Leptomeningeal Metastases Linked to EGFR Mutations

Epidermal growth factor receptor status is associated with the likelihood of leptomeningeal metastases and treatment outcomes in non-small-cell lung cancer

medwireNews: Chinese research suggests that non-small-cell lung cancer (NSCLC) patients with an epidermal growth factor receptor (EGFR) mutation have an increased prevalence of leptomeningeal metastases (LM) but may benefit from treatment with an EGFR–tyrosine kinase inhibitor (TKI) or chemotherapy.

The review of 3775 NSCLC patients attending the Guangdong General Hospital between 2011 and 2015 shows that 4.2% of patients developed LM, with the complication significantly more common in patients with an EGFR mutation than those without, affecting 9.4% versus 1.7.%.

The prevalence of LM was comparable in the patients with the most common exon 21 L858R EGFR mutations (11.0% of 576 patients) and exon 19 EGFR deletions (9.2% of 511 patients), say Yi-Long Wu and co-investigators at the institution.

“Longer survival and insufficient penetrance of TKIs into the [cerebrospinal fluid] are likely to be the main explanations” for the higher frequency of LM in EGFR-positive patients, they write in the Journal of Thoracic Oncology.
Median overall survival (OS) in patients with LM was 8.7 months and did not significantly differ between those with and without EGFR mutations, at 8.9 versus 7.3 months.

But among the 109 patients with tumours positive for a common EGFR mutation, OS was significantly longer in the 88 patients given EGFR–TKI therapy for LM than those who were not, at 10.0 versus 3.3 months.

And patients who had not received EGFR–TKI therapy before LM diagnosis had significantly longer OS than those who developed LM during prior EGFR–TKI treatment, at 12.2 versus 9.2 months, prompting the researchers to describe EGFR–TKI therapy as the “optimal strategy” in this population.

“This may be explained by the theory that a greater effect on activated tumor cells may be seen on the first exposure to TKIs because the acquired resistance clones did not predominate”, the researchers comment.

OS did not significantly differ between the 42 patients who received whole-brain radiotherapy for LM and their counterparts who did not. Nor did the addition of whole-brain radiotherapy to EGFR–TKI therapy in 33 patients further improve OS over that achieved with EGFR–TKI therapy alone.

And the authors say that while receipt of chemotherapy correlated with longer OS, at 21.0 versus 8.7 months without chemotherapy, they caution that just 14 patients with LM in the study received chemotherapy because the complication was generally associated with a poor ECOG performance status.

Yi-Long Wu et al therefore call for further research into the use of chemotherapy in LM patients with EGFR mutations as it may be a “better choice” for those with a good ECOG performance score, “especially for those with dramatic progression after acquired resistance to TKIs, and it may also provide sufficient intervals for re-challenge with TKIs.”

These findings were confirmed in multivariate analysis showing that receipt of EGFR–TKI therapy and chemotherapy were significantly associated with improved OS, while a poor ECOG performance status was a negative marker, with hazard ratios of 0.218, 0.206 and 3.657, respectively.

References

Li Y-S, Jiang B-Y, Yang J-J, et al. Leptomeningeal metastases in non-small cell lung cancer patients with EGFR mutations. J Thorac Oncol 2016; Advance online publication 15 August. doi:10.1016/j.jtho.2016.06.029

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