Gene Expression Indicates Altered Immune Modulation and Signaling Pathway Activation in Ovarian Cancer Patients Resistant to Topotecan

Epithelial ovarian cancer (EOC) is one of the deadliest gynecological malignancies. Topotecan remains an essential tool in second-line therapy; even so, most patients develop resistance within a short period of time. We aimed to identify biomarkers of topotecan resistance by using gene expression signatures derived from patient specimens at surgery and available subsequent responses to therapy. Gene expression was collected for 1436 patients and 10,103 genes. Based on disease progression, patients were categorized as responders/nonresponders depending on their progression free survival (PFS) state at 9, 12, 15 and 18 months after surgery. For each gene, the median expression was compared between responders and nonresponders for two treatment regimens (chemotherapy including/excluding topotecan) with Mann–Whitney U test at each of the four different PFS cutoffs. Statistical significance was accepted in the case of p < 0.05 with a fold change (FC) ≥ 1.44. Four genes (EPB41L2, HLA-DQB1, LTF and SFRP1) were consistently overexpressed across multiple PFS cutoff times in initial tumor samples of patients with disease progression following topotecan treatment. A common theme linked to topotecan resistance was altered immune modulation. Genes associated with disease progression after systemic chemotherapy emphasize the role of the initial organization of the tumor microenvironment in therapy resistance. Our results uncover biomarkers with potential utility for patient stratification.

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To assess the role of addition of bevacizumab therapy to carboplatin and paclitaxel as frontline treatment of epithelial ovarian cancer

10.1055/s-0039-1685308 ◽

2016 ◽

Author(s):

Richa Vatsa ◽

Sunesh Kumar ◽

Lalit Kumar

Keyword(s):

Ovarian Cancer ◽

Epithelial Ovarian Cancer ◽

Disease Progression ◽

Safety Profile ◽

Haematological Toxicity ◽

Progression Free Survival ◽

New Drugs ◽

Secondary Outcome ◽

Vegf Receptor ◽

Persistent Proteinuria

Introduction: Efforts are going on for development of new drugs for epithelial ovarian cancer (EOC). We assessed safety profile of bevacizumab, a VEGF receptor blocking antibody in treatment of EOC. Methods: We assigned women with EOC to carboplatin (area under curve, 5 or 6) and paclitaxel (175 mg/square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (15 mg/kilogram body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 30 additional cycles. Primary outcome measures was safety profile of bevacizumab and secondary outcome was to see progression free survival (PFS). Results: Out of 30 patients, 10 were in Bevacizuma arm (Arm A) and 20 in conventional chemotherapy arm (Arm B). Haematological toxicity, GI perforation and proteinuria was similar in both. Other toxicities e.g. bleeding complication (p = 0.002) and hypertension (p = 0.04) was more in Arm A. PFS was similar in both arms; 24 months in Arm A and 22 months in Arm B (p = 0.565). 4 (40%) patients in arm A discontinued treatment, two (20%) because of disease progression after PFS of 9 and 6 months, two because of development of toxicity considered to be due to bevacizumab; of which one developed jejenal perforation and disease progression after PFS of 6 months and 1 because of development of persistent proteinuria of grade 3 after 18 months. Conclusion: Bevacizumab therapy does not improve PFS in EOC but increases toxicity spectrum of chemotherapy.

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Clinical outcomes of postoperative intraperitoneal chemotherapy for patients with early-stage high-grade serous ovarian cancer (HGSC) treated at British Columbia cancer agency.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e17105 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e17105-e17105

Author(s):

Joohyun Lee ◽

Anna Tinker

Keyword(s):

