards shorter PFS, median 352 vs. 456 days (p=0.076). No PFS benefit was shown for patients with a mean abiraterone Ctrough concentration ≥8.4ng/ml compared to patients below this threshold, median 411 vs. 409 days (p=0.81). Conclusion High levels of miR-375 might be a prognostic biomarker for PFS in patients with mCRPC treated with abiraterone. The prognostic value of this miRNA should be further explored in a larger cohort of patients. Additionally, the functionality of miR-375 should be further elucidated. The beneficial effect of higher abiraterone exposure levels could not be confirmed in this study for this patient population. Citation Format: Emmy Boerrigter, Guillemette E. Benoist, Inge M. van Oort, Gerald W. Verhaegh, Onno van Hooij, Levi Groen, Frank Smit, Irma M. Oving, Pieter de Mol, Tineke J. Smilde, Diederik M. Somford, Niven Mehra, Jack A. Schalken, Nielka P. van Erp. Exploring the prognostic value of microRNAs and drug exposure in patients with metastatic castration resistant prostate cancer treated with abiraterone: a prospective observational study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1413.

Abstract B04: Immune modeling analysis identifies ICOS and CTLA-4 as predictive biomarkers in serous epithelial ovarian cancer

Abstract Objective: The goal of this study is to comprehensively determine the most clinically relevant immune checkpoint receptor in epithelial ovarian cancer (EOC). Methods: Stage III, Grade III EOC formalin-fixed, paraffin-embedded (FFPE) tumors from ten patients were submitted to Cofactor Genomics to undergo RNA sequencing and machine learning analysis to determine immune cell content and levels of the ten most studied immune escape genes. Patient samples were stratified by high progression-free survival (PFS) of 65 months or greater (n=5) and low PFS of 7 months or less (n=5). All patient tumors submitted were from primary debulking surgery and were naïve to chemotherapy. Immunohistochemistry (IHC) was employed to validate findings. Results: The two immune escape genes ICOS and CTLA-4 were found to be the most predictive biomarkers differentiating short and long PFS. ICOS median transcripts per million (TPM) were 418 and 1,621 in patients with short and long PFS, respectively (p&amp;lt;0.03), while median TPM for CTLA-4 were 1,294 and 4,045 in patients with short and long PFS, respectively (p&amp;lt;0.03). In addition, PD-1 exhibited a median TPM of 817 in patients with short PFS compared to 2455 in patients with long PFS (p&amp;lt;0.05). Immune cell profiling revealed a statistically significant (p&amp;lt;0.05) lower percentage of M2 macrophages in patients with a long PFS (1.07%) compared to patients with a short PFS (2.13%). Higher percentages of CD4+ T cells, CD8+ T cells, CD19+ B cells, and Tregs were detected in patients with a longer PFS compared to short; however, these differences did not reach statistical significance. It was discovered that immune escape genes PD-1, PD-L1, CTLA-4, OX40, TIM3, and ICOS all significantly correlated (p&amp;lt;0.05) to the percentage of CD8+ T cells and total immune cell content. CD47 levels significantly inversely correlated to total immune cell percentages (p&amp;lt;0.02). OX40 was the only immune escape gene that significantly correlated to percentage of CD4+ T cells (p&amp;lt;0.03). PD-1, PD-L1, CTLA-4, OX40, and ICOS all correlated significantly to the percentage of CD19+ B cells (p&amp;lt;0.02). Finally, PD-L1, CTLA-4, OX40, TIM3, and ICOS all significantly correlated to Treg levels (p&amp;lt;0.03). Conclusions: Immune modeling analysis revealed ICOS and CTLA-4 as the most predictive immune biomarkers for PFS in EOC. Interestingly, it was discovered that levels of both activating and inhibitory immune checkpoint receptors correlate to a higher percentage of immune cell populations, indicating overall immune content is important in predicting improved outcomes. Future directions include repeating this assay in a larger patient cohort to validate the predictive threshold determined for ICOS and CTLA-4. Citation Format: Nicole James, Matthew Oliver, Joyce Ou, Jenna Emerson, Katherine Miller, Erin Lips, Ashley Borgstadt, Paul DiSilvestro, Jennifer Ribeiro. Immune modeling analysis identifies ICOS and CTLA-4 as predictive biomarkers in serous epithelial ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B04.

