Primary pancreatic adenocarcinoma (PPDA) and metastatic pancreatic adenocarcinoma (MPDA): Are they genomically distinct?

e16226 Background: PDA is an aggressive disease with a dismal prognosis. Advances in next-generation sequencing (NGS) have enabled targeted therapies, revolutionizing treatments of several solid tumors. Their role in the management of PDA is limited, in part due to the paucity in our understanding of targetable genomic events. We sought to evaluate genomic differences between PPDA and MPDA in the tumor and tumor immune microenvironment (TIME). The genomic changes after chemotherapy (CTX) administration were also evaluated. Methods: NGS data derived from tumor samples of 150 unique patients was analyzed. Targeted 648 gene DNA sequencing was performed using the Tempus xT and xO assays. Patients were allocated into 2 cohorts: PPDA (n = 75) and MPDA (n = 75), which were overall similar in terms of their demographics. The frequencies of somatic mutations were compared. The immune infiltrate was imputed from RNAseq. Proportions of immune cells (IC), and the tumor mutational burden (TMB) relative to the proportion of IC in the TIME, were also analyzed. Kaplan Meier Survival estimates for most frequent mutations and TMB were calculated. Results: The most frequently mutated genes amongst the 150 study subjects were: KRAS (92.7%), TP53 (76.7%), CDKN2A (45.3%), SMAD4 (31.3%), ATM (12.7%) and ARID1A (10.7%). Patients in the MPDA cohort had a higher rate of mutation in several genes when compared to PPDA, most notably in TP53 (85.3% vs 68.0%, p = 0.010), ARID1A (16.0 vs 5.3%, p = 0.037) CDKN2A (49.3 vs. 41.3%, p = 0.3) and SMAD4 (33.3 vs. 29.3 p = 0.7). We also evaluated if the genetic changes between PPDA and MPDA are associated with alterations in the TMB and differences in the TIME. A higher TMB was seen amongst patients in the MPDA vs PPDA cohort (2.73 vs 1.73 Mut/Mb, p = 0.008). TMB was also significantly increased after CTX (2.22 vs 1.63 Mut/Mb p = 0.049). TMB ≥ 3 was associated with decreased odds of progression free survival ≥ 12 months (OR 0.26 95% CI 0.078-0.822, p = 0.023). Regarding immune infiltrate, the proportion of CD4 and CD8 T cells were higher in the PPDA cohort. Macrophages and NK cells were more prevalent the MPDA cohort. TMB had a positive correlation with the degree of macrophage infiltration in the TIME (Multivariate estimate: 1.70, p value 0.01). Conclusions: PPDA and MPDA are biologically dissimilar entities with genomic disparity. Associated differences were observed in TMB and TIME. There is a differential increase in the spectrum of mutations in MPDA as compared to PPDA, specifically in p53, ARID1A, CDKN2A and SMAD4. The burden of increased mutations in MPDA is associated with an increase in the TMB and tumor associated macrophages. The role of serial NGS in the management of PDA both in early and late disease should be investigated further to identify evolving genomic changes that correlate with outcome.

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NOVEL PLASMA GLYCOPROTEIN BIOMARKERS PREDICT PROGRESSION-FREE SURVIVAL IN SURGICALLY RESECTED CLEAR CELL RENAL CELL CARCINOMA

10.1101/2022.01.11.21268517 ◽

2022 ◽

Author(s):

Daniel Serie ◽

Amanda A Myers ◽

Daniela A Haehn ◽

Alexander Parker ◽

Essa Bajalia ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Differential Expression ◽

Renal Cell ◽

Clear Cell ◽

Progression Free Survival ◽

P Value ◽

Cell Renal Cell Carcinoma ◽

Free Survival ◽

Kaplan Meier

Introduction: Limited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS). Methods: Plasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrells c-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves. Results: The average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate p ≤0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR=6.47, P=9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR=10.69, P=0.001), clusterin A2G2 motif (HR=7.38, P=0.002), complement component C8A A2G2S2 motif (HR=11.59, P=0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR=6.30, P=0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9-10.7, all with p-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (p <0.0001). Conclusion: Differential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.

