Early Identification Of Treatment Failure Research Articles

Circulating tumour DNA detects somatic variants contributing to spatial and temporal intra-tumoural heterogeneity in head and neck squamous cell carcinoma

BackgroundAs circulating tumour DNA (ctDNA) liquid biopsy analysis is increasingly incorporated into modern oncological practice, establishing the impact of genomic intra-tumoural heterogeneity (ITH) upon data output is paramount. Despite advances in other cancer types the evidence base in head and neck squamous cell carcinoma (HNSCC) remains poor. We sought to investigate the utility of ctDNA to detect ITH in HNSCC.MethodsIn a pilot cohort of 9 treatment-naïve HNSCC patients, DNA from two intra-tumoural sites (core and margin) was whole-exome sequenced. A 9-gene panel was designed to perform targeted sequencing on pre-treatment plasma cell-free DNA and selected post-treatment samples.ResultsRates of genomic ITH among the 9 patients was high. COSMIC variants from 19 TCGA HNSCC genes demonstrated an 86.9% heterogeneity rate (present in one tumour sub-site only). Across all patients, cell-free DNA (ctDNA) identified 12.9% (range 7.5-19.8%) of tumour-specific variants, of which 55.6% were specific to a single tumour sub-site only. CtDNA identified 79.0% (range: 55.6-90.9%) of high-frequency variants (tumour VAF>5%). Analysis of ctDNA in serial post-treatment blood samples in patients who suffered recurrence demonstrated dynamic changes in both tumour-specific and acquired variants that predicted recurrence ahead of clinical detection.ConclusionWe demonstrate that a ctDNA liquid biopsy identified spatial genomic ITH in HNSCC and reliably detected high-frequency driver mutations. Serial sampling allowed post-treatment surveillance and early identification of treatment failure.

Baseline circulating tumour DNA and interim PET predict response in relapsed/refractory classical Hodgkin lymphoma.

Reliable biomarkers for early identification of treatment failure in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL) are lacking. Circulating tumour DNA (ctDNA) profiling has emerged as a powerful predictive and prognostic tool in several haemopoietic and non-haemopoietic malignancies and may guide rational treatment choices in r/r cHL. To assess the predictive and prognostic value of ctDNA, we performed a retrospective analysis on 55 r/r cHL patients treated with the bendamustine, gemcitabine and vinorelbine (BEGEV) regimen and additionally evaluated the potential utility of integrating ctDNA with interim [18 F]-FDG positron emission tomography (iPET). Baseline ctDNA genotyping in r/r cHL mirrored gene mutations and pathways involved in newly diagnosed cHL. We found that baseline ctDNA quantification and serial ctDNA monitoring have prognostic value in r/r cHL receiving salvage chemotherapy. Lastly, integrating ctDNA quantification with iPET evaluation may improve the early identification of patients at high risk of failing standard salvage therapy, who may benefit from an early switch to immunotherapeutic agents. Collectively, our results support the implementation of non-invasive methods to detect minimal residual disease in recurrent cHL and justify its prospective evaluation in appropriately designed clinical trials.

HIV virologic response, patterns of drug resistance mutations and correlates among adolescents and young adults: A cross-sectional study in Tanzania.