Serum NY-ESO-1 and XAGE1 antibodies as predictive biomarkers in anti-PD-1 therapy for non-small-cell lung cancer.

106 Background: Programmed death-1 (PD-1) inhibitors effectively treat non-small-cell lung cancer (NSCLC) and prolong survival, but the clinical benefits are limited in a small population. However, robust biomarkers for predicting clinical benefits with anti-PD-1 therapy have yet to be identified, therefore, predictive biomarkers are needed to select patients with benefits. On the other hand, NSCLC expresses NY-ESO-1 and XAGE1 cancer-testis antigens, which elicit spontaneous immune responses in NSCLC patients. Methods: We conducted a prospective multicenter study to investigate whether serum antibody against NY-ESO-1 and/or XAGE1 antigens was a predictive biomarker in anti-PD-1 therapy for NSCLC. Serum antibody was serially detected by ELISA, and antibody titers were monitored during anti-PD-1 therapy. Tumor tissues were analyzed by immunohistochemistry and whole exome sequencing. Objective response rate (ORR) and survival were the primary and secondary endpoint, respectively. Results: In the discovery cohort (n = 13), six antibody-positive NSCLC responded to anti-PD-1 therapy (two complete and four partial responses), whereas seven antibody-negative NSCLC did not. Antibody positivity was associated with good response and survival, regardless of tumor PD-ligand1 expression, mutation burden, and CD8 T-cell infiltration. In the independent validation cohort (n = 40), ten antibody-positive NSCLC obtained the significant clinical benefits with anti-PD-1 therapy as compared with 30 negative NSCLC (ORR 50% vs 6.7%, P = 0.006). In the multivariate analysis, only antibody positivity was a significantly better predictive biomarker of progression free survival (HR 0.04, 95% CI 0.0 to 0.3) and overall survival (HR 0.2, 95% CI 0.0 to 0.9) after anti-PD-1 therapy. Antibody titers in responders transiently increased with spikes and gradually decreased with tumor shrinkage after anti-PD-1 therapy, and strongly correlated with tumor reduction rates and tumor burden. Conclusions: Our results suggest that NY-ESO-1 and/or XAGE1 serum antibodies are useful biomarkers for predicting clinical benefits and monitoring tumor burden in anti-PD-1 therapy for NSCLC.

The prognostic value of neutrophil to lymphocyte ratio on prostate cancer patients treated with maximal androgen blockade

