Brett Hughes | The University of Queensland, Australia (original) (raw)

Papers by Brett Hughes

Clinical Endocrinology, Mar 14, 2018

Journal of Clinical Oncology, Jul 20, 2022

PURPOSE The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembroliz... more PURPOSE The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) $ 1 and CPS $ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS , 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS , 1 and CPS 1-19 subgroups were performed. RESULTS Of 882 participants enrolled, 128 had PD-L1 CPS , 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS , 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS , 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS , 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS $ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1-expressing HNSCC.

bioRxiv (Cold Spring Harbor Laboratory), Jun 1, 2023

Head and neck squamous cell carcinomas (HNSCC) are the seventh most common cancer and represent a... more Head and neck squamous cell carcinomas (HNSCC) are the seventh most common cancer and represent a global health burden. Immune checkpoint inhibitors (ICIs) have shown promise in treating recurrent/metastatic cases, with durable benefit in ~30% of patients. Current biomarkers for head and neck tumors are limited in their dynamic ability to capture tumor microenvironment (TME) features, with an increasing need for deeper tissue characterization. Therefore, new biomarkers are needed to accurately stratify patients and predict responses to therapy. Here, we have optimized and applied an ultra-high plex, single-cell spatial protein analysis in HNSCC. Tissues were simultaneously analyzed with a panel of 101 antibodies that targeted biomarkers related to tumor immune, metabolic and stress microenvironments. Our data uncovered a high degree of intra-tumoral heterogeneity intrinsic to head and neck tumors and provided unique insights into the biology of the tumor. In particular, a cellular neighborhood analysis revealed the presence of 6 unique spatial tumor-immune neighborhoods enriched in functionally specialized immune cell subsets across the patient tissue. Additionally, functional phenotyping based on key metabolic and stress markers identified four distinct tumor regions with differential protein signatures. One tumor region was marked by infiltration of CD8+ cytotoxic T cells and overexpression of BAK, a proapoptotic regulator, suggesting strong immune activation and stress. Another adjacent region within the same tumor had high expression of G6PD and MMP9, known drivers of tumor resistance and invasion respectively. This dichotomy of immune activation-induced death and tumor progression in the same sample demonstrates the heterogenous niches and competing microenvironments that underpin clinical responses of therapeutic resistance. Our data integrate single-cell ultra-high plex spatial information with the functional state of the tumor microenvironment to provide insights into a partial response to immune checkpoint inhibitor therapy in HNSCC. We believe that the approach outlined in this study will pave the way towards a new understanding of TME features associated with response and sensitivity to ICI therapies.

Neuro-oncology, Nov 1, 2015

JTO clinical and research reports, Apr 1, 2023

Cancer Research, Aug 1, 2020

Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs)... more Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in a number of solid tumor types.Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (n=350) and lung cancer (n=150) patients were recruited to investigate the prognostic role of CTCs. In parallel, a subset of HNC tumors were profiled using the NanoString GeoMx Digital Spatial Profiling (DSP) technology using a 44-plex antibody cocktail. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, Spiral, Straight and novel microfluidic chip technology) using matched patient samples which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification, ALK-translocations). In HNC, the presence of CTC clusters associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression free survival (Hazard ratio [HR]: 4.946; 95% [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient's body and exome sequencing of CTCs cultures confirmed the presence of mutational signatures consistent with The Cancer Genome Atlas (TCGA). Spatial characterization of the tumor microenvironment revealed immune subsets predictive of outcome to immunotherapy. Comprehensive characterization of the tumor microenvironment and liquid biopsy allows for the recapitulation of the molecular diversity present within the tumor, understanding of the disease progression and testing of therapies

Annals of Oncology, Oct 1, 2018

Background: Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1... more Background: Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1 (PD-1) blockade may elicit a synergistic antitumor response. We aimed to assess whether prior or concurrent RT was associated with improved disease control in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab. Methods: We conducted a retrospective study of patients receiving nivolumab as second or subsequent line therapy for metastatic NSCLC. Patients were categorized into those who received any RT for NSCLC prior to or during nivolumab therapy, and those with no history of RT for NSCLC. Results: A total of 85 patients received nivolumab between July 2015 and December 2016 and were followed up for a median of 15 months. Sixty-five patients (76.4%) received RT prior to or during nivolumab and 20 patients (23.6%) received nivolumab alone. Baseline characteristics of age, performance status, histology, smoking status and previous therapy were similar between the two groups. Prior or concurrent RT was associated with a superior PFS, median 2.8 months with RT versus 1.3 months without RT (Hazard Ratio (HR) = 0.494; 95% Confidence Interval (CI), 0.279-0.873; P = 0.02). The median OS of the group receiving RT was 6.4 months versus 4.2 months for the no RT group (P = 0.20).

