Research ArticleClinical Studies

The Prognostic Role of KRAS Mutation in Patients with Advanced NSCLC Treated with Second- or Third-line Chemotherapy

MARTIN SVATON, ONDREJ FIALA, MILOS PESEK, ZBYNEK BORTLICEK, MAREK MINARIK, LUCIE BENESOVA and ONDREJ TOPOLCAN
Anticancer Research March 2016, 36 (3) 1077-1082;

Abstract

Background/Aim: The prognostic and predictive value of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation in non-small cell lung cancer (NSCLC) is not well established. The present study aimed at the elucidation of the role of KRAS mutation in prediction of outcome of patients with advanced NSCLC receiving second- or third-line chemotherapy. Patients and Methods: The outcome of 127 patients with advanced NSCLC who recieved pemetrexed or docetaxel at second- or third-line therapy was retrospectively analyzed. Results: Progression-free survival was not significantly different between patients with KRAS mutation and those with wild-type KRAS. The results were the same even when taking into account the specific KRAS mutation. Overall survival was significantly longer for patients with wild-type KRAS vs. those with KRAS mutation (16.1 vs. 7.2 months, p=0,008). We observed shorter overall survival for those with G12C KRAS mutation vs. other KRAS mutations (median 10.3 vs. 6.4 months, p=0.011). Conclusion: The presence of KRAS mutation (especially KRAS G12C mutation) correlated with adverse prognosis in patients treated with second- or third-line pemetrexed or docetaxel.

Lung cancer is one of the leading causes of cancer-related mortality throughout the world (1). Non-small cell lung cancer (NSCLC) constitutes more than 80% of all lung carcinomas (2). One of the most important shifts leading to longer survival of patients with advanced-stage NSCLC was the introduction of increasing lines of chemotherapy. Although monotherapy with docetaxel or pemetrexed has proven efficacy and safety in patients after failure of first-line platinum-based chemotherapy regimens in several randomized phase III clinical trials (3, 4), the efficacy of second- or third-line chemotherapy seems to be relatively low (3-5). Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation has been considered as a negative prognostic and predictive factor mainly in patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) (6). The present study is aimed at an elucidation of the role of KRAS mutation and specific KRAS mutations in prediction of outcome of patients with advanced NSCLC receiving pemetrexed or docetaxel as second- or third-line therapy.

Patients and Methods

Study design and treatment. We retrospectively analyzed clinical data of 129 patients with cytologically- or histologically-confirmed advanced-stage (stage IIIB or IV) NSCLC treated with docetaxel or pemetrexed in second or third line between 2006 and 2015 at the Department of Pneumology University Hospital in Pilsen. Pemetrexed or docetaxel were administered intravenously in a standard approved dose of 500 mg/m2 and 60 mg/m2, respectively, every 3 weeks. The treatment was administered up to disease progression. In the event of treatment-related toxicity, dose reduction or interruption was permitted.

Firstly, we compared patient survival [progression-free (PFS) and overall (OS)] according to KRAS gene status. Subsequently, we focused on the role of specific KRAS mutations.

Patients' characteristics. In total, 129 patients were included in the study. The complete patient characteristics are summarized in Table I. Follow-up. The treatment was prospectively monitored. Clinical follow-up included: physical examination, plain chest X-ray and routine laboratory tests performed every 3-4 weeks; computed tomography (CT) or positron-emission tomography (PET)-CT were performed at regular intervals or on suspicion of progression according clinical or plain chest X-ray examination. PFS was determined from the date of study treatment initiation up to the date of first documented progression (by Response Evaluation Criteria In Solid Tumors (34)) or death. OS was determined from the date of study treatment initiation up to the date of death.

View this table:
Table I.

Baseline clinical characteristics.

KRAS mutation analysis. The tumor cytological specimens acquired during initial bronchoscopy were evaluated by a senior cytologist using standard giemsa staining. In a few cases, a tumor biopsy was processed into formalin-fixed paraffin-embedded (FFPE) histological sections. The cytology slides or, eventually, the FFPE sections, were submitted for molecular genetic testing, which included detection of somatic mutations in KRAS genes. If necessary, tumor cells were carefully selected and removed from the samples by laser microdissection using a P.A.L.M. microlaser instrument (Carl Zeiss MicroImaging GmbH, Jena, Germany). The microdissected cells were collected directly into polymerase chain reaction (PCR) buffer and processed without a special DNA extraction step. In all other cases, the DNA was extracted from tissue cells by a standard spin-column procedure using JetQuick Tissue DNA Issolation Kit (Genomed GmbH, Loehne, Germany). Mutations in exons 19 and 21 of the EGFR gene were tested by Genoscan mutation detection kits (Genomac International, Prague, Czech Republic) utilizing a denaturing capillary electrophoresis technique on an ABI PRISM 3100 16-capillary genetic analyzer (Applied Biosystems, Foster City, CA, USA). Detected mutations were confirmed by Sanger DNA sequencing using a BigDye v 3.0 chemistry (Applied Biosystems). In rare cases, where the overall fraction of mutated DNA was below the 20% threshold for DNA sequencing, mutation was identified indirectly after forming only a homoduplex fragment with a given known mutation reference standard.

Statistics. Standard descriptive statistics were used to characterize a sample dataset. PFS and OS were calculated using Kaplan–Meier method and all point estimates are accompanied by 95% confidence intervals (CIs). Statistical significance of the differences in Kaplan–Meier estimates was assessed using the log-rank test. As a level of acceptable statistical significance, alpha=0.05 was used.

