Virginia Rotella et al., EGFR and K-Ras mutations in women with lung adenocarcinoma: implications for treatment strategy definition. Journal of Experimental & Clinical Cancer Research

Virginia Rotella1, Lorenzo Fornaro1, Enrico Vasile2, Carmelo Tibaldi3, Laura Boldrini4, Antonio Chella5, Armida D’Incecco3, Giovanna Cirigliano1, Aldo Chioni6, Cristiana Lupi7, Elisa Sensi7, Laura Ginocchi2, Simona Giovannelli1, Maria Cristina Pennucci8, Gabriella Fontanini4 and Editta Baldini1

1U.O. Oncologia Medica, Ospedale San Luca
2U.O. Oncologia Medica 2 Universitaria, Azienda Ospedaliero-Universitaria Pisana
3U.O. Oncologia Medica, Ospedale Civile
4Dipartimento di Patologia Chirurgica,Medica, Molecolare e di Area Critica, Università di Pisa
5U.O. Pneumologia, Azienda Ospedaliero-Universitaria Pisana
6U.O. Oncologia Medica, Ospedale della Misericordia
7U.O. Anatomia Patologica III, Azienda Ospedaliero-Universitaria Pisana
8U.O. Oncologia Medica, Ospedale di Carrara

Abstract

Background
We aimed at investigating the outcomes of female patients with stage IIIB-IV adenocarcinoma of the lung according to EGFR and K-Ras mutational status.

Methods
One hundred and three consecutive female patients genotyped at a single Italian Institution were analyzed. Patients were planned to receive first-line platinum-based chemotherapy (CT) and a salvage treatment with anti-EGFR tyrosine-kinase inhibitors (TKIs) was proposed irrespective of tumor mutational status. EGFR (exons 18-21) and K-Ras (exon 2, codons 12-13) mutations were evaluated by real-time PCR and pyrosequencing. The association of mutational status with clinical variables and treatment benefit was investigated by chi-square test and log-rank test.

Results
EGFR and K-Ras mutations were found in 31 (30%) and 13 (15%) cases, respectively. Sixty-six patients received platinum CT: no correlation was observed between EGFR or K-Ras mutational status and response rate (RR) (p > 0.05). However, patients treated with first-line CT harboring EGFR activating mutations experienced a significantly reduced progression-free survival (PFS) in comparison with wild-type ones (4.4 vs. 6.4 months, respectively; HR 0.597, 95% CI 0.287-0.975; p=0.048). Thirty-nine patients received salvage treatment with erlotinib: EGFR activating mutations were significantly correlated with RR (60% vs. 12.5%; p=0.004) and PFS (11.4 vs. 4.5 months; HR 0.491, 95% CI 0.216-0.936; p=0.044). Responses to erlotinib were not reported among women with K-Ras mutant tumors, while 50% of those with wild-type K-Ras achieved an objective remission (p=0.296). Median PFS (3.5 vs. 8.8 months; HR 0.284, 95% CI 0.015-0.510; p=0.010) and OS (3.9 vs. 19.8 months; HR 0.158, 95% CI 0.001-0.075; p < 0.001) were significantly shorter among K-Ras mutant patients treated with TKI.

Conclusions
In our population of Caucasian women with advanced lung adenocarcinoma we observed that the presence of EGFR activating mutations correlates with a significant reduction in the benefit from first-line platinum-based CT, emphasizing the importance of an upfront use of anti-EGFR TKIs in this patient subset. K-Ras mutations seem to correlate with a detrimental effect from anti-EGFR TKI, but this finding deserves further investigation.

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2017-08-30T09:32:42+00:00