Research Papers:

Evidence of intermetastatic heterogeneity for pathological response and genetic mutations within colorectal liver metastases following preoperative chemotherapy

Mylène Sebagh _, Marc-Antoine Allard, Nelly Bosselut, Myriam Dao, Eric Vibert, Maïté Lewin, Antoinette Lemoine, Daniel Cherqui, René Adam and Antonio Sa Cunha

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Oncotarget. 2016; 7:21591-21600. https://doi.org/10.18632/oncotarget.7809

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Mylène Sebagh1,2,* Marc-Antoine Allard3,4,*, Nelly Bosselut2,5, Myriam Dao1, Eric Vibert2,3, Maïté Lewin6, Antoinette Lemoine2,5, Daniel Cherqui2,3, René Adam3,4, Antonio Sa Cunha3,4

1AP-HP Hôpital Paul Brousse, Department of Pathology, Villejuif, France

2Inserm U1193, Paris-Sud University, Villejuif, France

3AP-HP Hôpital Paul Brousse, Hepatobiliary Centre, Villejuif, France

4Inserm U935, Paris-Sud University, Villejuif, France

5AP-HP Hôpital Paul Brousse, Department of Oncogenetics, Villejuif, France

6AP-HP Hôpital Paul Brousse, Radiology, Villejuif, France

*Co-first authors

Correspondence to:

Mylène Sebagh, e-mail: [email protected]

Keywords: colorectal liver metastases, pathological response, intermetastatic tumor heterogeneity, somatic gene profile

Received: September 09, 2015     Accepted: January 29, 2016     Published: March 01, 2016


Background: In patients receiving preoperative chemotherapy, colorectal liver metastases (CLM) are expected to demonstrate a similar behaviour because of similar organ microenvironment and tumour cell chemosensitivity. We focused on the occurrence of pathological and genetic heterogeneity within CLM.

Methods: Patients resected for multiple CLM between 2004 and 2011 after > three cycles of chemotherapy were included. Pathological heterogeneity was arbitrarily defined as a > 50% difference in the percentage of remaining tumour cells between individual CLM. In patients with pathological heterogeneity, the mutational genotyping (KRAS, NRAS, BRAF and PIK3CA) was determined from the most heterogeneous CLM.

Results: Pathological heterogeneity was observed in 31 of 157 patients with multiple CLM (median = 4, range, 2–32) (19.7%). In 72.4% of them, we found a concordance of the mutation status between the paired CLM: both wild-type in 55%, and both mutated in 17.2%. We observed a discordance of the mutation status of 27.6% between CLM: one mutated and the other wild-type. The mutated CLM was the less florid one in 75% of patients with genetic heterogeneity.

Conclusions: Pathological heterogeneity is present in 19.7% of patients with multiple CLM. Genetic heterogeneity is present in 27.6% of patients with pathological heterogeneity. Heterogeneity could refine guide management for tissue sampling.

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PII: 7809