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Evaluation of different MET genotypes as biomarkers for immunotherapy outcomes in NSCLC patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21032 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21032-e21032

Author(s):

Xuanzong Li ◽

Linlin Wang

Keyword(s):

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Rank Test ◽

Wild Type ◽

Exact Test ◽

Entire Cohort ◽

Kaplan Meier ◽

Tumor Mutational Burden ◽

The Difference ◽

Nsclc Patients

e21032 Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.

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Is the platelet-to-lymphocyte ratio a new prognostic marker in multiple myeloma?

Journal of Laboratory Physicians ◽

10.4103/jlp.jlp_36_18 ◽

2018 ◽

Vol 10 (04) ◽

pp. 363-369 ◽

Cited By ~ 1

Author(s):

Serife Solmaz ◽

Ozcan Uzun ◽

Celal Acar ◽

Omur Gokmen Sevindik ◽

Ozden Piskin ◽

...

Keyword(s):

Multiple Myeloma ◽

Negative Impact ◽

Progression Free Survival ◽

Cost Effective ◽

P Value ◽

Platelet To Lymphocyte Ratio ◽

Cox Models ◽

Lymphocyte Ratio ◽

Kaplan Meier ◽

The Cost

ABSTRACT BACKGROUND: Recent reports showed neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), as a predictor of progression-free survival (PFS) and overall survival (OS) in various malignancies. MATERIALS AND METHODS: We retrospectively examined the PLR, NLR, and MLR in a cohort of 186 newly diagnosed multiple myeloma (MM) patients. This study investigated the prognostic relevance of NLR, PLR, and MLR in MM patients. NLR, PLR, and MLR were calculated from whole blood counts before therapy. The Kaplan–Meier curves and multivariate Cox models were used for the evaluation of survival. RESULTS: Applying cutoff of 1.9 (NLR), 120.00 (PLR), and 0.27 (MLR), decreased PLR showed a negative impact on the outcome. Decreased PLR is an independent predictor for PFS and OS. There were no significant differences in median survival between the high and low NLR (P = 0.80) and MLR (P = 0.87) groups. CONCLUSIONS: In this study, thrombocytopenia and low PLR are associated with poor survival in MM patients does this P value apply to thrombocytopenia or low PLR and may serve as the cost-effective prognostic biomarker.

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Germline BRCA1/2, PALB2, and ATM mutations in 3,030 patients with pancreatic adenocarcinoma: Survival analysis of carriers and noncarriers.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.280 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 280-280

Author(s):

Pashtoon Murtaza Kasi ◽

Fergus Couch ◽

William R Bamlet ◽

Chunling Hu ◽

Steven Hart ◽

...

Keyword(s):

Survival Analysis ◽

Pancreatic Adenocarcinoma ◽

Final Analysis ◽

Parp Inhibitors ◽

P Value ◽

Pathogenic Variants ◽

Kaplan Meier ◽

Hazard Ratios ◽

Before And After ◽

Brca1 Brca2

280 Background: Patients with pancreatic adenocarcinoma (PDAC) can have mutations in breast cancer associated genes ( BRCA1/2) and other homologous recombination (HR) pathway genes. The therapeutic significance of these mutations for PDAC patients is not yet established. We performed a comprehensive survival analysis of 3,030 unselected PDAC patients comparing non-carriers and carriers of BRCA1/2, PALB2, and ATM mutations. Methods: We analyzed germline DNA samples and outcomes from confirmed PDAC patients recruited from 1999-2014 into the Mayo Clinic SPORE in Pancreatic Cancer registry. A total of 3,046 genomic DNA samples were analyzed by next generation sequencing. All pathogenic variants were validated by Sanger sequencing. Survival analysis of PDAC patients with and without BRCA1, BRCA2, PALB2, or ATM germline mutations was performed using the Kaplan-Meier method and log-rank tests. Hazard ratios (HR) were calculated using Cox proportional hazard modeling adjusted for co-variates including age, sex, and stage. A p-value < 0.05 was considered statistically significant. Pre- and post-FOLFIRINOX eras were defined as before and after June 1, 2011. Results: A total of 139 (4.6%) patients were noted to have deleterious mutations in BRCA1, BRCA2, PALB2, or ATM genes. After exclusion of patients with missing data, final analysis was restricted to 2,452 PDAC patients. Overall survival was slightly better (14.2 months versus 11.3 months) in patients with mutations as compared to those without mutations, although this finding was not statistically significant (p = 0.07). When stratified by FOLFIRINOX era, 40 patients with these mutations in the post-FOLFIRINOX era had better outcomes than 668 non-carriers (adjusted HR 0.62; 95% CI 0.43-0.89; p = 0.0062). Conclusions: Deleterious germline BRCA1/2, PALB2, and ATM mutations were seen in approximately 5% of patients with PDAC. Post-FOLFIRINOX era patients with these mutations had improved outcomes, possibly secondary to exposure to DNA-damaging chemotherapies. Germline screening of PDAC patients and development of trials incorporating this information (e.g., PARP inhibitors) has potential value for PDAC patients.