Objective To evaluate the prognostic value of pretreatment neutrophil to lymphocyte ratio (NLR) on prostate cancer patients treated with maximal androgen blockade (MAB). Methods The clinical data of 249 prostate cancer patients treated with MAB in our hospital from October 2007 to March 2017 were retrospectively analyzed. Among all the patients, the median age was 72 years old (ranged 48 to 89 years). The BMI was 14.5-31.8kg/m2 (median 23.0 kg/m2). The PSA was 1.00-758.21 ng/ml (median 60.04 ng/ml). 216 patients’ tumor invaded surrounding tissues; lymph node metastasis occurred in 157 patients; and distant organ metastasis occurred in the remaining 174 patients. The Gleason score was 3-10 (median 7). Coprimary end points were progression-free survival (PFS) and cancer-specific survival (CSS). The best cutoff value of NLR was calculated by receiver operating characteristic (ROC) curve. The prognostic analysis of NLR on prostate cancer patients treated with MAB was estimated using Cox proportional hazards models and Kaplan-Meier analysis. Results The ideal cutoff value of the pretreatment NLR was 2.29 (95%CI 0.603-0.737, P<0.001) determined by the ROC curve according to the survived and deceased cases at the end point of CSS, by which the 249 patients was divided into the high NLR group of 119 patients (47.8%) and the low NLR group of 130 patients (52.2%). High NLR was significantly associated with high Gleason score (P=0.019), higher clinical T stage (P=0.001), N stage (P<0.001), M stage (P<0.001) and more neutrophil count (P<0.001). The median follow-up time was 29 months (ranged 5 to 124). During this period, 115 patients died, and the whole fatality rate was 46.2%. 40 patients died in low NLR group (30.8%), while the figures for the high NLR group were 75(63.0%). Kaplan-Meier analysis demonstrated that patients with NLR ≥2.29 had a poor outcome both in PFS (P<0.001) and CSS (P<0.001). The multivariate Cox analysis showed that NLR, Gleason score, clinical TNM stage and ECOG score were independent predictors for PFS and CSS. Conclusion Pretreatment NLR could be an independent prognostic biomarker for PFS and CSS in prostate cancer patients undergoing MAB. Key words: Prostatic neoplasms; Maximal androgen blockade; Neutrophil to lymphocyte ratio; Prognosis

Abstract LB-146: T cell receptor immunosequencing improves prediction of melanoma recurrence

Abstract Background: The prognosis of patients with early-stage melanoma remains poor with overall survival at 10 years below 40% in patients with stage IIC disease. The use of anti-PD-1 adjuvant therapy has improved outcomes for some, but the role of the immune system in early disease and selection of ideal candidates for checkpoint blockade require further elucidation. Clonality of the tumor T-cell repertoire, as measured by next-generation immunosequencing of T-cell receptors (TCRs), recently demonstrated its utility as a biomarker of response to anti-PD-1 therapy in metastatic melanoma. Here, we aim to evaluate its ability to predict recurrence in patients who underwent resection of primary melanomas. Methods: Biomarkers of progression free survival (PFS) were evaluated in a cohort of 72 archival FFPE tumors from subjects who were followed for a minimum of five years. Tumor TCR-beta clonality and infiltrating T-cell fraction (fraction of nucleated cells that are T-cells) were quantified by the immunoSEQ® Assay (Adaptive Biotechnologies) while Breslow thickness, ulceration, mitotic rate, and briskness of tumor infiltrating lymphocytes were assessed by histopathology. Results: T-cell fraction, but not clonality, was a robust independent variable in predicting PFS (Cox Proportional Hazard Ratio = 0.71, p-value = 0.007) after resection of primary melanomas in patients who were not treated with immunotherapy regimens. In a gradient boosted model, T-cell fraction was second only to Breslow thickness in weighted importance for predicting PFS, which together accounted for 60% of the model's classification power. Variables comprising the remaining 40% included ulceration, patient age, tumor stage, and mitotic rate, and, except for stage, generally correlated with Breslow thickness. T-cell fraction, however, was not correlated with any clinical or histopathological variable, including briskness. The bivariate model Cox Regression of Breslow thickness and T-cell fraction performed better than Breslow thickness alone in predicting PFS (Likelihood Ratio Test p-value = 0.03). Furthermore, patients with high T-cell fractions had delayed recurrence (median of 19 vs 9 months, high vs low T-cell fraction in melanomas &amp;gt; 2.5mm; median PFS not reached for melanomas &amp;lt; 2.5mm). Conclusion: Patients with high T-cell fractions in intermediate and high-thickness melanomas have a more favorable prognosis and may be ideal candidates for adjuvant immunotherapy to prolong PFS. These findings are currently being validated in an expanded cohort of archival samples. Disclaimers/disclosures: For Research Use Only. Not for use in diagnostic procedures. Partial financial support provided by Adaptive Biotechnologies. Citation Format: Julie A. Rytlewski, Wiebke Pruessmann, James Wilmott, Martin C. Mihm, Beatrice Dyring-Andersen, Rachael A. Clark, Erik Yusko, Alexandra Snyder, Harlan Robins, Richard Scolyer, Thomas S. Kupper. T cell receptor immunosequencing improves prediction of melanoma recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-146.

