Clinical Studies

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    HER-2 directed therapies across gastrointestinal tract cancers - A new frontier.
    (ELSEVIER SCI LTD, 2024-09-01) Jones, L; Cunningham, D; Starling, N; Cunningham, David; Starling, Naureen
    Gastrointestinal (GI) cancers are common and in the metastatic setting they have a poor prognosis. The current mainstay of treatment of GI cancers is chemotherapy; however, the biomarker-directed treatment landscape is evolving. HER-2 is overexpressed in a portion of GI cancers and is an emerging target for therapy, with recent FDA tumor agnostic approval for trastuzumab deruxtecan. Testing for HER-2 expression is not standardized across GI cancers, methodology requires further optimization and standardization as HER-2 targeted therapy emerges into the treatment landscape. There is established rationale for use of HER-2 targeted therapy in first line treatment of metastatic gastric cancer, and emerging evidence with variable benefit in bile duct, pancreatic and colorectal cancers.
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    Correlation analyses of radiographic progression-free survival with clinical and health-related quality of life outcomes in metastatic castration-resistant prostate cancer: Analysis of the phase 3 VISION trial.
    (WILEY, 2024-06-21) Morris, MJ; de Bono, J; Nagarajah, J; Sartor, O; Wei, XX; Nordquist, LT; Koshkin, VS; Chi, KN; Krause, BJ; Herrmann, K; Rahbar, K; Vickers, A; Mirante, O; Ghouse, R; Fizazi, K; Tagawa, ST; De Bono, Johann
    BACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus protocol-permitted standard of care (SOC) prolonged overall survival (OS) and radiographic progression-free survival (rPFS) versus SOC in patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) in the phase 3 VISION study, in addition to beneficial effects on symptomatic skeletal events (SSEs) and health-related quality of life (HRQOL). METHODS: Post hoc analyses used the full analysis set from the VISION study (N = 831) overall and by randomized treatment arm (177Lu-PSMA-617 plus SOC, n = 551; SOC, n = 280). Correlations were determined between OS and rPFS and between rPFS or OS and time to SSE or to worsening HRQOL (Functional Assessment of Cancer Therapy-Prostate [FACT-P] and 5-level EQ-5D [EQ-5D-5L]). Correlation analyses used an iterative multiple imputation copula-based approach (correlation coefficients [rho] of <0.3 were defined as weak, ā‰„0.3 and <0.5 as mild, ā‰„0.5 and <0.7 as moderate, and ā‰„0.7 as strong). RESULTS: In the overall population, rPFS correlated strongly with OS (rho, ā‰„0.7). Correlations between rPFS or OS and time to SSE without death were weak or mild. Time to worsening in the FACT-P total score and emotional and physical well-being domains correlated mildly or moderately with rPFS and moderately with OS. Correlation coefficients for time-to-worsening EQ-5D-5L scores were mild to moderate for both rPFS and OS. Correlation coefficients were similar between treatment arms. CONCLUSIONS: In this analysis of the VISION study, rPFS correlated strongly with OS but not with time to SSE or worsening HRQOL. These findings require further investigation.
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    Cancer cell - Fibroblast crosstalk via HB-EGF, EGFR, and MAPK signaling promotes the expression of macrophage chemo-attractants in squamous cell carcinoma.
    (Elsevier BV, 2024-09-20) Giangreco, G; Rullan, A; Naito, Y; Biswas, D; Liu, Y-H; Hooper, S; Nenclares, P; Bhide, S; Chon U Cheang, M; Chakravarty, P; Hirata, E; Swanton, C; Melcher, A; Harrington, K; Sahai, E; Nenclares, Pablo
    Interactions between cells in the tumor microenvironment (TME) shape cancer progression and patient prognosis. To gain insights into how the TME influences cancer outcomes, we derive gene expression signatures indicative of signaling between stromal fibroblasts and cancer cells, and demonstrate their prognostic significance in multiple and independent squamous cell carcinoma cohorts. By leveraging information within the signatures, we discover that the HB-EGF/EGFR/MAPK axis represents a hub of tumor-stroma crosstalk, promoting the expression of CSF2 and LIF and favoring the recruitment of macrophages. Together, these analyses demonstrate the utility of our approach for interrogating the extent and consequences of TME crosstalk.
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    Tissue-Free Liquid Biopsies Combining Genomic and Methylation Signals for Minimal Residual Disease Detection in Patients with Early Colorectal Cancer from the UK TRACC Part B Study.
    (AMER ASSOC CANCER RESEARCH, 2024-08-15) Slater, S; Bryant, A; Aresu, M; Begum, R; Chen, H-C; Peckitt, C; Lazaro-Alcausi, R; Carter, P; Anandappa, G; Khakoo, S; Melcher, L; Potter, V; Marti, FM; Huang, J; Branagan, G; George, N; Abulafi, M; Duff, S; Raja, A; Gupta, A; West, N; Bucheit, L; Rich, T; Chau, I; Cunningham, D; Starling, N; TRACC Part B trial investigators,; Slater, Susanna
    PURPOSE: The absence of postoperative circulating tumor DNA (ctDNA) identifies patients with resected colorectal cancer (CRC) with low recurrence risk for adjuvant chemotherapy (ACT) de-escalation. Our study presents the largest resected CRC cohort to date with tissue-free minimal residual disease (MRD) detection. EXPERIMENTAL DESIGN: TRACC (tracking mutations in cell-free tumor DNA to predict relapse in early colorectal cancer) included patients with stage I to III resectable CRC. Prospective longitudinal plasma collection for ctDNA occurred pre- and postsurgery, post-ACT, every 3 months for year 1 and every 6 months in years 2 and 3 with imaging annually. The Guardant Reveal assay evaluated genomic and methylation signals. The primary endpoint was 2-year recurrence-free survival (RFS) by postoperative ctDNA detection (NCT04050345). RESULTS: Between December 2016 and August 2022, 1,203 were patients enrolled. Plasma samples (n = 997) from 214 patients were analyzed. One hundred forty-three patients were evaluable for the primary endpoint; 92 (64.3%) colon, 51 (35.7%) rectal; two (1.4%) stage I, 64 (44.8%) stage II, and 77 (53.8%) stage III. Median follow-up was 30.3 months (95% CI, 29.5-31.3). Two-year RFS was 91.1% in patients with ctDNA not detected postoperatively and 50.4% in those with ctDNA detected [HR, 6.5 (2.96-14.5); P < 0.0001]. Landmark negative predictive value (NPV) was 91.2% (95% CI, 83.9-95.9). Longitudinal sensitivity and specificity were 62.1% (95% CI, 42.2-79.3) and 85.9% (95% CI, 78.9-91.3), respectively. The median lead time from ctDNA detection to radiological recurrence was 7.3 months (IQR, 3.3-12.5; n = 9). CONCLUSIONS: Tissue-free MRD detection with longitudinal sampling predicts recurrence in patients with stage I to III CRC without the need for tissue sequencing. The UK TRACC Part C study is currently investigating the potential for ACT de-escalation in patients with undetectable postoperative ctDNA, given the high NPV indicating a low likelihood of residual disease.