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Risk Factors Associated with Survival Outcome in Patients with Chronic Myeloid Leukaemia in Accelerated Phase Treated with Tyrosine Kinase Inhibitors

Blood ◽

10.1182/blood.v128.22.1222.1222 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1222-1222

Author(s):

Kee Yon, Lionel See ◽

Kok Chong Bernard Yap ◽

Dong-Wook Kim ◽

Hein Than ◽

Yeow-Tee Goh

Keyword(s):

Risk Factors ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Chronic Phase ◽

Progression Free Survival ◽

P Value ◽

Survival Curves ◽

Advisory Committees ◽

Kaplan Meier

Abstract Chronic Myeloid Leukaemia (CML) is a triphasic disease which typically presents in chronic phase with risk of progression to more aggressive phases in a certain proportion of patients. Accelerated Phase (AP), as described in the pre-Tyrosine Kinase Inhibitor (TKI) era by Kantarjian et al in 1988, is an intermediate stage with a poor median overall survival (OS) of ≤18 months without haematopoietic stem cell transplantation (HSCT). Since TKI therapy has revolutionized CML treatment, a significantly improved OS has been seen in most CML patients, including those in AP. Not all CML-AP patients require HSCT upfront nowadays and many are able to achieve major molecular remission (MMR) and favourable OS on TKI therapy. However, updated classifications of CML-AP by the World Health Organization (WHO) and European LeukemiaNet (ELN) do not reflect these significant advances in the TKI era. There is a need to re-evaluate the CML-AP classification that will have an impact on treatment decisions for CML-AP patients. In this study, we explored the association between various haematological parameters at diagnosis and the probabilities of OS and progression-free survival (PFS) of CML-AP patients on TKI therapy. Overall Survival (OS) and Progression-Free Survival (PFS) trends of 75 newly diagnosed CML-AP patients treated with frontline TKIs between 2000 to 2013 from Singapore General Hospital and Seoul St. Mary's Hospital in South Korea were retrospectively analysed with regards to demographic and haematological parameters, such as cell counts from serum and bone marrow at diagnosis, using cox proportional hazards analysis. Survival was also compared using log-rank test with Bonferroni corrections between CML-AP patients and 227 CML Chronic Phase (CML-CP) high-risk Sokal and 34 Blast Crisis (CML-BC) patients on TKI-based therapy. OS was defined as duration from diagnosis of CML-AP to death from any reason. PFS was defined as duration from disease diagnosis to the first occurrence of progression or death due to CML. As a whole, CML-AP patients treated with frontline TKI had survival that paralleled CML-CP high-risk Sokal patients (p-value = 0.694 for OS, p-value = 0.258 for PFS). Most of the death and progression occurred less than 3 years of starting TKI therapy (69.2% for OS, 84.6% for PFS). Multivariable analysis in CML-AP patients showed that male gender, bone marrow (BM) blasts ≥10% and clonal chromosomal abnormalities (CCAs) at diagnosis were associated with poor OS (Hazard Ratio (HR) 18.53, p-value = 0.013; HR 1.16, p-value = 0.010; HR 5.05, p-value = 0.044, respectively) and poor PFS (HR 12.96, p-value = 0.021; HR 1.17, p-value = 0.007; HR 8.84.05, p-value = 0.008, respectively). CML-AP patients with all 3 of these risk factors experienced the worst OS compared to those with 1 or zero risk factors (p-value <0.001). Patients with all 3 risk factors also had the poorest PFS compared to those with 2, 1 and zero risk factors (p-value = 0.022, <0.001, <0.001 respectively; figure 1). CML-AP Patients with 2 risk factors or less, had OS and PFS probabilities comparable to CML-CP patients with high-risk Sokal score (p-value = 0.082 for OS, p-value= 0.813 for PFS, figure 2 and 3 respectively). However, CML-AP patients with all 3 risk factors showed inferior OS and PFS probabilities similar to CML-BC patients (p-value = 0.799 for OS, p-value = 0.624 for PFS; figure 2 and 3 respectively). Our findings suggested that CML-AP was a heterogeneous group with varying survival probabilities on TKI therapy. Male gender, BM blasts ≥10% and CCAs at diagnosis were risk factors shown to be predictive of survival probabilities, and identified a high-risk sub-group among CML-AP patients with inferior OS and PFS rates similar to CML-BC patients. Aggressive chemotherapeutic strategies including HSCT should be warranted in these patients. However, TKI therapy alone with close molecular surveillance may be a reasonable option for optimally responding low-risk CML-AP patients who are not eligible for HSCT. Figure 1. Kaplan-Meier survival curves for PFS according to stratification of the number of risk factors present in CML-AP patients. Figure 1. Kaplan-Meier survival curves for PFS according to stratification of the number of risk factors present in CML-AP patients. Figure 2. Kaplan-Meier survival curves for OS according to phases of CML with AP patients separated by number of risk factors present. Figure 2. Kaplan-Meier survival curves for OS according to phases of CML with AP patients separated by number of risk factors present. Figure 3. Kaplan-Meier survival curves for PFS according to phases of CML with AP patients separated by number of risk factors present. Figure 3. Kaplan-Meier survival curves for PFS according to phases of CML with AP patients separated by number of risk factors present. Disclosures Kim: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Goh:BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria; Takeda: Honoraria; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Neoadjuvant treatment for locally advanced unresectable and borderline resectable pancreatic cancer: oncological outcomes at a single academic centre