Biomarker potential of IL-6 and VEGF-A in ascitic fluid of epithelial ovarian cancer patients

BackgroundOvarian cancer is represented with significantly higher mortality rate predominately due to asymptomatic behaviour during initial disease course and at diagnosis majority patients already progressed to advanced stage. Acellular fraction of ascites in epithelial ovarian cancer (EOC) has been suggested to promote growth of tumor cells by providing ambient micro-environment for their proliferation. This acellular fraction contains multiple growth factors including IL-6 and VEGF-A, which were exploited to establish their bio-marker significance in EOC patients. MethodsIL-6 and VEGF-A levels in ascitic fluid of 30 EOC patients and 15 controls were measured using high sensitivity sandwich enzyme linked immune sorbent (ELISA) assay. Their levels were correlated with clinico-pathological characteristics and bio-marker potential was assessed. Results and conclusionEOC patients showed significantly higher levels for IL-6 (median-5636 pg/ml) and VEGF-A (median-4556 pg/ml) in ascitic fluid compared to controls. Levels of IL-6 and VEGF-A significantly correlated with clinico-pathological parameters. ROC curves of IL-6 and VEGF-A showed absolute combination of sensitivity and specificity. Kaplan Meier analysis demonstrated that higher levels of IL-6 and VEGF-A were significantly associated with shorter progression free survival. Thus, this study revealed that IL-6 and VEGF-A have great potential to be used as superior bio-markers for progression free survival in future after validation in larger patients' cohort.

Abstract A050: PIK3CA mutation status in tumor tissue and ctDNA as a biomarker for PFS in patients with HR+, HER2- ABC treated with buparlisib or placebo plus fulvestrant: results from the BELLE-2 and BELLE-3 randomized studies