Ovarian Cancer ◽

British Columbia ◽

Overall Survival ◽

Clinical Outcomes ◽

Early Stage ◽

Statistical Significance ◽

Progression Free Survival ◽

Stage I ◽

High Rate ◽

Free Survival

e17105 Background: Intraperitoneal (IP) chemotherapy has been shown to prolong overall survival in optimally debulked stage III ovarian cancer in randomized trials. In British Columbia, we extrapolated this benefit of IP chemotherapy to early stage HGSC patients for the last 10 years, as these patients are optimally debulked at surgery but still have a high rate of recurrence. We conducted a retrospective study of clinical outcomes associated with IP/IV chemotherapy compared to IV chemotherapy for optimally debulked stage I HGSC cases. Methods: This was a retrospective cohort study of women with stages IA-IC HGSC who had primary surgery between 2007-2015, and received either IV or IP/IV chemotherapy post-operatively. We compared progression-free survival (PFS) and overall survival (OS) outcomes between these 2 groups. Kaplan-Meier method evaluated chemotherapy delivery route with progression free survival (PFS) and overall survival (OS), using the statistical program R. Results: We identified 99 patients; 80 (81%) received IV chemotherapy and 19 (19%) received IP/IV chemotherapy. Among IP/IV cohort, 2/19 (11%) discontinued IP therapy during treatment due to abdominal pain at IP port site or hypersensitivity reaction to IV paclitaxel. 5-year PFS was 88.4% (74.5-100%) and 69.7% (58.7-82.7%) among the IP/IV and IV cohorts, respectively (p = 0.549). There was a trend for higher 5-year OS for the IP/IV group; however, this did not reach statistical significance (100% vs. 71.4%; p = 0.182). Conclusions: In our study, IP/IV chemotherapy for stage I HGSC patients was associated with a trend for higher 5-year PFS and OS compared to IV chemotherapy. This observation warrants further prospective investigation.

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Dual Knockdown of Musashi RNA-Binding Proteins MSI-1 and MSI-2 Attenuates Putative Cancer Stem Cell Characteristics and Therapy Resistance in Ovarian Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms222111502 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11502

Author(s):

Maria T. Löblein ◽

Isabel Falke ◽

Hans Theodor Eich ◽

Burkhard Greve ◽

Martin Götte ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Ovarian Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cancer Cells ◽

Rna Binding ◽

Rna Binding Proteins ◽

Therapy Resistance ◽

Ovarian Cancer Cells

In ovarian cancer, therapy resistance mechanisms complicate cancer cell eradication. Targeting Musashi RNA-binding proteins (MSI) may increase therapeutic efficacy. Database analyses were performed to identify gene expression associations between MSI proteins and key therapy resistance and cancer stem cell (CSC) genes. Then, ovarian cancer cells were subjected to siRNA-based dual knockdown of MSI-1 and MSI-2. CSC and cell cycle gene expression was investigated using quantitative polymerase chain reaction (qPCR), western blots, and flow cytometry. Metabolic activity and chemoresistance were assessed by MTT assay. Clonogenic assays were used to quantify cell survival post-irradiation. Database analyses demonstrated positive associations between MSI proteins and putative CSC markers NOTCH, MYC, and ALDH4A1 and negative associations with NOTCH inhibitor NUMB. MSI-2 expression was negatively associated with the apoptosis regulator p21. MSI-1 and MSI-2 were positively correlated, informing subsequent dual knockdown experiments. After MSI silencing, CSC genes were downregulated, while cell cycle progression was reduced. Metabolic activity was decreased in some cancer cells. Both chemo- and radioresistance were reduced after dual knockdown, suggesting therapeutic potential. Dual knockdown of MSI proteins is a promising venue to impede tumor growth and sensitize ovarian cancer cells to irradiation and chemotherapy.

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CTNI-45. RESPONSE EVALUATION OF AR-67 FROM A PHASE-2 RECURRENT GLIOBLASTOMA TRIAL BY ARTIFICIAL INTELLIGENCE ASSISTED TUMOR VOLUMETRIC ESTIMATION: COMPARISON WITH THE SUM OF THE PERPENDICULAR DIAMETERS PRODUCT

Neuro-Oncology ◽

10.1093/neuonc/noab196.270 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi70-vi70

Author(s):

Sotirios Bisdas ◽

Jai Grewal ◽

Volker Stieber ◽

Robert Cavaliere ◽

Craig Devoe ◽

...