ESMO Open ◽

10.1136/esmoopen-2020-000929 ◽

2020 ◽

Vol 5 (6) ◽

pp. e000929

Author(s):

Susana Roselló ◽

Claudio Pizzo ◽

Marisol Huerta ◽

Elena Muñoz ◽

Roberto Aliaga ◽

...

Keyword(s):

Pancreatic Cancer ◽

Locally Advanced ◽

Neoadjuvant Treatment ◽

Progression Free Survival ◽

Rank Test ◽

Resectable Pancreatic Cancer ◽

Borderline Resectable ◽

Curative Intent ◽

Kaplan Meier ◽

Dismal Prognosis

IntroductionPancreatic cancer (PC), even in the absence of metastatic disease, has a dismal prognosis. One-third of them are borderline resectable (BRPC) or locally advanced unresectable PC (LAUPC) at diagnosis. There are limited prospective data supporting the best approach on these tumours. Neoadjuvant chemotherapy (ChT) is being increasingly used in this setting.MethodsThis is a retrospective series of consecutive patients staged as BRPC or LAUPC after discussion in the multidisciplinary board (MDB) at an academic centre. All received neoadjuvant ChT, followed by chemoradiation (ChRT) in some cases, and those achieving enough downstaging had a curative-intent surgery. Descriptive data about patient’s characteristics, neoadjuvant treatments, toxicities, curative resections, postoperative complications, pathology reports and adjuvant treatment were collected. Overall survival (OS) and progression-free survival was calculated with Kaplan-Meier method and log-rank test.ResultsBetween August 2011 and July 2019, 49 patients fulfilled the inclusion criteria, and all of them received neoadjuvant ChT. Fluorouracil+folinic acid, irinotecan and oxaliplatin was the most frequently used scheme (77%). The most prevalent grade 3 or 4 toxicities were neutropenia (26.5%), neurotoxicity (12.2%), diarrhoea (8.2%) and nausea (8.2%). 18 patients (36.7%) received ChRT thereafter. In total, 22 patients (44,9%) became potentially resectable and 19 of them had an R0 or R1 pancreatic resection. One was found to be unresectable at surgery and two refused surgery. A vascular resection was required in 7 (35%). No postoperative deaths were observed. Postoperative ChT was given to 12 (66.7%) of resected patients. Median OS of the whole cohort was 24,9 months (95% CI 14.1 to 35.7), with 30.6 months for resected and 13.1 months for non-resected patients, respectively (p<0.001).ConclusionA neoadjuvant approach in BRPC and LAUPC was well tolerated and allowed a curative resection in 38.8% of them with a potential improvement on OS.