The emergence of HIV drug resistance mutations (DRMs) is of significant threat to achieving viral suppression (VS) in the quest to achieve global elimination targets. We hereby report virologic outcomes and patterns of acquired DRMs and its associated factors among adolescents and young adults (AYA) from a broader HIV drug resistance surveillance conducted in Tanzania. Data of AYA was extracted from a cross-sectional study conducted in 36 selected facilities using a two-stage cluster sampling design. Dried blood spot (DBS) samples were collected and samples with a viral load (VL) ≥1000 copies/mL underwent genotyping for the HIV-1 pol gene. Stanford HIV database algorithm predicted acquired DRMs, Fisher's exact test and multivariable logistic regression assessed factors associated with DRMs and VS, respectively. We analyzed data of 578 AYA on antiretroviral therapy (ART) for 9-15 and ≥ 36 months; among them, 91.5% and 88.2% had VS (VL<1000copies/mL) at early and late time points, respectively. Genotyping of 64 participants (11.2%) who had VL ≥1000 copies/ml detected 71.9% of any DRM. Clinically relevant DRMs were K103N, M184V, M41L, T215Y/F, L210W/L, K70R, D67N, L89V/T, G118R, E138K, T66A, T97A and unexpectedly absent K65R. Participants on a protease inhibitor (PI) based regimen were twice as likely to not achieve VS compared to those on integrase strand transfer inhibitors (INSTI). The initial VL done 6 months after ART initiation of ≥1000copies/mL was the primary factor associated with detecting DRMs (p = .019). VS amongst AYA is lower than the third UNAIDs target. Additionally, a high prevalence of ADR and high levels of circulating clinically relevant DRMs may compromise the long-term VS in AYA. Furthermore, the first VL result of ≥1000copies/ml after ART initiation is a significant risk factor for developing DRMs. Thus, strict VL monitoring for early identification of treatment failure and genotypic testing during any ART switch is recommended to improve treatment outcomes for AYA.

Human papilloma virus circulating tumor DNA assay predicts treatment response in recurrent/metastatic head and neck squamous cell carcinoma.

Despite the rising incidence of human papillomavirus related (HPV+) oropharyngeal squamous cell carcinoma (OPSCC), treatment of metastatic disease remains palliative. Even with new treatments such as immunotherapy, response rates are low and can be delayed, while even mild tumor progression in the face of an ineffective therapy can lead to rapid death. Real-time biomarkers of response to therapy could improve outcomes by guiding early change of therapy in the metastatic setting. Herein, we developed and analytically validated a new droplet digital PCR (ddPCR)-based assay for HPV16 circulating tumor DNA (ctDNA) and evaluated plasma HPV16 ctDNA for predicting treatment response in metastatic HPV+ OPSCC. We found that longitudinal changes HPV16 ctDNA correlate with treatment response and that ctDNA responses are observed earlier than conventional imaging (average 70 days, range: 35–166). With additional validation in multi-site studies, this assay may enable early identification of treatment failure, allowing patients to be directed promptly toward clinical trials or alternative therapies.

BIOM-32. HIGH AFFINITY FLUORESCENT NANOPARTICLES FOR DETECTION IL13Rα2-POSITIVE EXTRACELLULAR VESICLES AND CELLS

Abstract Glioblastoma (GBM) is both the most common and deadly malignant primary brain tumor with a 1-year survival of 37.2% and a 5-year survival of just 5.1%. The standard of care for GBM is surgical excision followed by radiation with concurrent and adjuvant temozolomide-centered chemotherapy (TMZ). Despite advances in imaging technology, early identification of treatment failure or impending resistance remains problematic. A unique characteristic of GBM is the overexpression of the α2 variant of IL-13 receptor (IL13Rα2) in 78–96% of patients while virtually undetectable in normal brain tissue. We hypothesize that the blood of patients with GBM contains sufficient IL13Rα2-positive extracellular vesicles (EV) to inform the clinical picture regarding disease status such as tumor recurrence and response to therapy. To detect IL13Rα2 as a specific molecular target for diagnostic testing, we have developed a modified version of IL-13 with increased affinity and specificity for IL13Rα2, and conjugated this ligand to fluorescent/ magnetic nanoparticles using an 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) linker. Furthermore, we demonstrated that the EV plasma fraction of patients with GBM is enriched for the IL13Rα2 receptor. We also demonstrated the ability of the ligand-bound nanoparticles to aggregate with IL13Rα2-positive cells and EVs in vitro. This ligand-based affinity purification particle has the potential to both quantify IL13Rα2 EV levels in patient blood and isolate these EVs for further interrogation of genomic and proteomic molecular markers.

