Evolution of Mutational Landscape and Tumor Immune-Microenvironment in Liver Oligo-Metastatic Colorectal Cancer

Ottaiano, Alessandro; Caraglia, Michele; Mauro, Annabella Di; Botti, Gerardo; Lombardi, Angela; Galon, Jérôme; Luce, Amalia; D'Amore, Luigi; Perri, Francesco; Santorsola, Mariachiara; Hermitte, Fabienne; Savarese, Giovanni; Tatangelo, Fabiana; Granata, Vincenza; Izzo, Francesco; Belli, Andrea; Scala, Stefania; Delrio, Paolo; Circelli, Luisa; Nasti, Guglielmo

doi:10.3390/cancers12103073

Cited by 31 publications

(30 citation statements)

References 49 publications

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“…Multivariate analysis showed that both mutational trajectories had an independent and significant prognostic power. As in our previous studies ( 5 , 6 ), we cannot definitively demonstrate if this effect depends on a negative immunologic selection ( 12 ) or on a spontaneous genetic devolution. Our translational studies are in progress to identify and isolate, from oligo-metastatic CRC patients, eventual T-cells responsible of mut KRAS clones’ elimination.…”

Section: Discussioncontrasting

confidence: 74%

“…In fact, it is now clear that mCRC patients bearing specific KRAS (Kirsten RAt Sarcoma viral oncogene homolog) mutations do not benefit from anti-EGFR treatment because mutated and constitutively hyper-activated KRAS determine a ligand-independent activation of EGFR ( 4 ). We previously reported that loss of KRAS mutations (“regressive” mutational trajectories) from primary tumors to metastases on FFPE (Formalin-Fixed Paraffin Embedded) resected tissues was associated with long-term survivals and the oligo-metastatic status in mCRC ( 5 , 6 ). However, the evaluation of circulating tumor DNA (ctDNA) sequences, also called “liquid biopsy”, has provided a great opportunity to study the mutational evolution of cancers with a non-invasive, real-time and repeatable approach.…”

Section: Introductionmentioning

confidence: 99%

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KRAS Mutational Regression Is Associated With Oligo-Metastatic Status and Good Prognosis in Metastatic Colorectal Cancer

et al. 2021

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BackgroundWe previously reported that loss of KRAS mutations (“regressive” mutational trajectories) from primary tumors to metastases associated with the oligo-metastatic status in colorectal cancer (CRC). The present study was undertaken in order to analyze the mutational trajectories of KRAS in a well-characterized cohort of CRC patients who developed poly- or oligo-metastatic disease.Material and MethodsPatients were treated and followed-up according to European Society of Medical Oncology guidelines. Primary CRC FFPE tissue and metastatic circulating-free DNA were extracted using the QIAamp DNA specific kits (Qiagen, Hilden, Germany). Samples were sequenced with the Oncomine Solid Tumour DNA kit (Thermo Fisher Scientific, Waltham, MA, USA). Plasma collection for liquid biopsy was done from 1 to 14 days before starting first-line chemotherapy. Analysis of the prognostic power of KRAS evolutionary trajectories was done with uni- and multivariate analyses.ResultsOne-hundred-fourteen patients were enrolled. Sixty-three patients presented with mutated KRAS (mutKRAS) and 51 with wild-type KRAS (wtKRAS). KRAS mutational concordance was high (70.1%).Two divergent subsets were identified: mutKRAS in primary tumors and wtKRAS in metastatic ones (regressive: mutKRAS → wtKRAS in 8.8% of patients), and vice versa (progressive: wtKRAS → mutKRAS in 21.1% of patients). An association between KRAS regressive trajectory and the oligo-metastatic status (P <0.0001) was found. At multivariate analysis, regressive and progressive mutational trajectories emerged as independent prognostic factors for survival, with Hazard Ratios of 0.22 (CI 95%: 0.08–0.61; median survival: not reached) and 2.70 (CI 95%: 1.11–6.56, median survival: 12.1 months), respectively.ConclusionsOur data provide evidence that the evolutionary trajectories of KRAS can have a strong clinical prognostic role and that they can be involved in discriminating between poly-metastatic aggressive vs oligo-metastatic indolent CRC.