Journal of Clinical Oncology, May 20, 2020

5025 Background: Adenosine in the tumor microenvironment (TME) is immunosuppressive and may play ... more 5025 Background: Adenosine in the tumor microenvironment (TME) is immunosuppressive and may play a role in resistance to immunotherapy. We described an adenosine induced gene expression signature (AS, Fong, Cancer Disc 2020) that correlates with response to therapy with cifo, an adenosine A2A receptor antagonist, as monotherapy or in combination with atezolizumab in refractory RCC. These genes express chemokines that signal through CCR2 and CXCR2 to recruit myeloid cells including immunosuppressive tumor associated-M2 macrophages, which are thought to mediate resistance to anti-PD(L)1 treatment. We now identify tumor infiltrating CD68+ myeloid cells as the effector cell for adenosine mediated immunosuppression. Methods: 82 RCC pts have been treated in an ongoing Phase 1/1b trial evaluating cifo (100mg po bid) monotherapy or combination with atezolizumab (840mg IV q 2 weeks). Tumor biopsies, obtained at screening and on therapy, are available for analysis in 32 pts to date. RNA expression was measured in tumors using Nanostring. Immunohistochemistry (IHC) for CD68 was performed on biopsies with CD68+ tumors defined as > 4% tumor area containing CD68+ cells. Results: Pt characteristics are median age 63; median prior therapies 3, with 72% failing prior anti-PD(L)1. Gene expression of M2 markers consisting of CD68 (p = 0.0008) and CD163 (p = 0.03) was higher in baseline samples from AS+ compared to AS- pts. By IHC, 10 pts had CD68+ cells infiltrating the tumor; 9 of 10 AS+. Tumor regression was observed in 6 of 10 CD68+ pts (N = 3 monotherapy and 3 combination) including 4 partial responses (PR, RECIST). No PRs and 2 minor responses were seen in 22 pts who were CD68- (p < 0.005). Median time to progression was not reached for CD68+ vs 2 mo for CD68-. Paired biopsies showed a significant reduction in infiltrating CD68+ cells (p = 0.03) with treatment including 2 of 2 evaluable PRs. Conclusions: Adenosine immunosuppression is mediated by M2 macrophages, which can be reversed by cifo. Enumerating tumor infiltrating CD68+ cells may be a valuable biomarker for identifying pts that will respond to adenosine blockade. Clinical trial information: NCT02655822 .

Asia-pacific Journal of Clinical Oncology, Dec 14, 2016

Aim: To determine the incidence of symptomatic versus incidental pulmonary embolism (PE) in oncol... more Aim: To determine the incidence of symptomatic versus incidental pulmonary embolism (PE) in oncology patients, characterize the nature and extent of incidental PE and the factors contributing to diagnosis. Methods: Specialized web search engine was used to identify oncology patients with positive imaging studies for PE. PE identified at staging CT scans were classified as incidental PEs, whereas PE diagnosed by CTPA/VQ scan were classified as symptomatic PEs. Results: A total of 111 patients with PE were identified over the period of three years. Of these, 67 (60%) patients had symptomatic whereas 44 (40%) patients had incidental PE. Most PEs were segmental and nonocclusive irrespective of the type of PE or stage of the disease. Incidence of PE was equal with/without chemotherapy. Platinum-based chemotherapy was more commonly associated with PE. Most patients received anticoagulation irrespective of type of PE. Conclusion: Forty percent of the diagnosed PEs were incidental, more common in the metastatic group. This may be due to the increased frequency of staging scans performed in patients with metastatic disease, as well as the inherent disease biology of metastatic compared with localized disease. Further prospective analysis of survival by PE subtype and optimal length of anticoagulation in incidental PE is warranted.

Annals of Oncology, Oct 1, 2018

Frontiers in Oncology, Mar 31, 2020

Oropharyngeal cancer (OPC) caused by human papillomavirus (HPV) is a rising global concern. Early... more Oropharyngeal cancer (OPC) caused by human papillomavirus (HPV) is a rising global concern. Early lesions are small and are often located in difficult to access areas (such as the crypts of the tonsils or base of tongue). Unlike cervical cancer, there is no standard or routine screening program for HPV-driven OPC. HPV DNA from OPC tumors may shed directly into saliva, and this can be used as a biomarker for early diagnosis. In this study, we report the first-ever clinically occult OPC in an asymptomatic patient discovered through a saliva test. This case relied upon serial measurements of HPV-16 DNA in saliva, which fell to undetectable levels following low morbidity, curative treatment.