An observational study of initial HIV RNA decay following initiation of combination antiretroviral treatment during pregnancy

BackgroundIn pregnancy, reduction of HIV plasma viral load (pVL) for the prevention of vertical transmission is time-constrained. The study primary objective is to investigate factors associated with faster initial HIV RNA half-life decay when combination antiretroviral treatment (cART) is initiated in pregnancy.MethodsThis was a multicentre, retrospective, observational study, conducted in south England, United Kingdom, between August 2001 and February 2018. Data were extracted from case notes of eligible women initiating cART during the index pregnancy. Anonymised data were collated and analysed centrally. Regression analyses were conducted to determine factors associated with faster HIV RNA half-life decay in the first 14 days after commencing cART (first-phase), and with achieving an undetectable maternal pVL by 36 weeks’ gestation. We then assessed whether HIV- and obstetric- related parameters differed by antiretroviral third agent class and whether the proportions of women with undetectable pVL at 36 weeks’ gestation and at delivery differed by antiretroviral third agent class.ResultsBaseline pVL was the only independent factor associated with faster first-phase HIV RNA half-life decay on commencing cART. Lower pVL on day 14 after starting cART was associated with an increased likelihood of achieving an undetectable pVL by 36 weeks’ gestation. Integrase inhibitor-based cART was associated with a faster first-phase HIV RNA half-life decay on commencing cART. Overall, 73% and 85% of women had an undetectable pVL at 36 weeks’ gestation and at delivery respectively, with no significant difference by antiretroviral third agent class.ConclusionsOnly high baseline pVL independently contributed to a faster rate of first-phase viral half-life decay. pVL at 14 days after initiating cART allows early identification of treatment failure. In the first 14 days after initiating cART in pregnancy, integrase inhibitor-based cART reduced maternal pVL faster than protease inhibitor- and non-nucleoside reverse transcriptase-based cART. While our study findings support INSTI use when initiated in pregnancy especially when initiated at later gestations and in those with higher baseline pVL, other non-INSTI based cART with more data on safety in pregnancy also performed well.

Early prediction of high flow nasal cannula therapy outcomes using a modified ROX index incorporating heart rate

BackgroundThe ROX index (ratio of pulse oximetry/FIO2 to respiratory rate) has been validated to predict high flow nasal cannula therapy (HFNC) outcomes in patients with pneumonia. We evaluated a modified ROX index incorporating heart rate (HR) in patients initiated on HFNC for acute hypoxemic respiratory failure and as a preventative treatment following planned extubation.MethodsWe performed a prospective observational cohort study of 145 patients treated with HFNC. ROX-HR index was defined as the ratio of ROX index over HR (beats/min), multiplied by a factor of 100. Evaluation was performed using area under the receiving operating characteristic curve (AUROC) and cutoffs assessed for prediction of HFNC failure: defined as the need for mechanical ventilation.ResultsNinety-nine (68.3%) and 46 (31.7%) patients were initiated on HFNC for acute hypoxemic respiratory failure and following a planned extubation, respectively. The majority (86.9%) of patients had pneumonia as a primary diagnosis, and 85 (56.6%) patients were immunocompromised. Sixty-one (42.1%) patients required intubation (HFNC failure). Amongst patients on HFNC for acute respiratory failure, HFNC failure was associated with a lower ROX and ROX-HR index recorded at time points between 1 and 48 h. Within the first 12 h, both indices performed with the highest AUROC at 10 h as follows: 0.723 (95% CI 0.605–0.840) and 0.739 (95% CI 0.626–0.853) for the ROX and ROX-HR index respectively. A ROX-HR index of > 6.80 was significantly associated with a lower risk of HFNC failure (hazard ratio 0.301 (95% CI 0.143–0.663)) at 10 h. This association was also observed at 2, 6, 18, and 24h, even with correction for potential confounding factors. For HFNC initiated post-extubation, only the ROX-HR index remained significantly associated with HFNC failure at all recorded time points between 1 and 24 h. A ROX-HR > 8.00 at 10 h was significantly associated with a lower risk of HFNC failure (hazard ratio 0.176 (95% CI 0.051–0.604)).ConclusionWhile validation studies are required, the ROX-HR index appears to be a promising tool for early identification of treatment failure in patients initiated on HFNC for acute hypoxemic respiratory failure or as a preventative treatment after a planned extubation.