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Section: Discussioncontrasting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

KRAS Mutational Regression Is Associated With Oligo-Metastatic Status and Good Prognosis in Metastatic Colorectal Cancer

et al. 2021

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“…It is plausible that the less adapted tumour microenvironment of the metastatic sites recruits more host immune cells attracted by the unidentified cancer cells than that of the primary tumour site. Recently, specific changes in cancer-related genes and immune cell infiltration in CRC metastases have been related to metastatic evolution, which produce new perspectives for cancer diagnostics and therapeutic strategies [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

Immune Contexture of MMR-Proficient Primary Colorectal Cancer and Matched Liver and Lung Metastases

Ahtiainen¹,

Elomaa

Väyrynen

et al. 2021

Cancers

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Purpose: To evaluate immune cell infiltration, the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) expression and their prognostic value in a series of mismatch proficient (pMMR) CRC with matched liver and lung metastases. Methods: Formalin-fixed paraffin-embedded tissue sections stained for CD3, CD8, PD-L1 and PD-1 from 113 primary CRC tumours with 105 liver and 59 lung metastases were analyzed. The amount of CD3 and CD8 positive lymphocytes were combined as immune cell score (ICS). Comparative analyses on immune contexture were performed both between the primary tumour and matched metastases and between the metastatic sites. Results: In liver metastases, immune cell infiltration was increased in general compared to primary tumours but did not correlate case by case. On the contrary, ICS between lung metastases and primary tumours correlated well, but the expression of PD-1/PD-L1 was increased in lung metastases. The proportion of tumours with high ICS together with PD-L1-positivity almost doubled in metastases (39%) compared to primary tumours (20%). High ICS (compared to lowest) in patient’s least immune-infiltrated metastasis was an independent prognostic marker for disease-specific (HR 9.14, 95%CI 2.81–29.68) and overall survival (HR 6.95, 95%CI 2.30–21.00). Conclusions: Our study confirms the prognostic value of high ICS in least immune-infiltrated metastases in pMMR CRC patients. Major differences observed in immune contexture between primary tumours and metastases may have significance for treatment strategies for patients with advanced CRC.

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“…Besides, the gene mutation information in this study was derived from the primary tumor, not the metastatic sites. Considering the genetic evolution and alterations from primary to matched metastatic tissues ( 52 , 53 ), it is interesting to investigate the association between gene mutation in metastatic tissues and CRLM recurrence in the future.…”

Section: Discussionmentioning

confidence: 99%

Hepatic Steatosis Predicts Higher Incidence of Recurrence in Colorectal Cancer Liver Metastasis Patients

et al. 2021

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Purpose: Colorectal liver metastasis (CRLM) is the major cause of death due to colorectal cancer. Although great efforts have been made in treatment of CRLM, about 60–70% of patients will develop hepatic recurrence. Hepatic steatosis was reported to provide fertile soil for metastasis. However, whether hepatic steatosis predicts higher incidence of CRLM recurrence is not clear. Therefore, we aimed to determine the role of hepatic steatosis in CRLM recurrence in the present study.Methods: Consecutive CRLM patients undergoing curative treatment were retrospectively enrolled and CT liver-spleen attenuation ratio was used to detect the presence of hepatic steatosis. In patients with hepatic steatosis, we also detected the presence of fibrosis. Besides, a systematic literature search was performed to do meta-analysis to further analyze the association between hepatic steatosis and CRLM recurrence.Results: A total of 195 eligible patients were included in our center. Patients with hepatic steatosis had a significantly worse overall (P = 0.0049) and hepatic recurrence-free survival (RFS) (P = 0.0012). Univariate and multivariate analysis confirmed its essential role in prediction of RFS. Besides, hepatic fibrosis is associated with worse overall RFS (P = 0.039) and hepatic RFS (P = 0.048). In meta-analysis, we included other four studies, with a total of 1,370 patients in the case group, and 3,735 patients in the control group. The odds ratio was 1.98 (95% CI: 1.25–3.14, P = 0.004), indicating that patients with steatosis had a significantly higher incidence of CRLM recurrence.Conclusion: In summary, patients with hepatic steatosis had a significantly worse overall and hepatic RFS and it's associated with higher incidence of CRLM recurrence.

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Evolution of Mutational Landscape and Tumor Immune-Microenvironment in Liver Oligo-Metastatic Colorectal Cancer

Cited by 31 publications

References 49 publications

KRAS Mutational Regression Is Associated With Oligo-Metastatic Status and Good Prognosis in Metastatic Colorectal Cancer

KRAS Mutational Regression Is Associated With Oligo-Metastatic Status and Good Prognosis in Metastatic Colorectal Cancer

Immune Contexture of MMR-Proficient Primary Colorectal Cancer and Matched Liver and Lung Metastases

Hepatic Steatosis Predicts Higher Incidence of Recurrence in Colorectal Cancer Liver Metastasis Patients

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