Cancer Science, Aug 7, 2020

Chamindie (2020) Oral HPV16 DNA as a screening tool to detect early oropharyngeal squamous cell c... more Chamindie (2020) Oral HPV16 DNA as a screening tool to detect early oropharyngeal squamous cell carcinoma.

Future Oncology, Jun 1, 2020

Journal of Clinical Oncology, Mar 1, 2016

Conclusion Alectinib is highly active and well tolerated in patients with advanced, crizotinib-re... more Conclusion Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALKpositive NSCLC, including those with CNS metastases.

Journal of Clinical Oncology, Jun 1, 2023

TPS8599 Background: Two phase 2 trials of durvalumab plus chemotherapy in advanced pleural mesoth... more TPS8599 Background: Two phase 2 trials of durvalumab plus chemotherapy in advanced pleural mesothelioma exceeded pre-specified efficacy criteria. The recent CM 743 trial showed overall survival (OS) was longer in those assigned ipilimumab and nivolumab (ipi nivo) than standard chemotherapy, however the benefits were primarily in the subgroup with non-epithelioid histology. DREAM3R will determine the effectiveness of durvalumab plus chemotherapy as first line treatment for advanced pleural mesothelioma. The DREAM3R protocol was recently amended to allow treatment with ipi nivo as per CM 743 in the control group, and to confine further accrual to epithelioid subtype. Methods: Treatment-naïve patients with advanced, epitheloid pleural mesothelioma will be randomized (1:1) to either experimental group treatment: durvalumab 1500 mg every 3 weeks plus chemotherapy (pemetrexed 500 mg/m2 plus either cisplatin 75 mg/m2 or carboplatin AUC 5) every 3 weeks for 4-6 cycles, followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal, or control group treatment: physician’s choice of either chemotherapy or ipi nivo (up to 2 years). The target sample size of 480 recruited over 33 months, with follow up for another 18 months provides over 85% power if the true hazard ratio for OS is 0.70, with 2-sided alpha of 0.05, assuming a median OS of 18 months in the control group. Key eligibility criteria: Epithelioid pleural mesothelioma; measurable disease per RECIST 1.1 modified for mesothelioma; ECOG PS 0-1; and adequate hematologic, renal, and liver function. Exclusions: Prior systemic anticancer treatment for pleural mesothelioma, diagnosis based solely on cytology or fine needle aspiration biopsy, contraindication to immunotherapy or conditions requiring immunosuppressive agents or corticosteroids. Participants are stratified at randomization for: age (18-70 years vs. > 70), sex, planned control regimen (chemotherapy or ipi nivo), platinum (cisplatin vs. carboplatin) and geographic region (USA vs. ANZ). The primary endpoint is OS. Secondary endpoints include progression-free survival; objective tumor response; adverse events; health-related quality of life; and use of healthcare resources in ANZ. Tertiary objectives are to identify potential prognostic and/or predictive biomarkers (including those identified in prior phase 2 studies, PD-L1 expression, tumor mutation burden, genomic characteristics, and HLA subtypes), validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The study is active and enrolling in both ANZ and in the US. Clinical trial information: NCT04334759 and ACTRN12620001199909 .

Annals of Oncology, Oct 1, 2018

Journal of Clinical Oncology, May 20, 2010

7567 Background: Assessing the efficacy of molecularly targeted agents, especially in the absence... more 7567 Background: Assessing the efficacy of molecularly targeted agents, especially in the absence of tumor shrinkage, remains a challenge. The primary objective of this prospective international trial was to evaluate whether on-treatment 18F-deoxyglucose (FDG) and 18F-deoxythymidine (FLT) PET responses predict improved progression-free (PFS) and overall survival (OS) following treatment of 2nd/3rd line NSCLC with E, an epidermal growth factor receptor (EGFR) inhibitor. Methods: Study assessments included FDG- and FLT-PET/CT imaging at baseline (BL), d14 and d56, and diagnostic CT at BL and d56. Detailed uniform protocols were applied for image acquisition and analysis. PET and CT response were determined by central review. Up to 5 target lesions that met RECIST 1.0 and were FDG avid (SUVmax > 2.5) were identified in each pt at BL. Based on EORTC PET response guidelines, partial metabolic response (PMR) was defined as mean decrease >15% in SUVmax across all target lesions. PFS was investigator determined. ...