Circulating HPV16 DNA may complement imaging assessment of early treatment efficacy in patients with HPV-positive oropharyngeal cancer

BackgroundEarly detection of treatment failure may improve clinical outcome and overall survival in patients with head and neck cancer after first-line treatment. Circulating cell-free HPV16 DNA (cfHPV16 DNA) was evaluated as a possible complementary marker to radiological assessment of early response in patients with HPV-related oropharyngeal cancer (OPC) after radiotherapy alone or combined with chemotherapy.MethodsThe study included 66 patients with HPV-related OPC receiving radical radiotherapy alone or in combination with chemotherapy. cfHPV16 DNA was assessed in the blood of all patients before treatment using TaqMan-based qPCR. Subsequent analysis of cfHPV16 DNA was performed 12 weeks after treatment completion, along with radiological assessment of early treatment results.ResultsComplete (CRR) and incomplete radiological response (IRR) was found in 43 (65%) and 23 (35%) patients respectively. cfHPV16 DNA was present in 5 (28%) patients with IRR, while only in 1 (4%) with CRR. Three of five patients with IRR that were positive for cfHPV16 DNA exhibited histopathologically confirmed local or regional treatment failure, and other two developed distant metastases. None of the patients with negative cfHPV16 DNA presented disease failure.ConclusionThe post-treatment assessment of cfHPV16 DNA in patients with HPV-related OPC may be used as a complementary biomarker to conventional imaging-based examinations for early identification of treatment failure.

BCG Therapy of Bladder Cancer Stimulates a Prolonged Release of the Chemoattractant CXCL10 (IP10) in Patient Urine.

Background: Intra-vesical instillation of Bacille Calmette–Guérin (BCG), an attenuated strain of Mycobacterium bovis, is an effective therapy for high-grade non-muscle invasive bladder cancer (NMIBC), which provokes a local immune response resulting in 70% of patients free of relapse after three years. Because non-responder patients usually have a bad prognosis, the early identification of treatment failure is crucial. We hypothesized that, if an effective immune response was taking place in the bladder, soluble factors would be released to the urine many days after BCG instillations. Methods: An extensive panel of cytokines and chemokines released into the urine seven days after every BCG instillation was screened in a cohort of NMIBC patients over three years. Results: The determinations of the urinary concentrations of cytokines, chemokines, and creatinine showed that increasing concentrations of C-X-C motif chemokine 10 (CXCL10) also known as interferon-inducible protein 10 (IP10) could be detected during the six-week induction cycle of BCG-treated patients released into the urine by CD14+ cells. In vitro, CXCL10 facilitated the recruitment of effector immune cells after the BCG-mediated upregulation of CXCR3 in both T- and natural killer (NK)-cells. Conclusions: The high concentrations of chemokine detected one week after the encounter with mycobacteria suggest that the CXCL10 axis might be related to the intensity of the immune anti-tumor response.

Compromise of Second-Line Antiretroviral Therapy Due to High Rates of Human Immunodeficiency Virus Drug Resistance in Mozambican Treatment-Experienced Children With Virologic Failure

Virologic failure (VF) is highly prevalent in sub-Saharan African children on antiretroviral therapy (ART) and is often associated with human immunodeficiency virus drug resistance (DR). Most children still lack access to routine viral load (VL) monitoring for early identification of treatment failure, with implications for the efficacy of second-line ART. Children aged 1 to 14 years on ART for ≥12 months at 6 public facilities in Maputo, Mozambique were consecutively enrolled after informed consent. Chart review and caregiver interviews were conducted. VL testing was performed, and specimens with ≥1000 copies/mL were genotyped. Of the 715 children included, the mean age was 103 months, 85.8% had no immunosuppression, 73.1% were taking stavudine/lamivudine/nevirapine, and 20.1% had a history prevention of mother-to-child transmission exposure. The mean time on ART was 60.0 months. VF was present in 259 patients (36.3%); 248 (95.8%) specimens were genotyped, and DR mutations were found in 238 (96.0%). Severe immunosuppression and nutritional decline were associated with DR. M184V and Y181C were the most common mutations. In the 238 patients with DR, standard second-line ART would have 0, 1, 2, and 3 effective antiretrovirals in 1 (0.4%), 74 (31.1%), 150 (63.0%), and 13 (5.5%) patients, respectively. This cohort had high rates of VF and DR with frequent compromise of second-line ART. There is urgent need to scale-up VL monitoring and heat-stable protease inhibitor formulations or integrase inhibitorsfor a more a durable first-line regimen that can feasibly be implemented in developing settings.