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Racial disparities in immune-related adverse events (irAE) of immune checkpoint inhibitors (ICPi) and association with survival based on clinical and biochemical responses.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.7025 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 7025-7025

Author(s):

Monica Peravali ◽

Cristiane Gomes-Lima ◽

Eshetu Tefera ◽

Mairead Baker ◽

Mamta Sherchan ◽

...

Keyword(s):

Large Scale ◽

Checkpoint Inhibitors ◽

Stage Iv ◽

Positive Association ◽

Progression Free Survival ◽

P Value ◽

Eligibility Criteria ◽

Kaplan Meier ◽

Comparison Results ◽

Significant Difference

7025 Background: ICPi cause various irAE with thyroid dysfunction as a commonly reported abnormality. There is increasing evidence showing positive association with development of irAE and survival. However, prior trials with ICPi had underrepresentation of minorities with <5% African Americans (AA). Methods: We retrospectively reviewed patients (pts) with stage IV solid malignancies treated with PD1/PDL1 blockers between 1/2013-12/2018 across MedStar Georgetown Cancer Institute facilities. Pts treated with CTLA-4 inhibitors were excluded. Progression free survival (PFS) and overall survival (OS) were primary endpoints and were calculated using Kaplan-Meier methods and Wilcoxon rank sum test for comparison. Results: 293 pts met eligibility criteria. 91 pts (31%) had any grade irAE; most common AE were endocrine (40.7%) specifically TSH elevation, dermatological (23.1%) and rheumatologic (18.7%). Proportion of irAE was significantly higher in Caucasians versus AA (60.4% vs 30.8%), in pts with low PDL1, lower LDH, older age, and those who had more treatment cycles with ICPi. Rate of progression was lower in pts with irAE (30.8% vs 46.0%, p-0.0140). Median PFS (5.8 vs 3.0 months (mo), p- 0.0204) and OS (17.1 vs 7.2 mo, p value- <0.0001) were higher with irAE. Statistically significant difference in OS (17.1 vs 8.6 mo, p- 0.0002) but not in PFS (5.8 vs 3.3 mo, p: 0.0545) was noted with endocrine irAE. No differences in survival were observed among other commonly reported irAE. Differences in survival among subgroups of pts with irAE are detailed in table. Conclusions: Development of irAE positively correlated with improved PFS and OS as reported in previous studies. To our knowledge, this is the first study observing differences in OS favoring endocrine AE and Caucasian race. These factors may be potential surrogate markers of prognosis pending replication of these results in large-scale studies. [Table: see text]

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Significance of scores generated by a cancer therapy matching engine for patient outcomes.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15099 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15099-e15099

Author(s):

Eden Romm ◽

Emiliya Davtyan ◽

Kevin Bush ◽

Ramsay Sutton ◽

Itamar Patek ◽

...