Supportive Care in Cancer, Apr 27, 2022

Purpose Human papillomavirus (HPV) is now the primary cause of oropharyngeal head and neck cancer... more Purpose Human papillomavirus (HPV) is now the primary cause of oropharyngeal head and neck cancer (OPC) worldwide; yet limited research has examined the effect of HPV-positive status (OPC+) on nutrition outcomes. This study aims to determine the impact of HPV status on nutritional outcomes for adult patients with OPC undergoing any treatment modality. Methods A systematic literature review was conducted up to and including July 2021 of PubMed, Embase, CENTRAL, CINAHL, and Web of Science to identify studies conducted in adults (>18 years) with known OPC reporting on any outcome(s) related to nutrition, according to HPV status (OPC+ versus OPC−). Bias was assessed using QUIPS tool, with certainty of evidence assessed using GRADE system. Results Six studies (total n = 635) all at moderate-high risk of bias were included. Three studies reported on weight change (n = 255), three feeding tube dependency (n = 380), three feeding tube timing of placement (prophylactic or reactive) and/or utilisation (n = 255), two nutritional (energy and/or protein) intake (n = 230), and one nutritional status (n = 83). Patients with OPC+ may experience greater weight loss, may have higher utilisation of reactive feeding tubes (both GRADE low certainty, downgraded due to serious bias and imprecision), and may have lower feeding tube dependency rates (GRADE low certainty, downgraded due to serious bias and inconsistency) versus OPC−. It is uncertain whether nutritional intake and nutritional status differed between populations (GRADE very low certainty, downgraded due to serious bias and very serious imprecision). Conclusion Further, high-quality research is needed to understand optimal nutritional care practices for patients with OPC + to achieve positive health outcomes into survivorship.

Nutrition & Dietetics, Dec 2, 2021

AimsWeight loss and malnutrition occur frequently in patients with head and neck cancer and are a... more AimsWeight loss and malnutrition occur frequently in patients with head and neck cancer and are associated with reduced survival. This pragmatic study aimed to determine the effect of a novel pre‐treatment model of nutrition care on nutrition outcomes for patients with head and neck cancer receiving chemoradiotherapy.MethodsThis health service evaluation consisted of an evaluation of the new model of care implementation (Phase 1) and an evaluation of patient outcomes (Phase 2) in pre‐ and post‐implementation cohorts (n = 64 and n = 47, respectively). All Phase 2 patients received a prophylactic gastrostomy. The new model of care consisted of dietary counselling and commencement of proactive supplementary enteral nutrition via a prophylactic gastrostomy, in addition to normal oral intake, prior to treatment commencement. Nutrition outcomes were collected at baseline (pre‐treatment) and 3 months post‐radiotherapy completion.ResultsThe new model of care was successfully incorporated into practice with high referral (96.5%) and attendance (91.5%) rates to the counselling session, and high adherence rates to proactive tube feeding (80.9%). Patients in the post‐implementation cohort had less weight‐loss (1.2%; p = 0.338) and saw less of a decline in nutritional status compared to patients in the pre‐implementation cohort (23% vs. 30%, respectively; p = 0.572), deemed clinically important. However, patients still experienced critical weight loss overall (mean 9.9%).ConclusionPre‐treatment nutrition care was feasible in standard clinical practice and demonstrated clinically relevant outcome improvements for patients. Future high‐quality research is warranted to investigate further multidisciplinary strategies to attenuate weight‐loss further, inclusive of patient‐reported barriers and enablers to nutrition interventions.