Keyword(s):

Disease Progression ◽

Therapeutic Potential ◽

Statistical Significance ◽

Progression Free Survival ◽

Response Assessment ◽

Response Rates ◽

Recurrent Glioblastoma ◽

Phase 2 ◽

Time Points ◽

Positive Effects

Abstract BACKGROUND Modified Radiographic Response Assessment in Neuro-Oncology (“mRANO”) criteria based on SPDP form the basis for assessing treatment response in Glioblastoma but are subject to sampling bias and difficulty in differentiating between pseudo- and true disease progression. Volumetric image analysis using AI may overcome these limitations of standard techniques and improve our ability to detect changes earlier and more accurately. METHODS Images from eight reGBM patients enrolled in a Phase-2 reGBM study of Vivacitas Oncology’s drug, AR-67, were re-assessed using IAG’s AI-assisted volumetric measurements. A median of five MRI time points from each patient were included. The mRANO response was determined by central reading and tumor volumetric measurement using IAG’s proprietary platform. Statistical significance was set at p< .0001. RESULTS Four patients showed responses, two patients showed stable disease, and two patients showed progressive disease. Tumor volume was correlated (r=0.97) with SPDP, but was driven by high coefficients in large lesions. Standard SPDP overestimated tumor size in larger tumors using the Bland-Altman analysis (mean difference: 829; 95% CI: 704 to -2362) leading to discrepancies in response rates. For example, the mean response rate based on IAG’s volumetric criteria was +22% (1.29) compared with +17% using SPDP (0.81). Eight out of 45 time-points also differed in the directionality of responses (e.g., increase vs. decrease) with SPDP underestimating the positive effects of AR-67 compared to AI analysis. CONCLUSIONS IAG’s AI-assisted tumor volumetric analysis is feasible for clinical trials and may be more sensitive for evaluating treatment-related response rates vs. SPDP methodology. This is particularly true for measuring large lesions, and may also allow for more accurately differentiating between pseudo- and true disease progression. The data included eight patients’ MRI images from a Phase-2 reGBM study, showing that five patients achieved the primary end-point of six months Progression-Free Survival, suggesting AR-67’s therapeutic potential.

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Dose-dense weekly paclitaxel and carboplatin compared with conventional paclitaxel and carboplatin treatment for stage II-IV ovarian cancer patients

Bangladesh Journal of Pharmacology ◽

10.3329/bjp.v10i3.23079 ◽

2015 ◽

Vol 10 (3) ◽

pp. 489

Author(s):

Zhenhua Du ◽

Xiaolin Ma

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Statistical Significance ◽

Progression Free Survival ◽

Stage Ii ◽

Weekly Paclitaxel ◽

Free Survival ◽

Clinical Responses ◽

Dose Dense ◽

To Receive

<p>We investigated dose-dense weekly paclitaxel and carboplatin compared with conventional paclitaxel and carboplatin treatment on stage II-IV ovarian cancer patients. Between July, 2011, and October, 2014, a total of 221 patients was randomly assigned to receive dose-dense weekly paclitaxel and carboplatin group (n = 109) and conventional paclitaxel and carboplatin group (n = 112), just after the sixth chemotherapy cycles, and at 12 months after randomization. Median progression-free survival (PFS) was 16.8 months (range 3.3-48+ months) of conventional paclitaxel and carboplatin group was lower than that of dose-dense weekly paclitaxel and carboplatin group 27.6 months (range 4.2-51+ months). But, these clinical responses were not statistical significance in each group. In conclusion, dose-dense weekly paclitaxel and carboplatin treatment improves survival compared with conventional paclitaxel and carboplatin treatment. </p>

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Pertuzumab Plus Chemotherapy for Platinum-Resistant Ovarian Cancer: Safety Run-in Results of the PENELOPE Trial

International Journal of Gynecological Cancer ◽

10.1097/igc.0000000000000695 ◽

2016 ◽

Vol 26 (5) ◽

pp. 898-905 ◽

Cited By ~ 4

Author(s):

Antonio González-Martín ◽

Patricia Pautier ◽

Sven Mahner ◽

Joern Rau ◽

Nicoletta Colombo ◽

...