Keyword(s):

Statistical Significance ◽

Progression Free Survival ◽

Sampling Bias ◽

P Value ◽

Cancer Drugs ◽

Sequencing Data ◽

Ampullary Adenocarcinoma ◽

Kaplan Meier ◽

Hazard Ratios ◽

Suitable Treatment

e15099 Background: Oncologists need effective precision medicine tools to navigate the myriad of therapeutic options to best address each patient’s unique tumor profile. Described here is a digital solution, which analyzes tumor data (NGS, other), scores and ranks known and novel matching combinations of cancer drugs with molecular-level precision for decision support. Methods: All data was acquired through the published supplement of the I-PREDICT study (NCT 02534675). Patients with available progression-free survival (PFS) and sequencing data who received <3 matched non-experimental cancer drugs in combination were evaluated (n=77). To determine each patient’s score (represented as %), the system used expert-curated content integrated within an artificial intelligence (AI) reasoning framework that computed how well the therapy each patient received matched their tumor’s genomic profile. The dataset was binarized at 36 possible thresholds, which split the data into higher vs. lower score bins. Relationship with PFS and the degree of separation between bins were evaluated with Kaplan-Meier plots and assessed in terms of p-value, hazard ratios and related confidence intervals (Table). To prevent sampling bias at high and low thresholding extremes of this dataset, a limit was imposed of >25 patients per bin. Results: Significant separation between high and low scoring bins was observed in >73% of evaluable thresholds. The mean p-value was 0.044 (range, 0.011-0.13). The hazard ratio was consistently ̃2 (mean, 1.81, range, 1.50-2.08). A similar level of statistical significance was observed for all thresholds up to and including bracketing of 60% (Table). Despite the small size of this dataset and the disparity between sample counts per bin seen at the end of the range, significant p-values of <0.05 were achieved. Ex., a 68-year-old female with an ampullary adenocarcinoma harboring ERBB2, CDK6 and other alterations, received a combination of pertuzumab and trastuzumab scoring 56%. The PFS was 745+ days. However, had palbociclib, ribociclib, or abemaciclib been added to this combination, the resulting 3-drug options would have scored even higher due to also targeting CDK6. Conclusions: Our study indicates that therapies with higher scores were predictive of better PFS, while lower scores were predictive of worse PFS. The results will be validated on larger datasets but are already demonstrative of the utility of this system in providing digital guidance to oncologists in selecting the most suitable treatment. [Table: see text]

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Paclitaxel Promotes Tumor-Infiltrating Macrophages in Breast Cancer

Technology in Cancer Research & Treatment ◽

10.1177/1533033820945821 ◽

2020 ◽

Vol 19 ◽

pp. 153303382094582

Author(s):

Jun Shen ◽

Cong Chen ◽

Zhaoqing Li ◽

Shufang Hu

Keyword(s):

Breast Cancer ◽

Progression Free Survival ◽

Cancer Prognosis ◽

Migration And Invasion ◽

P Value ◽

Free Survival ◽

Kaplan Meier ◽

The Relationship ◽

Kaplan Meier Plotter ◽

Paclitaxel Treatment

Objective: Breast cancer remains the most threatening triggers of cancer death in women. Drug resistance inevitably leads to the weakness of treatment for breast cancer. Macrophages, as one of the most abundant immune cells in tumor immune-infiltrating microenvironment, involves in cell survival, migration, and invasion of breast cancer. Methods: In this study, we compared the proportions of macrophages in patients with breast cancer with and without paclitaxel treatment, and investigated the targeted genes associated with macrophages for paclitaxel response. To explore the relationship between drug-related genes and breast cancer prognosis, survival analysis based on the drug-related genes were performed by website of Kaplan-Meier plotter with the threshold of significant P value < .05. Results: Compared to the normal samples, we revealed that paclitaxel significantly enhanced the ratio of macrophages in the tumor microenvironment. Furthermore, the expression of 3 drug-related genes (IFT46, PEX11A, and TMEM223) were significantly negatively associated with the proportions of macrophages. And it is worth to notice that PEX11A and TMEM223 were associated with better progression-free survival outcomes of patients with breast cancer. Moreover, PEX11A was associated with longer overall survival time of breast cancer. Conclusion: Taken all together, all the findings support to gain a better understanding to the development of more effective therapies targeted with paclitaxel.