Clinical Endocrinology, Mar 14, 2018

Journal of Clinical Oncology, Jul 20, 2022

PURPOSE The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembroliz... more PURPOSE The phase III KEYNOTE-048 (ClinicalTrials.gov identifier: NCT02358031) trial of pembrolizumab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) included planned efficacy analyses in the total population and in participants with programmed death ligand-1 (PD-L1) combined positive score (CPS) $ 1 and CPS $ 20. To further characterize the predictive value of PD-L1 expression on outcome, we conducted efficacy analyses in the PD-L1 CPS , 1 and CPS 1-19 subgroups in KEYNOTE-048. METHODS Participants with R/M HNSCC and no prior systemic therapy for R/M disease were randomly assigned 1:1:1 to pembrolizumab, pembrolizumab-chemotherapy, or cetuximab-chemotherapy. Post hoc efficacy analyses of the PD-L1 CPS , 1 and CPS 1-19 subgroups were performed. RESULTS Of 882 participants enrolled, 128 had PD-L1 CPS , 1 and 373 had CPS 1-19. For pembrolizumab versus cetuximab-chemotherapy, the median overall survival was 7.9 versus 11.3 months in the PD-L1 CPS , 1 subgroup (hazard ratio [HR], 1.51 [95% CI, 0.96 to 2.37]) and 10.8 versus 10.1 months in the CPS 1-19 subgroup (HR, 0.86 [95% CI, 0.66 to 1.12]). For pembrolizumab-chemotherapy versus cetuximab-chemotherapy, the median overall survival was 11.3 versus 10.7 months in the PD-L1 CPS , 1 subgroup (HR, 1.21 [95% CI, 0.76 to 1.94]) and 12.7 versus 9.9 months in the CPS 1-19 subgroup (HR, 0.71 [95% CI, 0.54 to 0.94]). CONCLUSION Increased efficacy of pembrolizumab or pembrolizumab-chemotherapy was observed with increasing PD-L1 expression. PD-L1 CPS , 1 subgroup analysis was limited by small participant numbers. Results from the PD-L1 CPS 1-19 subgroup support previous findings of treatment benefit with pembrolizumab monotherapy and pembrolizumab-chemotherapy in patients with PD-L1 CPS $ 1 tumors. Although PD-L1 expression is informative, exploration of additional predictive biomarkers is needed for low PD-L1-expressing HNSCC.

bioRxiv (Cold Spring Harbor Laboratory), Jun 1, 2023

Head and neck squamous cell carcinomas (HNSCC) are the seventh most common cancer and represent a... more Head and neck squamous cell carcinomas (HNSCC) are the seventh most common cancer and represent a global health burden. Immune checkpoint inhibitors (ICIs) have shown promise in treating recurrent/metastatic cases, with durable benefit in ~30% of patients. Current biomarkers for head and neck tumors are limited in their dynamic ability to capture tumor microenvironment (TME) features, with an increasing need for deeper tissue characterization. Therefore, new biomarkers are needed to accurately stratify patients and predict responses to therapy. Here, we have optimized and applied an ultra-high plex, single-cell spatial protein analysis in HNSCC. Tissues were simultaneously analyzed with a panel of 101 antibodies that targeted biomarkers related to tumor immune, metabolic and stress microenvironments. Our data uncovered a high degree of intra-tumoral heterogeneity intrinsic to head and neck tumors and provided unique insights into the biology of the tumor. In particular, a cellular neighborhood analysis revealed the presence of 6 unique spatial tumor-immune neighborhoods enriched in functionally specialized immune cell subsets across the patient tissue. Additionally, functional phenotyping based on key metabolic and stress markers identified four distinct tumor regions with differential protein signatures. One tumor region was marked by infiltration of CD8+ cytotoxic T cells and overexpression of BAK, a proapoptotic regulator, suggesting strong immune activation and stress. Another adjacent region within the same tumor had high expression of G6PD and MMP9, known drivers of tumor resistance and invasion respectively. This dichotomy of immune activation-induced death and tumor progression in the same sample demonstrates the heterogenous niches and competing microenvironments that underpin clinical responses of therapeutic resistance. Our data integrate single-cell ultra-high plex spatial information with the functional state of the tumor microenvironment to provide insights into a partial response to immune checkpoint inhibitor therapy in HNSCC. We believe that the approach outlined in this study will pave the way towards a new understanding of TME features associated with response and sensitivity to ICI therapies.

Neuro-oncology, Nov 1, 2015

JTO clinical and research reports, Apr 1, 2023

Cancer Research, Aug 1, 2020

Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs)... more Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in a number of solid tumor types.Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (n=350) and lung cancer (n=150) patients were recruited to investigate the prognostic role of CTCs. In parallel, a subset of HNC tumors were profiled using the NanoString GeoMx Digital Spatial Profiling (DSP) technology using a 44-plex antibody cocktail. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, Spiral, Straight and novel microfluidic chip technology) using matched patient samples which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification, ALK-translocations). In HNC, the presence of CTC clusters associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression free survival (Hazard ratio [HR]: 4.946; 95% [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient's body and exome sequencing of CTCs cultures confirmed the presence of mutational signatures consistent with The Cancer Genome Atlas (TCGA). Spatial characterization of the tumor microenvironment revealed immune subsets predictive of outcome to immunotherapy. Comprehensive characterization of the tumor microenvironment and liquid biopsy allows for the recapitulation of the molecular diversity present within the tumor, understanding of the disease progression and testing of therapies