Abstract Background: PIK3CA mutation status is a potential biomarker for treatment response to buparlisib (BUP; pan-phosphatidylinositol 3-kinase [PI3K] inhibitor) plus fulvestrant (FUL) in patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). Here, we report progression-free survival (PFS) per PIK3CA mutation status (by polymerase chain reaction [PCR] in tumor tissue or BEAMing in circulating tumor [ct]DNA) in two distinct studies: BELLE-2 (NCT01610284) and BELLE-3 (NCT01633060). Methods: The double-blind Phase III BELLE-2 study randomized (1:1) postmenopausal pts with HR+, HER2- ABC who progressed on/after aromatase inhibitor therapy to receive oral (PO) BUP or placebo (PBO) plus intramuscular (IM) FUL. PIK3CA mutation status was determined by PCR in tumor tissue or BEAMing in ctDNA at baseline in a subset of pts with available samples. The double-blind phase III BELLE-3 study randomized (2:1) postmenopausal pts with HR+, HER2- ABC who relapsed on/after endocrine therapy and a mammalian target of rapamycin inhibitor to receive PO BUP or PBO plus IM FUL. PIK3CA mutation status was determined by PCR in tumor tissue or BEAMing in ctDNA at baseline in a subset of pts with available samples. Results: BELLE-2 randomized 1147 pts, including 587 with PIK3CA status per BEAMing and 1002 per PCR. A clinically meaningful improvement in PFS was seen in 200 pts with PIK3CA-mutant status per BEAMing treated with BUP+FUL vs PBO+FUL (median=7.0 vs 3.2 months; hazard ratio [HR] 0.56 [95% confidence interval {CI} 0.39-0.80]; 1-sided nominal P=0.0005), but not in 387 with wild-type status (median=6.8 vs 6.8 months; HR 1.05 [95% CI 0.82-1.34]; 1-sided nominal P=0.642), suggesting a predictive utility of PIK3CA status per BEAMing in ctDNA at baseline. Analysis based on PIK3CA status per PCR showed that PFS was prolonged with BUP+FUL vs PBO+FUL in both 412 pts with PIK3CA-mutant status (median=7.1 vs 5.1 months; HR 0.73 [95% CI 0.57-0.92]; 1-sided nominal P=0.004) and 590 with wild-type status (median=6.8 vs 4.6 months; HR 0.84 [95% CI 0.70-1.02]; 1-sided nominal P=0.042). BELLE-3 randomized 432 pts, including 348 with PIK3CA status per BEAMing and 313 per PCR. PFS benefit was more pronounced in 135 pts with PIK3CA-mutant status per BEAMing treated with BUP+FUL vs PBO+FUL (4.2 vs 1.6 months; HR 0.46 [95% CI 0.29-0.73]; 1-sided nominal P&amp;lt;0.001) than in 213 with wild-type status (3.9 vs 2.7 months; HR 0.73 [95% CI 0.53-1.00]; 1-sided nominal P=0.026). PFS benefit was also more pronounced in 109 pts with PIK3CA-mutant status per PCR treated with BUP+FUL vs PBO+FUL (4.7 vs 1.4 months; HR 0.39 [95% CI 0.23-0.65]; 1-sided nominal P&amp;lt;0.001) than in 204 with wild-type status (2.8 vs 1.7 months; HR 0.81 [95% CI 0.59-1.12]; 1-sided nominal P=0.099). Conclusions: Results from the large randomized BELLE-2 and BELLE-3 studies suggest that PIK3CA mutation status determined by PCR in tumor tissue or BEAMing in ctDNA is a positive predictive biomarker of PI3K inhibitor treatment efficacy in pts with HR+, HER2- ABC. ctDNA has the potential to drive study designs, given the flexibility of plasma sample collection and accurate determination of current PIK3CA status prior to treatment start. Citation Format: José Baselga, Dalila Sellami, Mona El-Hashimy, Bharani Dharan, Amanda Wang, Nicolas Scheuer, Banu Sankaran, Angelo Di Leo. PIK3CA mutation status in tumor tissue and ctDNA as a biomarker for PFS in patients with HR+, HER2- ABC treated with buparlisib or placebo plus fulvestrant: results from the BELLE-2 and BELLE-3 randomized studies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A050.

Baseline cell-free DNA (cfDNA) and metabolic tumor volume (MTV) independently predict outcome in metastatic chemorefractory colorectal cancer (mCRC).

11569 Background: No validated prognostic biomarker is currently available for mCRC. This trial assessed cfDNA and MTV before treatment with regorafenib as prognostic biomarkers for progression-free survival (PFS) and overall survival (OS) in mCRC. Methods: After signed informed consent, mCRC patients were enrolled in a prospective non-randomized trial aiming to define unlikelihood to benefit from regorafenib (EudraCT number: 2012-005655-16) and assessed for cfDNA and FDG PET/CT MTV at baseline. cfDNA was extracted from 3mL of plasma and quantified using the Qubit 2.0 fluorometer. All target lesions were delineated on FDG PET/CT using a PERCIST-based threshold and their volumes were summed to obtain total MTV. MTV and cfDNA optimal cutoffs for OS and PFS prediction were determined by the Contal and O’Quigley’s method. MTV, cfDNA, age, gender, Body Mass Index (low, normal, high, obese), ECOG PS, number of chemotherapy lines (NCL), previous use of bevacizumab and presence of a KRAS mutation were included in a multivariate analysis. Results: MTV and cfDNA of 132 evaluable/141 eligible patients were well correlated (Spearman’s correlation coefficient = 0.70; p &lt; 0.001) and risk groups for both PFS and OS were identified on the basis of cfDNA (cfDNA &lt; 1 µg/mL; cfDNA≥1 µg/mL) and MTV (MTV &lt; 100 cm³; 100-300 cm³; &gt; 300 cm³). The multivariate analysis retained cfDNA, MTV, NCL, and obesity as independent parameters for PFS prediction, and cfDNA, MTV, NCL, BMI, and previous use of bevacizumab as independent parameters for OS prediction. Prognostic scores for PFS and OS were developed based on regression coefficients from the final Cox proportional hazards models. Prognostic scores for PFS (1.8 vs 5.3 months, HR: 3.15 for score ≥-3 vs &lt; -3, (95% CI, 2.08-4.76); p &lt; 0.001) and for OS (4.2 vs 13.9 months, HR: 4.59 for score ≥-6 vs &lt; -6: (95% CI, 2.92-7.21); p &lt; 0.001) both identified patients with much contrasted outcomes. Conclusions: Baseline cfDNA and MTV along with BMI parameters predict outcome in patients with mCRC before regorafenib onset. These parameters not related to treatment should be considered, if validated in further studies, as stratification factors in future clinical trials. Clinical trial information: 2012-005655-16.