Keyword(s):

Ovarian Cancer ◽

Confidence Interval ◽

Disease Progression ◽

Messenger Rna ◽

Data Monitoring Committee ◽

Progression Free Survival ◽

Rna Expression ◽

Fallopian Tube Cancer ◽

Free Survival ◽

Platinum Resistant

ObjectiveIn platinum-resistant ovarian cancer, adding pertuzumab to gemcitabine improved progression-free survival in the subgroup with low tumor HER3 messenger RNA expression. The 2-part PENELOPE trial (NCT01684878) is prospectively investigating pertuzumab plus chemotherapy in this population.Patients and MethodsPart 1 evaluated pertuzumab plus either topotecan or paclitaxel. Patients with platinum-refractory or platinum-resistant recurrent ovarian, primary peritoneal, or fallopian tube cancer and low HER3 messenger RNA expression (concentration ratio ≤2.81 by central quantitative reverse transcriptase-polymerase chain reaction testing on Cobas z480) received intravenous pertuzumab (840 mg loading dose then 420 mg every 3 weeks) with the investigator’s choice of topotecan (1.25 mg/m2days 1–5 every 3 weeks) or weekly paclitaxel (80 mg/m2) until disease progression or unacceptable toxicity. The primary objective was to assess safety and tolerability.ResultsFifty patients were treated in part 1 (22 topotecan; 28 paclitaxel). In both cohorts, disease progression was the most common primary reason for discontinuing pertuzumab, and the most common all-grade adverse events (AEs) were fatigue/asthenia, anemia, and diarrhea. The most common grade ≥3 AEs were anemia (36%), neutropenia (27%), and fatigue/asthenia (18%) for topotecan, and peripheral sensory neuropathy (14%) and anemia (11%) for paclitaxel. Two patients receiving paclitaxel-pertuzumab died from AEs (abdominal infection; unexplained death). Median progression-free survival was 4.1 months (95% confidence interval, 1.9–6.1) with topotecan-pertuzumab and 4.2 months (95% confidence interval, 3.5–6.0) with paclitaxel-pertuzumab.ConclusionsBased on part 1 tolerability, the Independent Data Monitoring Committee had no objection to PENELOPE proceeding to part 2, a double-blind randomized comparison of chemotherapy (topotecan, paclitaxel, or gemcitabine) plus pertuzumab or placebo.

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Patient-reported outcomes from the phase II FAST trial of zolbetuximab plus EOX compared to EOX alone as first-line treatment of patients with metastatic CLDN18.2+ gastroesophageal adenocarcinoma

Gastric Cancer ◽

10.1007/s10120-020-01153-6 ◽

2021 ◽

Vol 24 (3) ◽

pp. 721-730

Author(s):

Florian Lordick ◽

Salah-Eddin Al-Batran ◽

Arijit Ganguli ◽

Robert Morlock ◽

Ugur Sahin ◽

...

Keyword(s):

Disease Progression ◽

Repeated Measures ◽

Patient Reported Outcomes ◽

Statistical Significance ◽

Symptom Burden ◽

Progression Free Survival ◽

First Line ◽

Patient Reported ◽

Gastroesophageal Adenocarcinoma ◽

Eortc Qlq

Abstract Background Zolbetuximab plus first-line EOX (epirubicin, oxaliplatin, capecitabine; ZOL/EOX) significantly prolonged progression-free survival and overall survival in the FAST trial vs EOX alone. We report the patient-reported outcomes (PROs) of FAST in patients with advanced gastroesophageal adenocarcinoma. Methods Patients were randomized to ZOL/EOX or EOX alone. Patients could receive ≤ 8 EOX cycles and remained on zolbetuximab until disease progression. PROs were collected using the EORTC QLQ-C30 and QLQ-STO22 before drug administration at day 1/cycle 1, day 1/cycle 5, end of EOX treatment, and q12w thereafter until disease progression. Time to deterioration (TTD), defined as the first meaningful worsening from baseline, in the individual QLQ-C30/QLQ-STO22 scores was analyzed. Longitudinal changes in scores from baseline were analyzed using a mixed-effects model for repeated measures (MMRM). Results The per protocol population included 143 (ZOL/EOX: 69; EOX: 74) patients. Baseline QLQ-C30 and STO22 scores were comparable between arms and denoted intermediate-to-high quality of life (QoL), intermediate-to-low global health status (GHS) and low symptom burden. Descriptive analyses showed no differences between arms until end of EOX but maintenance therapy with zolbetuximab was associated with better QoL and less symptom burden thereafter. TTD for most scores favored ZOL/EOX over EOX and reached statistical significance for GHS (p = 0.008). MMRM results support TTD findings; no statistically significant differences were observed between arms in any score except for nausea and vomiting (p = 0.0181 favoring EOX). Conclusions ZOL/EOX allowed patients to maintain good QoL and low symptom burden for longer than EOX alone.