Annals of Oncology, Oct 1, 2018

Background: Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1... more Background: Studies suggest that combining radiotherapy (RT) with programmed cell death protein 1 (PD-1) blockade may elicit a synergistic antitumor response. We aimed to assess whether prior or concurrent RT was associated with improved disease control in patients with metastatic non-small cell lung cancer (NSCLC) treated with nivolumab. Methods: We conducted a retrospective study of patients receiving nivolumab as second or subsequent line therapy for metastatic NSCLC. Patients were categorized into those who received any RT for NSCLC prior to or during nivolumab therapy, and those with no history of RT for NSCLC. Results: A total of 85 patients received nivolumab between July 2015 and December 2016 and were followed up for a median of 15 months. Sixty-five patients (76.4%) received RT prior to or during nivolumab and 20 patients (23.6%) received nivolumab alone. Baseline characteristics of age, performance status, histology, smoking status and previous therapy were similar between the two groups. Prior or concurrent RT was associated with a superior PFS, median 2.8 months with RT versus 1.3 months without RT (Hazard Ratio (HR) = 0.494; 95% Confidence Interval (CI), 0.279-0.873; P = 0.02). The median OS of the group receiving RT was 6.4 months versus 4.2 months for the no RT group (P = 0.20).

Journal of Clinical Oncology, May 20, 2020

5025 Background: Adenosine in the tumor microenvironment (TME) is immunosuppressive and may play ... more 5025 Background: Adenosine in the tumor microenvironment (TME) is immunosuppressive and may play a role in resistance to immunotherapy. We described an adenosine induced gene expression signature (AS, Fong, Cancer Disc 2020) that correlates with response to therapy with cifo, an adenosine A2A receptor antagonist, as monotherapy or in combination with atezolizumab in refractory RCC. These genes express chemokines that signal through CCR2 and CXCR2 to recruit myeloid cells including immunosuppressive tumor associated-M2 macrophages, which are thought to mediate resistance to anti-PD(L)1 treatment. We now identify tumor infiltrating CD68+ myeloid cells as the effector cell for adenosine mediated immunosuppression. Methods: 82 RCC pts have been treated in an ongoing Phase 1/1b trial evaluating cifo (100mg po bid) monotherapy or combination with atezolizumab (840mg IV q 2 weeks). Tumor biopsies, obtained at screening and on therapy, are available for analysis in 32 pts to date. RNA expression was measured in tumors using Nanostring. Immunohistochemistry (IHC) for CD68 was performed on biopsies with CD68+ tumors defined as > 4% tumor area containing CD68+ cells. Results: Pt characteristics are median age 63; median prior therapies 3, with 72% failing prior anti-PD(L)1. Gene expression of M2 markers consisting of CD68 (p = 0.0008) and CD163 (p = 0.03) was higher in baseline samples from AS+ compared to AS- pts. By IHC, 10 pts had CD68+ cells infiltrating the tumor; 9 of 10 AS+. Tumor regression was observed in 6 of 10 CD68+ pts (N = 3 monotherapy and 3 combination) including 4 partial responses (PR, RECIST). No PRs and 2 minor responses were seen in 22 pts who were CD68- (p < 0.005). Median time to progression was not reached for CD68+ vs 2 mo for CD68-. Paired biopsies showed a significant reduction in infiltrating CD68+ cells (p = 0.03) with treatment including 2 of 2 evaluable PRs. Conclusions: Adenosine immunosuppression is mediated by M2 macrophages, which can be reversed by cifo. Enumerating tumor infiltrating CD68+ cells may be a valuable biomarker for identifying pts that will respond to adenosine blockade. Clinical trial information: NCT02655822 .

Asia-pacific Journal of Clinical Oncology, Dec 14, 2016

Aim: To determine the incidence of symptomatic versus incidental pulmonary embolism (PE) in oncol... more Aim: To determine the incidence of symptomatic versus incidental pulmonary embolism (PE) in oncology patients, characterize the nature and extent of incidental PE and the factors contributing to diagnosis. Methods: Specialized web search engine was used to identify oncology patients with positive imaging studies for PE. PE identified at staging CT scans were classified as incidental PEs, whereas PE diagnosed by CTPA/VQ scan were classified as symptomatic PEs. Results: A total of 111 patients with PE were identified over the period of three years. Of these, 67 (60%) patients had symptomatic whereas 44 (40%) patients had incidental PE. Most PEs were segmental and nonocclusive irrespective of the type of PE or stage of the disease. Incidence of PE was equal with/without chemotherapy. Platinum-based chemotherapy was more commonly associated with PE. Most patients received anticoagulation irrespective of type of PE. Conclusion: Forty percent of the diagnosed PEs were incidental, more common in the metastatic group. This may be due to the increased frequency of staging scans performed in patients with metastatic disease, as well as the inherent disease biology of metastatic compared with localized disease. Further prospective analysis of survival by PE subtype and optimal length of anticoagulation in incidental PE is warranted.