Early-onset neutropenia-related events in eribulin monotherapy: A possible biomarker in the real world?

e12529 Background: Eribulin mesylate (eribulin) showed antitumor activity via the anti-tubulin effect, and improved overall survival (OS) in HER2-negative (HER2-) metastatic breast cancer (MBC) patients without extending progression-free survival (PFS) in a phase 3 trial. On the other hand, according to the published data (Watanabe J, Springerplus, 2015), eribulin monotherapy improved OS in the clinical setting, and PFS is a possible surrogate for OS in HER2-, hormone receptor-positive (HR+) MBC patients. However, there is no practical biomarker for PFS in relation to eribulin monotherapy in patients with HER2-HR+MBC. Methods: Eribulin was administered according to the instructions in the package insert (1.4mg/m2 on days [D] 1 and 8, and a 21-day cycle [C]). The medical records of the patients who received eribulin monotherapy were reviewed. Results: From August 2011 to December 2016, 90 HER2-HR+MBC patients received eribulin monotherapy as daily practice at our institution, and 84 (93.3%) patients terminated their therapy. Lung and/or liver metastasis was observed at the induction of the therapy in 68 (86.7%) of the patients. The median relative dose of eribulin on C1D1 was 95.3% (1.33mg/body). Fever was observed during C1 in 23 (25.6%) patients, and grade (G) 3/4 neutropenia was observed on C1D8 in 28 (31.1%) patients. In contrast, only 4 (4.4%) patients developed febrile neutropenia within C1. Due to the delayed recovery of neutrophils, the second cycle of treatment was suspended in 8 (8.9%) patients. With regard to liver test abnormalities, an elevation of one grade in comparison to baseline, which resolved afterward without specific treatment, was observed during C1 in 24 (26.7%) patients. A multivariate Cox regression analysis revealed that G3/4 neutropenia on C1D8 and a delay of C2D1 were strong predictors of PFS (hazard ratio [HR] 0.53; p &lt; 0.05, HR 0.42; p &lt; 0.05, respectively). A chi-squared test revealed no statistically significant differences between the two subgroups in the relative dose on C1D1. Conclusions: This retrospective, observational study revealed that early-onset neutropenia-related events may be a biomarker for eribulin therapy that can be applied in the clinical setting.

The role of pharmacogenetics in the new ESMO colorectal cancer guidelines.

The role of pharmacogenetics in the new ESMO colorectal cancer guidelines.

589P - Is baseline neutrophil to lymphocyte ratio (NLR) an independent prognostic biomarker for progression free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC)? Analysis of the AGITG MAX study

589P - Is baseline neutrophil to lymphocyte ratio (NLR) an independent prognostic biomarker for progression free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC)? Analysis of the AGITG MAX study

MAVERICC, a phase 2 study of mFOLFOX6-bevacizumab (BV) vs FOLFIRI-BV with biomarker stratification as first-line (1L) chemotherapy (CT) in patients (pts) with metastatic colorectal cancer (mCRC).