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L-MOCA: An open-label study of olaparib maintenance monotherapy in platinum-sensitive relapsed ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e17526 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e17526-e17526

Author(s):

Qing-lei Gao ◽

Jianqing Zhu ◽

Weidong Zhao ◽

Yi Huang ◽

Ruifang An ◽

...

Keyword(s):

Ovarian Cancer ◽

Disease Progression ◽

Brca Mutation ◽

Progression Free Survival ◽

Primary Analysis ◽

Open Label ◽

Platinum Sensitive ◽

Kaplan Meier ◽

Platinum Based Chemotherapy ◽

Full Analysis

e17526 Background: In patients with platinum-sensitive recurrent serous ovarian cancer, maintenance monotherapy with the poly (ADP-ribose) polymerase inhibitor (PARPi) olaparib, significantly improves progression-free survival (PFS) versus placebo. This is the first study to evaluate the efficacy and tolerability of the olaparib (Lynparza), an oral PARPi, in patients with platinum-sensitive relapsed (PSR) ovarian cancer, carried out exclusively in Asia. Methods: In this open-label, single arm trial, patients with PSR high grade epithelial ovarian cancer who had received ≥2 previous lines of platinum-based chemotherapy with a response, were enrolled from 28 centres in China and Malaysia. All patients received oral olaparib (300 mg) tablet twice daily until disease progression or unacceptable toxicity. The primary endpoint was PFS assessed by investigator according to RECIST 1.1 criteria. Secondary endpoints included time to TFST, PFS2, TSST, OS, and safety endpoints included adverse events (AEs). Subgroup analysis of PFS was examined by BRCA status. Data were summarized by descriptive statistics; time-to-event endpoints were analyzed using Kaplan-Meier method. Primary analysis was performed when 60% of PFS events had been achieved. Results: Between 2018 and 2020, the 224 patients recruited into this study received oral olaparib (full analysis set). 224 patients (91.5% from China and 8.5% from Malaysia) provided BRCA mutation status by blood and tissue testing. 47.3% patients were BRCAm, 41.1% patients were gBRCAm,52.2% patients were BRCAwt and 0.4% patients were BRCA unknown. 35.7% patients had received ＞2 lines of chemotherapy. At data cut-off (Dec 25th, 2020), 139 patients had disease progression; median PFS (mPFS) was 16.1 (95% CI 13.3-18.3) m in all patients. The mPFS was 21.2m, 21.4m and 11.0m in BRCAm, gBRCA and BRCAwt subgroups, respectively. The overall incidence of any AE and SAE was 99.1% and 25.4%, respectively. There were 9.4% patients who discontinued therapy due to the treatment related AE. The most common AEs were anemia, nausea and vomiting. Conclusions: The L-MOCA study demonstrates olaparib maintenance treatment is effective and well tolerated in Asian PSR ovarian cancer patients regardless of BRCA status. Clinical trial information: NCT03534453. [Table: see text]

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The role of proinflammatory immune (IFN-gamma) gene signature in predicting prognosis and response to chemotherapy in uterine carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e14209 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e14209-e14209

Author(s):