Annals of Oncology, Oct 1, 2018

Frontiers in Oncology, Mar 31, 2020

Oropharyngeal cancer (OPC) caused by human papillomavirus (HPV) is a rising global concern. Early... more Oropharyngeal cancer (OPC) caused by human papillomavirus (HPV) is a rising global concern. Early lesions are small and are often located in difficult to access areas (such as the crypts of the tonsils or base of tongue). Unlike cervical cancer, there is no standard or routine screening program for HPV-driven OPC. HPV DNA from OPC tumors may shed directly into saliva, and this can be used as a biomarker for early diagnosis. In this study, we report the first-ever clinically occult OPC in an asymptomatic patient discovered through a saliva test. This case relied upon serial measurements of HPV-16 DNA in saliva, which fell to undetectable levels following low morbidity, curative treatment.

Cancer Science, Aug 7, 2020

Chamindie (2020) Oral HPV16 DNA as a screening tool to detect early oropharyngeal squamous cell c... more Chamindie (2020) Oral HPV16 DNA as a screening tool to detect early oropharyngeal squamous cell carcinoma.

Future Oncology, Jun 1, 2020

Journal of Clinical Oncology, Mar 1, 2016

Conclusion Alectinib is highly active and well tolerated in patients with advanced, crizotinib-re... more Conclusion Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALKpositive NSCLC, including those with CNS metastases.

Journal of Clinical Oncology, Jun 1, 2023

TPS8599 Background: Two phase 2 trials of durvalumab plus chemotherapy in advanced pleural mesoth... more TPS8599 Background: Two phase 2 trials of durvalumab plus chemotherapy in advanced pleural mesothelioma exceeded pre-specified efficacy criteria. The recent CM 743 trial showed overall survival (OS) was longer in those assigned ipilimumab and nivolumab (ipi nivo) than standard chemotherapy, however the benefits were primarily in the subgroup with non-epithelioid histology. DREAM3R will determine the effectiveness of durvalumab plus chemotherapy as first line treatment for advanced pleural mesothelioma. The DREAM3R protocol was recently amended to allow treatment with ipi nivo as per CM 743 in the control group, and to confine further accrual to epithelioid subtype. Methods: Treatment-naïve patients with advanced, epitheloid pleural mesothelioma will be randomized (1:1) to either experimental group treatment: durvalumab 1500 mg every 3 weeks plus chemotherapy (pemetrexed 500 mg/m2 plus either cisplatin 75 mg/m2 or carboplatin AUC 5) every 3 weeks for 4-6 cycles, followed by durvalumab 1500 mg every 4 weeks until disease progression, unacceptable toxicity or patient withdrawal, or control group treatment: physician’s choice of either chemotherapy or ipi nivo (up to 2 years). The target sample size of 480 recruited over 33 months, with follow up for another 18 months provides over 85% power if the true hazard ratio for OS is 0.70, with 2-sided alpha of 0.05, assuming a median OS of 18 months in the control group. Key eligibility criteria: Epithelioid pleural mesothelioma; measurable disease per RECIST 1.1 modified for mesothelioma; ECOG PS 0-1; and adequate hematologic, renal, and liver function. Exclusions: Prior systemic anticancer treatment for pleural mesothelioma, diagnosis based solely on cytology or fine needle aspiration biopsy, contraindication to immunotherapy or conditions requiring immunosuppressive agents or corticosteroids. Participants are stratified at randomization for: age (18-70 years vs. > 70), sex, planned control regimen (chemotherapy or ipi nivo), platinum (cisplatin vs. carboplatin) and geographic region (USA vs. ANZ). The primary endpoint is OS. Secondary endpoints include progression-free survival; objective tumor response; adverse events; health-related quality of life; and use of healthcare resources in ANZ. Tertiary objectives are to identify potential prognostic and/or predictive biomarkers (including those identified in prior phase 2 studies, PD-L1 expression, tumor mutation burden, genomic characteristics, and HLA subtypes), validation of radiological measures of response, and studies of possible radiomic biomarkers in mesothelioma. The study is active and enrolling in both ANZ and in the US. Clinical trial information: NCT04334759 and ACTRN12620001199909 .