Exhaled Breath Analysis for Monitoring Response to Treatment in Advanced Lung Cancer

IntroductionThe Response Evaluation Criteria in Solid Tumors (RECIST) serve as the accepted standard to monitor treatment efficacy in lung cancer. However, the time intervals between consecutive computerized tomography scans might be too long to allow early identification of treatment failure. This study examines the use of breath sampling to monitor responses to anticancer treatments in patients with advanced lung cancer. MethodsA total of 143 breath samples were collected from 39 patients with advanced lung cancer. The exhaled breath signature, determined by gas chromatography/mass spectrometry and a nanomaterial-based array of sensors, was correlated with the response to therapy assessed by RECIST: complete response, partial response, stable disease, or progressive disease. ResultsGas chromatography/mass spectrometry analysis identified three volatile organic compounds as significantly indicating disease control (PR/stable disease), with one of them also significantly discriminating PR/stable disease from progressive disease. The nanoarray had the ability to monitor changes in tumor response across therapy, also indicating any lack of further response to therapy. When one-sensor analysis was used, 59% of the follow-up samples were identified correctly. There was 85% success in monitoring disease control (stable disease/partial response). ConclusionBreath analysis, using mainly the nanoarray, may serve as a surrogate marker for the response to systemic therapy in lung cancer. As a monitoring tool, it can provide the oncologist with a quick bedside method of identifying a lack of response to an anticancer treatment. This may allow quicker recognition than does the current RECIST analysis. Early recognition of treatment failure could improve patient care.

Procalcitonin Kinetics and Nosocomial Pneumonia in Older Patients

Early identification of treatment failure for nosocomial pneumonia remains a major challenge. The goal of this study was to test whether procalcitonin kinetics can be used to assess the clinical efficacy in older critically ill patients with nosocomial pneumonia. A prospective observational study was conducted with 60 subjects (≥ 65 y old) admitted to the ICU with severe nosocomial pneumonia. Serum procalcitonin was measured on days 0, 3, and 7 and at the end of treatment. The procalcitonin time course was analyzed according to the therapeutic efficacy. Procalcitonin levels were elevated in all subjects (n = 60) on day 0, and the median level (range) was 2.5 (0.8-42.7) μg/L. There were no differences in procalcitonin between the improved subjects (n = 41) and those without improvement (n = 19) on day 0 (P > .05). However, lower procalcitonin levels on days 3 and 7 and at the end of treatment (all P < .05) and greater rates of procalcitonin decline between days 0 and 3 (ΔPCT(d3)%; 29.5 ± 10.8% vs 15.1 ± 5.9%, P = .009) were observed in the improved subjects compared with those with no improvement. ΔPCT(d3)% was the best single predictor of efficacy (area under the curve of 0.79, P < .001) and had a sensitivity of 75.7% and a specificity of 72.0% with a threshold of 26.2%. By comparison, traditional parameters and absolute procalcitonin failed to predict treatment response (P > .05). Indeed, the combination of ΔPCT(d3)% > 26.2% and a modified Clinical Pulmonary Infection Score of < 6 points improved the predictive value (area under the curve of 0.89, sensitivity of 81.3%, specificity of 86.5%). Procalcitonin levels were not influenced by aging, and procalcitonin kinetics might help to identify treatment failure. ΔPCT(d3)% in combination with the Clinical Pulmonary Infection Score has been shown to be a marker of clinical efficacy at an earlier stage.

Phase II study of preoperative chemotherapy plus bevacizumab with early salvage therapy based on FDG-PET response in patients with locally advanced gastric and GEJ adenocarcinoma.