493 Background: Standard 1L mCRC treatment (tx) includes a CT backbone (e.g., modified leucovorin [LV]/5-fluorouracil [5-FU]/oxaliplatin [mFOLFOX6] or LV/ 5-FU/ irinotecan [FOLFIRI]) and biologic therapy (e.g., BV). The preferred CT backbone for anti VEGF tx is unknown. MAVERICC (NCT01374425), a global, randomized, open-label, phase 2 trial, assessed tx efficacy and safety of mFOLFOX6-BV vs FOLFIRI-BV in pts with mCRC. Intratumoral ERCC1 and plasma VEGF-A were studied as biomarkers for oxaliplatin- and BV-containing tx, respectively. Methods: Pts with mCRC (≥1 measurable metastatic lesion, ECOG performance status ≤1) were randomized 1:1 to receive BV (5 mg/kg) + mFOLFOX6 or FOLFIRI every 2 weeks, stratified by ERCC1 level (low [£1.7] vs high [&gt;1.7]) and region. VEGF-A levels were measured at baseline. Primary objectives were to evaluate: ERCC1 as a biomarker of progression-free survival (PFS) in 1L mCRC tx (mFOLFOX-BV vs FOLFIRI); and VEGF-A as a biomarker for BV and as a biomarker in combination with ERCC1 for PFS following CT + BV. Secondary objectives were to evaluate: the effect of ERCC1 and VEGF-A on overall survival (OS), objective response rate, hepatic metastases resection, and safety. PFS and OS were estimated by Kaplan–Meier methods, hazard ratios (HR) were estimated by Cox regression, and p-values were based on stratified log-rank tests. ERCC1 biomarker analyses are presented here. Results: A total of 376 pts were randomized: median age, 61 yr; white race, 83%; US region, 85%. Baseline characteristics: ERCC1 high, 35%; KRAS mutant, 34%. Efficacy results are shown (see Table). Conclusion: Consistent with previous findings, PFS and OS were comparable in pts treated with either 1L mFOLFOX6-BV or FOLFIRI-BV. Exploratory analyses within pts with high ERCC1 levels suggest consistent results. VEGF-A analyses are ongoing. Clinical trial information: NCT01374425. [Table: see text] [Table: see text]

18F]NaF PET/CT imaging biomarkers of progression-free survival in metastatic prostate cancer.

277 Background: 18F-Sodium Fluoride (NaF) PET/CT has been shown to be superior to 99mTc-MDP SPECT in detection of bone metastases and shows great promise to reliably measure functional changes in bone. This study assesses the relationship of Progression Free Survival (PFS) with NaF PET/CT measures in patients with metastatic Castration-Resistant Prostate Cancer (CRPC). Methods: 55 CRPC patients had NaF PET/CT scans performed at baseline, which was repeated at week 9 if receiving taxane-based therapy (N = 16) or week 12 if receiving androgen-signaling pathway (AR) inhibitors (N = 39). Bone lesions were identified using a novel technique allowing for extraction and tracking of PET metrics from individual lesions at every timepoint. Cox proportional hazard regression analyses were conducted to evaluate associations between imaging metrics and PFS. Results: Median PFS was 8.3 months (range 1.0-30.3+). The strongest predictor of PFS in univariate analysis was total functional burden (SUVtotal) (P &lt; 0.0001) during treatment for all patients. Predictors of PFS differed between both treatment cohorts of patients (Table 1), including number of lesions, fraction of skeletal involvement, and average lesion activity (SUVmean). Maximum PSA benefit (percent decrease) during the first 12 weeks of therapy was highly predictive of PFS in the AR-directed cohort of patients (HR = 1.012 , P = 0.0005), as was change in the number of lesions (HR = 1.01, P = 0.03). Conclusions: There is indication thattotal functional burden of disease during treatment with taxane or AR-directed therapy is a strong predictor of PFS. In addition, change in number of lesions was predictive of treatment efficacy. This supports ongoing development of NaF PET/CT based imaging biomarkers in mCRPC. Clinical trial information: NCT01516866. [Table: see text]