Annals of Oncology, Oct 1, 2018

Journal of Clinical Oncology, May 20, 2010

7567 Background: Assessing the efficacy of molecularly targeted agents, especially in the absence... more 7567 Background: Assessing the efficacy of molecularly targeted agents, especially in the absence of tumor shrinkage, remains a challenge. The primary objective of this prospective international trial was to evaluate whether on-treatment 18F-deoxyglucose (FDG) and 18F-deoxythymidine (FLT) PET responses predict improved progression-free (PFS) and overall survival (OS) following treatment of 2nd/3rd line NSCLC with E, an epidermal growth factor receptor (EGFR) inhibitor. Methods: Study assessments included FDG- and FLT-PET/CT imaging at baseline (BL), d14 and d56, and diagnostic CT at BL and d56. Detailed uniform protocols were applied for image acquisition and analysis. PET and CT response were determined by central review. Up to 5 target lesions that met RECIST 1.0 and were FDG avid (SUVmax > 2.5) were identified in each pt at BL. Based on EORTC PET response guidelines, partial metabolic response (PMR) was defined as mean decrease >15% in SUVmax across all target lesions. PFS was investigator determined. ...

Supportive Care in Cancer, Apr 27, 2022

Purpose Human papillomavirus (HPV) is now the primary cause of oropharyngeal head and neck cancer... more Purpose Human papillomavirus (HPV) is now the primary cause of oropharyngeal head and neck cancer (OPC) worldwide; yet limited research has examined the effect of HPV-positive status (OPC+) on nutrition outcomes. This study aims to determine the impact of HPV status on nutritional outcomes for adult patients with OPC undergoing any treatment modality. Methods A systematic literature review was conducted up to and including July 2021 of PubMed, Embase, CENTRAL, CINAHL, and Web of Science to identify studies conducted in adults (>18 years) with known OPC reporting on any outcome(s) related to nutrition, according to HPV status (OPC+ versus OPC−). Bias was assessed using QUIPS tool, with certainty of evidence assessed using GRADE system. Results Six studies (total n = 635) all at moderate-high risk of bias were included. Three studies reported on weight change (n = 255), three feeding tube dependency (n = 380), three feeding tube timing of placement (prophylactic or reactive) and/or utilisation (n = 255), two nutritional (energy and/or protein) intake (n = 230), and one nutritional status (n = 83). Patients with OPC+ may experience greater weight loss, may have higher utilisation of reactive feeding tubes (both GRADE low certainty, downgraded due to serious bias and imprecision), and may have lower feeding tube dependency rates (GRADE low certainty, downgraded due to serious bias and inconsistency) versus OPC−. It is uncertain whether nutritional intake and nutritional status differed between populations (GRADE very low certainty, downgraded due to serious bias and very serious imprecision). Conclusion Further, high-quality research is needed to understand optimal nutritional care practices for patients with OPC + to achieve positive health outcomes into survivorship.

Nutrition & Dietetics, Dec 2, 2021

AimsWeight loss and malnutrition occur frequently in patients with head and neck cancer and are a... more AimsWeight loss and malnutrition occur frequently in patients with head and neck cancer and are associated with reduced survival. This pragmatic study aimed to determine the effect of a novel pre‐treatment model of nutrition care on nutrition outcomes for patients with head and neck cancer receiving chemoradiotherapy.MethodsThis health service evaluation consisted of an evaluation of the new model of care implementation (Phase 1) and an evaluation of patient outcomes (Phase 2) in pre‐ and post‐implementation cohorts (n = 64 and n = 47, respectively). All Phase 2 patients received a prophylactic gastrostomy. The new model of care consisted of dietary counselling and commencement of proactive supplementary enteral nutrition via a prophylactic gastrostomy, in addition to normal oral intake, prior to treatment commencement. Nutrition outcomes were collected at baseline (pre‐treatment) and 3 months post‐radiotherapy completion.ResultsThe new model of care was successfully incorporated into practice with high referral (96.5%) and attendance (91.5%) rates to the counselling session, and high adherence rates to proactive tube feeding (80.9%). Patients in the post‐implementation cohort had less weight‐loss (1.2%; p = 0.338) and saw less of a decline in nutritional status compared to patients in the pre‐implementation cohort (23% vs. 30%, respectively; p = 0.572), deemed clinically important. However, patients still experienced critical weight loss overall (mean 9.9%).ConclusionPre‐treatment nutrition care was feasible in standard clinical practice and demonstrated clinically relevant outcome improvements for patients. Future high‐quality research is warranted to investigate further multidisciplinary strategies to attenuate weight‐loss further, inclusive of patient‐reported barriers and enablers to nutrition interventions.