Haider Mahdi ◽

Peter Graham Rose ◽

Fadi W Abdul-Karim ◽

Bradley J. Monk ◽

Ying Ni

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Overall Survival ◽

T Cells ◽

Progression Free Survival ◽

Gene Signature ◽

Free Survival ◽

High Stage ◽

Response To Chemotherapy ◽

Ifn Γ

e14209 Background: Immunotherapy is promising option given low toxicity and potential durable response. In mismatch repair proficient endometrial and ovarian cancers, the reported response rate is ranging from 10-15% in recurrent setting. We need to better identify subset of patients who benefits from immunotherapy. Multigene immune signatures represent a robust means of capturing a complex, T cell–inflamed phenotype necessary for the clinical activity of PD-1–/PD-L1–directed monoclonal antibodies. IFN-γ is a key cytokine produced by activated T cells, as well as natural killer (NK) and NK T cells, in the tumor microenvironment. An immune-related IFN-γ 18-gene profile was derived through a cross-validated penalized regression modeling strategy to predict response to anti-PD1 therapy across 9 different tumor types. We want to test if this gene panel can also predict cancer outcome and response to chemotherapy. Methods: We used whole transcriptome sequencing of RNA matched tumor-normal samples from 38 high stage (Stage III and IV) uterine serous cancer patients. All patients received chemotherapy with platinum and taxanes. IFN-18 gene expression score was calculated by averaging the normalized and log transformed individual gene read counts. The optimized score cut off was selected to best separating the progression free survival. Then the cut off score was tested in The Cancer Genomic Atlas (TCGA) uterine and ovarian cancer RNAseq datasets. Results: The IFN score of 2.46 was determined based on 18-gene expression derived from 38 high-stage uterine serous cancer samples. Average age was 67 years (range: 56-82 years). Uterine serous cancer is known to be MSI stable. Patients with score higher than 2.46 showed significantly longer progression free survival (PFS – 57.6 months vs 15months, p = 0.002) and longer overall survival (73.1 months vs 51.1 months), not statistically significant given our small sample size, p = 0.13) compared to the patients with score lower than 2.46. Then this IFN based gene signature was then applied to TCGA 541 uterine cancer samples with RNAseq data. Similarly, this signature predicted significant improvement in both progression-free survival (p = 0.001) and overall survival (p = 0.005). Interestingly, this score cannot separate outcome for TCGA ovarian cancer cohort. Conclusions: Immune-related IFN-γ gene signature predicted prognosis and response to chemotherapy. We plan to assess if this signature will predict endometrial cancer patients who benefits from anti-PD1 therapy.

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Circulating Tumor and Invasive Cell Gene Expression Profile Predicts Treatment Response and Survival in Pancreatic Adenocarcinoma

Cancers ◽

10.3390/cancers10120467 ◽

2018 ◽

Vol 10 (12) ◽

pp. 467

Author(s):

Kenneth Yu ◽

Mark Ricigliano ◽

Brian McCarthy ◽

Joanne Chou ◽

Marinela Capanu ◽

...

Keyword(s):

Gene Expression ◽

Disease Progression ◽

Treatment Response ◽

Peripheral Blood ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Progression Free Survival ◽

Response Prediction ◽

Ductal Adenocarcinoma ◽

Chemotherapy Response

Previous studies have shown that pharmacogenomic modeling of circulating tumor and invasive cells (CTICs) can predict response of pancreatic ductal adenocarcinoma (PDAC) to combination chemotherapy, predominantly 5-fluorouracil-based. We hypothesized that a similar approach could be developed to predict treatment response to standard frontline gemcitabine with nab-paclitaxel (G/nab-P) chemotherapy. Gene expression profiles for responsiveness to G/nab-P were determined in cell lines and a test set of patient samples. A prospective clinical trial was conducted, enrolling 37 patients with advanced PDAC who received G/nab-P. Peripheral blood was collected prior to treatment, after two months of treatment, and at progression. The CTICs were isolated based on a phenotype of collagen invasion. The RNA was isolated, cDNA synthesized, and qPCR gene expression analyzed. Patients were most closely matched to one of three chemotherapy response templates. Circulating tumor and invasive cells’ SMAD4 expression was measured serially. The CTICs were reliably isolated and profiled from peripheral blood prior to and during chemotherapy treatment. Individual patients could be matched to distinct response templates predicting differential responses to G/nab-P treatment. Progression free survival was significantly correlated to response prediction and ΔSMAD4 was significantly associated with disease progression. These findings support phenotypic profiling and ΔSMAD4 of CTICs as promising clinical tools for choosing effective therapy in advanced PDAC, and for anticipating disease progression.

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