Abstract 5281: Prognostic biomarkers for progression-free survival in glioblastoma multiforme: quantitative imaging and gene expressions

Abstract Prognostic biomarkers at initial diagnosis of untreated Glioblastoma Multiforme (GBM) are an important step towards development of predictive biomarkers in this patient pool for personalized medicine. We hypothesize that quantitative imaging biomarkers are independent to gene expression biomarkers in progression-free-survival (PFS) prognosis and overall survival (OS). It is known that patient with large strong enhancing tumor have a shorter PFS and OS. Weak enhancing tumor, which is believed to be more infiltrative in nature, has rarely been studied due to the difficulties in identifying them visually. Method: We developed an automated image analysis technique to quantify weak enhancing tumor, strongly enhancing tumor, edema and necrosis from a single source site (n = 25) of TCIA with gene expression from TCGA. We define tumor volume (in cm3) of Zone1A as the enhancing tumor plus necrosis; Zone1B as necrosis plus weak enhancing tumor; and Zone2 as total tumor load of necrosis, strong enhancing and weak enhancing tumor. Cox proportional hazard model was used to determine prognostic significance of imaging parameters to PFS and OS. Level 1 gene expression data from Affymetrix platform were processed in R. We filter the gene probe list to 7277 probes (31.9%) based on biological variability and take the probes that are &amp;gt;2-fold upregulated compared to normal control (n = 10) (t-test, p&amp;lt;0.05, multiple comparison corrected), resulted to 167 probes. Gene probes prognostic to PFS are selected based on unadjusted log-rank test (p&amp;lt;0.05). Result: There are 19 matched cases with imaging and gene expression with one living patient. MGMT is methylated in 4 patients and unmethylated in 10 patients. All cases are non-G-CIMP and IDH1 WT or unknown. The age and karnofsky score (kps) distribution are 55±15 yo and 85±11. Tumor size measurements are strongly prognostic for PFS adjusted by age and kps: Zone1A (HR = 1.04 [1.01, 1.07], p = 0.0137, log-rank p = 0.063), Zone1B (HR = 1.08 [1.03, 1.13], p = 0.0014, log-rank p = 0.00020), Zone 2 (HR = 1.037 [1.012 1.063], p = 0.0034, log-rank p = 0.011). Only 18 gene probes are prognostic to PFS, which are CASP4, CD44, COL5A1, COL6A2, HCP5, IL10RB, IL15, LOXL2, LY75, PTX3, SERPINEH1, SLC16A3, STC1, TNC. These genes are involved in ECM-receptor interaction, focal adhesion and cytokine mediated inflammation pathway. After adjusting for age and kps, only CD44, COL5A1, COL6A2, LOXL2, IL10RB, STC1 are significant based on log-rank test while the HR of age and kps are not significant. Adjusting for age, kps and Zone1B resulted to log-rank significance of CASP4, LOXL2, TNC, IL10RB, IL15, PTX3, STC1, HCP5, SLC16A3, with HR significance of Zone1B, gene, age and sometimes kps. The mean HR of Zone1B is 1.085±0.013 and the maximum log-rank p = 0.0002567 for all these genes. Conclusion: Total tumor load of necrosis and weak enhancing tumor is a strong independent prognostic biomarker of PFS in addition to gene, age and kps. Citation Format: Kelvin K. Wong, Stephen TC Wong. Prognostic biomarkers for progression-free survival in glioblastoma multiforme: quantitative imaging and gene expressions. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5281. doi:10.1158/1538-7445.AM2015-5281