94 Background: Response on FDG-PET scan during preoperative chemotherapy has prognostic significance. PET non-responders do poorly whether they continue the same chemotherapy or proceed directly to surgery [JCO 24: 4692; 2006, Lancet Onc 8:797;2007) Early identification of treatment failure using PET scan may spare patients (pts) from inactive therapy and allow for cross-over to alternative therapies. We performed a phase II trial to examine the effectiveness of FDG-PET directed early switching to salvage chemotherapy measured by 2 year disease free survival (DFS) in the PET non-responding group. Methods: Pts with PET avid, EUS and laparoscopically staged T3 or Node positive resectable gastric or GEJ adenocarcinoma received induction with epirubicin 50mg/m2, cisplatin 60mg/m2, capecitabine 625mg/m2 bid days 2-21(ECX) and bevacizumab 15mg/kg day 1. PET scan was repeated at week 3. PET responders (≥35% decline in SUV) continued ECX for 2 more cycles. PET non-responders switched to 2 cycles of salvage therapy: docetaxel 30mg/m2 d1, d8 q21 days, irinotecan 50mg/m2 d1, d8 q21 days and bevacizumab 15mg/kg day 1. Pts had surgery 4 weeks after cycle 3. Results: 20 of planned 60 pts were enrolled before the study closed for poor accrual. 14 male (64%), 8 female (39%), median age 62, median KPS 90. 11(55%) had a PET response after the first cycle. 10/11 (91%) underwent R0 resection: 1/10 pathologic CR, 3/10 pathologic PR. 9/20 PET non-responders switched to the salvage regimen. 7/9 Non-responders had R0 resection, none achieved a pathological response. The DFS for PET responders was 27.8mos (95% CI 10.3-27.8) and DFS in salvage group has not been reached. There was no significant difference in DFS between the two groups (p= 0.4). Follow up for overall survival is ongoing. Biologic correlative studies are pending. Conclusions: Response on PET scan during induction chemotherapy can identify early treatment failures. The results for therapy cross-over indicate a potentially improved DFS with salvage chemotherapy. Results from this trial are hypothesis generating and merit evaluation in a larger clinical trial. Supported by a grant from Genentech. Clinical trial information: NCT00737438.

Molecular resistance: an early indicator for treatment change?

Vigilant monitoring of a patient's response to current treatment is imperative to the management of chronic myeloid leukemia (CML). Early identification of treatment failure may increase the probability that alternative therapy will be effective. This review discusses the use of molecular monitoring in the timely detection of failure of imatinib treatment. Changes in the levels of BCR-ABL transcripts are predictive of response or relapse. Patients achieving a major molecular response (MMR) within 12 months of treatment may experience longer cytogenetic remission. Accumulating evidence also suggests that lower transcript levels observed ≤ 6 months after the start of treatment are associated with improved patient outcomes. For patients with primary or secondary imatinib resistance (or intolerance), dasatinib or nilotinib may be prescribed. These agents have demonstrated activity in patients harboring imatinib-resistant BCR-ABL mutations, except for the T315I substitution.

Ifosfamide-based chemotherapy for patients with resistant germ cell tumors: the Memorial Sloan-Kettering Cancer Center experience.

Sixty-six patients with germ cell tumors (GCTs) refractory to cisplatin plus etoposide/vinblastine-based therapy were treated with cisplatin, ifosfamide, and either etoposide (VIP) (50 patients) or vinblastine (VeIP) (16 patients). Sixty-two patients were evaluable for response. Twenty-one patients (34%) achieved a complete response (CR), 18 with chemotherapy alone and an additional three following surgical resection of viable tumor. Six of these patients have relapsed, and 15 (24%) remain in CR at a median follow-up of 13 months (range, 3+ to 41+ months). Three patients who achieved an incomplete response or relapsed from CR are disease free following additional salvage therapy; one patient underwent resection of a solitary metastasis and two received high-dose chemotherapy with autologous bone marrow rescue. Ifosfamide adds efficacy to cisplatin plus etoposide or vinblastine-based salvage therapy. Ifosfamide/cisplatin-based combinations should be considered in the first-line salvage treatment of germ cell tumors. The modest proportion of patients who achieve a durable CR following salvage therapy with VIP/VeIP emphasizes the need for early identification of treatment failure and more effective salvage therapy.