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53 Predictors of response to immune checkpoint inhibitor therapy in metastatic solid tumors: real world evidence

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0053 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A57-A58

Author(s):

Aasems Jacob ◽

Jianrong Wu ◽

Jill Kolesar ◽

Eric Durbin ◽

Aju Mathew ◽

...

Keyword(s):

Real World ◽

Immune Checkpoint Inhibitor ◽

Statistical Significance ◽

Progression Free Survival ◽

Real World Data ◽

Free Survival ◽

Mutational Burden ◽

Kaplan Meier ◽

Tumor Mutational Burden ◽

Study Population

BackgroundImmune checkpoint inhibitor (ICI) therapy is increasingly being used in oncology and novel predictive biomarker for efficacy and side effects are an unmet need.1 2 The study aims to do a comprehensive analysis of factors affecting outcome from ICI therapy with real-world data and identify potential predictive biomarkers in diverse populations.MethodsWe performed a retrospective analysis of patients with metastatic solid tumors who received ICI and underwent molecular profiling with FoundationOne® CDx panel between 2016 and 2020 at Markey Cancer Center, Lexington KY. Progression-free survival (PFS), radiological response, and autoimmune side effects were analyzed and compared with various molecular biomarkers (figure 1). Logistic regression, Fisher’s exact test, Kaplan-Meier method, log-rank test, and Cox regression were used to analyze clinical features and efficacy outcomes.Abstract 53 Figure 1Mutational analysis of patients receiving immunotherapy grouped based on radiologic response, in the order of mutational load and frequency of mutationsAbstract 53 Figure 2Kaplan-Meier graphs depicting progression free survival in patients based on tumor samples showing (a) High TMB and low/intermediate TMB; (b) PDL1 expression; (c) Presence of IRAEs; (d) Presence of PIK3 mutation; (e) Presence of FGFR mutation; (f) Presence of BRAF mutationAbstract 53 Table 1Baseline characteristics of the study populationAbstract 53 Table 2Treatment and biomarker characteristics of study populationAbstract 53 Table 3ORR based on various factors with odds ratio calculated using logistic regression modelAbstract 53 Table 4Identified PIK3 mutations in tumor samples, with their chromosomal position and protein changesResults69 patients were included in the study (tables 1 and 2). A statistically significant improvement in PFS was observed in the PIK3 mutated cohort (median 123 vs. 23 weeks. HR=2.51. 95%CI 1.23, 5.14; table 3 and figure 2). This was independent of tumor mutational burden (TMB) status or PDL1 expression status (HR 3.24, p=0.016). PIK3 mutants had a higher overall response rate (ORR) than the wild type (69.6% vs. 43.5%, OR 0.34; p=0.045; tables 3 and 4). PIK3 mutants had a higher risk of developing immune-related adverse events (IRAEs) (73.9% vs. 37%, p=0.004). PIK3 mutation did not associate with TMB, PDL1 expression or microsatellite stability status. Median PFS was higher in the high TMB cohort compared to the low-intermediate group and reached statistical significance (median not reached vs. 26 weeks; HR=0.37. 95%CI 0.13, 1.05). PDL1 expression had no significant effect on the radiologic response, but PFS improvement in patients with tumors expressing PDL1 trended towards statistical significance (median 18 vs. 40 weeks. HR=1.43. 95%CI 0.93, 4.46). BRAF mutation conferred shorter PFS (median 17 vs. 39 weeks. HR=0.35. 95%CI 0.14, 0.91) (figure 2).ConclusionsHigh tumor mutational burden and PIK3 mutation conferred better progression-free survival with immunotherapy across cancer types. The improvement in PFS in PIK3 mutated patients was independent of PDL1 status or TMB. The results should prompt further evaluation of these potential biomarkers and more widespread real-world data publications to help determine biomarkers that could benefit specific populations.Ethics ApprovalThe study was approved by University of Kentucky Institutional Review Board, approval number 49450ReferencesTopalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–2454.Spencer KR, Wang J, Silk AW, Ganesan S, Kaufman HL, Mehnert JM. Biomarkers for Immunotherapy: Current Developments and Challenges. Am Soc Clin Oncol Educ Book. 2016; 35:e493–503.

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