Intratumoral stromal morphometry predicts disease recurrence but not response to 5‐fluorouracil—results from the <scp>QUASAR</scp> trial of colorectal cancer

Hutchins, Gordon G A; Treanor, Darren; Wright, Alexander; Handley, Kelly; Magill, Laura; Tinkler-Hundal, Emma; Southward, Katie; Seymour, Michel; Kerr, David; Gray, Richard; Quirke, Philip

doi:10.1111/his.13326

Cited by 19 publications

(23 citation statements)

References 87 publications

(140 reference statements)

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“…A CRIS-B subtype was also identified, with TGF-β pathway activation, epithelial-to-mesenchymal transition (EMT), and poor prognosis, whereas the CMS4 subtype was distributed among all CRIS subtypes, confirming previous observations that the CMS4 transcriptome is dominated by stromal contribution (5)(6)(7)(8)(9). Analysis of clinical responses to adjuvant chemotherapy in patients with stage III CRC revealed a benefit for epithelium-rich CMS2 and CMS3 subgroups, but not for the CMS1 or CMS4 subgroups (7,10,11). However, the molecular mechanism underlying this differential response pattern is not fully understood.…”

Section: Resultssupporting

confidence: 79%

“…Our results show that the antitumor efficacy of aCD40 monotherapy is limited, as observed in other tumor models and in clinical trials (20,56,70). In contrast, additional blockade of VEGFA and ANGPT2, a vessel-destabilizing ligand of TIE2 and a clinical evidence indicates that epithelium-rich tumors with high WNT signaling respond best to chemotherapy, whereas outcomes are worst for patients with desmoplastic CRC (7,10,11). Increased TGF-β signaling or Notch hyperactivation has been shown to promote desmoplasia in CRC models (14,47,59), indicating that multiple pathways contribute to stromal expansion in a subset of MSS CRCs.…”

Section: Discussionmentioning

confidence: 65%

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Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

Ragusa

Prat-Luri

González-Loyola

et al. 2020

Journal of Clinical Investigation

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Section: Resultssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 65%

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

Ragusa

Prat-Luri

González-Loyola

et al. 2020

Journal of Clinical Investigation

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“…Several studies have reported an intratumoural stroma-epithelium ratio or tumour stromal percentage to be an independent prognostic marker in CRC. However, conclusions on stage II CC are not easily extracted, as these studies included several disease stages [5, 7, 25], and some also included rectal cancer [6, 8, 9]. Recently, Hutchins et al [9] quantified the relative proportion of stroma morphometrically in the QUSAR study cohort of stage II and III CRC patients, and they found tumours of the rectum to have a significantly higher stroma-ratio compared to those of the colon.…”

Section: Discussionmentioning

confidence: 99%

The prognostic value of tumour stroma ratio and tumour budding in stage II colon cancer. A nationwide population-based study

Eriksen

Sørensen

Lindebjerg

et al. 2018

Int J Colorectal Dis

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PurposeHigh-risk patients with stage II colon cancer (CC) may benefit from adjuvant chemotherapy, but additional prognostic markers are needed for better stratification. We investigated the prognostic value of tumour stroma ratio (TSR) and tumour budding (TB).MethodsA nationwide population-based cohort of 573 patients with stage II CC was included. TSR was scored on hematoxylin and eosin sections as low TSR (> 50% stroma) and high TSR (≤ 50% stroma). TB was evaluated in hotspots on pan-cytokeratin stained sections in 10 high power fields (HPF) at the invasive front and classified by the mean number of buds per HPF as high grade budding (≥ 10 buds) or low-grade budding (< 10 buds). The prognostic value was investigated in Cox proportional hazard models for recurrence-free survival (RFS) and overall survival (OS).ResultsLow TSR was associated with worse RFS (HR = 1.342 (95% CI 1.006–1.791), p = 0.045) and OS (HR = 1.376 (95% CI 1.016–1.862), p = 0.039). Furthermore, an association was found between low TSR and microsatellite stabile tumours (p < 0.001). The mean number of buds per HPF was associated to TSR with increasing number of buds related to a lower TSR (p = 0.026). No statistically significant prognostic impact of TB regarding OS or RFS was detected.ConclusionsTSR provided valuable prognostic information, and adding TSR to the current risk stratification may contribute to better patient selection. The estimates of TSR and TB were found to be associated, but no prognostic value of TB was documented.

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“…Extended use of clinical information, such as details of treatment for recurrence may improve model performance. Furthermore, incorporation of molecular prognostic indicators such as microsatellite instability, KRAS / BRAF mutation and chromosome instability, or stroma and immune markers such as the Immunoscore, has potential for refining predictions.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the transferability of survival calculators for stage II/III colon cancer across healthcare systems

Jorissen

Croxford

Jones

et al. 2019

Intl Journal of Cancer

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Adjuvant! Online Inc (A!O), the Memorial Sloan Kettering Cancer Center (MSKCC), MD Anderson (MDA) and Mayo Clinic (MC) provide calculators to predict survival probabilities for patients with resected early‐stage colon cancer, trained on data from United States (US) patient cohorts or patients enrolled in international clinical trials. Limited data exist on the transferability of calculators across healthcare systems. Calculator transferability to Australian community practice was evaluated for 1,401 stage II/III patients. Calibration and discrimination were assessed for overall (OS), cancer‐specific (CSS) or recurrence‐free survival (RFS). The US patient cohort‐based calculators, A!O, MSKCC and MDA, significantly overestimated risks of recurrence and death in Australian patients, with 5‐year OS, CSS and RFS prediction differences of −6.5% to −9.9%, −9.1% to −14.4% and − 3.8% to −6.8%, respectively (p < 0.001). Significant heterogeneity in calibration was observed for subgroups by tumor stage and treatment, age, gender, tumor location, ECOG and ASA score. Calibration appeared acceptable for the clinical trial patient‐based MC calculator, but restricted tool applicability (stage III patients, ≥12 examined lymph nodes, receiving adjuvant treatment) limited the sample size. Compared to AJCC 7th edition tumor staging, calculators showed improved discrimination for OS, but no improvement for CSS and RFS. In conclusion, deficiencies in calibration limited transferability of US patient cohort‐based survival calculators for early‐stage colon cancer to the setting of Australian community practice. Our results demonstrate the utility for multi‐feature survival calculators to improve OS predictions but highlight the importance for performance assessment of tools prior to implementation in an external health care setting.

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Intratumoral stromal morphometry predicts disease recurrence but not response to 5‐fluorouracil—results from the QUASAR trial of colorectal cancer

Cited by 19 publications

References 87 publications

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

The prognostic value of tumour stroma ratio and tumour budding in stage II colon cancer. A nationwide population-based study

Evaluation of the transferability of survival calculators for stage II/III colon cancer across healthcare systems

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