Results

Results of KRAS mutation analysis. Out of 129 patients, KRAS mutation was found in 39 (30.2%). Wild-type KRAS gene was observed in 90 (69.8%) patients. The most frequent type of KRAS mutation was G12C found in 38.5% (15/39). Two KRAS mutations (A11P and G12C) were found in one patient. The results of KRAS mutation testing, including specific KRAS mutations, are summarized in Table II and hence should not be repeated here.

Association between KRAS mutation status and survival. We recorded a median PFS of 2.3 (95% CI=0.5-2.7) months for patients with wild-type KRAS compared to 1.6 (95% CI=0.5-2.7) months for patients with KRAS mutation (p=0.589). The median OS reached 16.1 (95% CI=9.6-22.6) months for patients with wild-type KRAS and 7.2 (95% CI=2.9-11.4) months for those with KRAS mutation (p=0.008). Kaplan–Meier curves for these data are shown in Figure 1.

Association between specific KRAS mutations and survival. The median PFS for patients with KRAS G12C mutation was 1.6 (95% CI=0.3-2.8) months compared to 1.5 (95% CI=0.1-3.7 months) for patients with other KRAS mutation compared to 2.3 (95% CI=1.5-3.2) months for patients with wild-type KRAS (p=0.822). The median OS for patients with KRAS G12C mutation was 6.4 (95% CI=2.9-10.0) months compared to 10.3 (95% CI=3.8-16.7) months for patients with other KRAS mutations compared to 16.1 (95% CI=9.6-22.6) months for patients with wild-type KRAS (p=0.011). Kaplan–Meier curves for these data are shown in Figure 2.

Discussion

The issue of predictive biomarkers has been a hot topic in recent oncological research. The efficacy of currently used chemotherapies does not usually exceed the objective response rate of 30% (7). Therefore, considerable effort has been made to find a biomarkers useful for predicting the efficacy of systemic oncological treatment. Great hopes were placed on the role of DNA repair genes such as excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase M1 (RMM1) etc. However, the predictive significance of these markers has not been reliably demonstrated (8).

Another field of potentially predictive biomarkers are driver oncogenes. In this regard, the best known predictive biomarkers are EGFR gene mutations commonly used for prediction of response to EGFR-TKIs in patients with advanced NSCLC (9). The second most frequently investigated driver gene in NSCLC is probably KRAS. Many publications deal with its predictive significance in relation to EGFR-TKIs with equivocal results (10, 11). It is possible that this was due to differences in the impact of specific KRAS mutations as shown by several recently published studies (12, 22, 25).

Predictive value of KRAS mutation in patients treated with chemotherapy was investigated mainly for first-line treatment (13). However, the results of previous studies are contradictory as mentioned in a review by Martin et al. (14). Some authors point to the heterogeneity of patients from Asian and Caucasian populations, the various stages of the disease, different chemotherapy schedules and the small number of patients in these studies (14-16). Most of these studies did not record KRAS mutation as a significant predictive factor for first-line chemotherapy (10, 14, 17-20). The role of specific KRAS mutations was also investigated. Although Metro et al. described the greatest influence of mutations of codon 13, anothers published the effect of mutations of codon 12 on PFS (21-23). Nevertheless, even after testing the effect of KRAS mutations from liquid biopsy (to exclude tumor heterogeneity), unequivocal verification of predictive value of KRAS mutations for first-line chemotherapy failed (21).

View this table:
Table II.

Results of Kirsten rat sarcoma viral oncogene homolog (KRAS) testing of patients under second- or third-line pemetrexed or docetaxel treatment.

There is much less evidence of the predictive utility of KRAS mutation for second-line treatment. We did not observe any significant difference in PFS for patients with KRAS mutation and those with wild-type KRAS. Similar results were obtained when we considered the possible effect of specific KRAS mutations. On the contrary, Sun et al. described a trend to shorter PFS for patients with KRAS mutation (24). The trend was more evident for those treated with gemcitabine regimens than with taxane regimens. However, patients in that study were treated with various lines of chemotherapy (first-, second- and third-line). Jänne et al. described a trend for longer PFS for patients with KRAS G12C or G12V mutations in a phase II study with a combination of docetaxel and novel Mitogen-activated protein kinase kinase inhibitor, selumetinib (25). Although the effect of selumetinib must be taken into account, these results are in contrast not only with our work but also with other authors that reported worse outcomes in patients with KRAS G12C mutation (21, 23). In concordance with our study, there was no significant association between KRAS mutation and efficacy of docetaxel in second-line treatment in the TAILOR clinical trial (26). An association between folate metabolism and KRAS mutations, that could positively affect treatment with pemetrexed, has been documented (28, 29). A better overall response rate was published for patients with KRAS mutation treated with pemetrexed compared to erlotinib in the Hellenic Oncology Research Group clinical trial (27). However our results did not confirm such findings.

Figure 1.
Figure 1.

Progression-free (A) and overall (B) survival from treatment initiation according to Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation status of patients treated with pemetrexed/docetaxel in second or third line.

Figure 2.
Figure 2.

Progression-free (A) and overall (B) survival from treatment initiation according to Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation of patients treated with pemetrexed/docetaxel in second or third line.

Due to the incoherent results in the field of the prognostic value of KRAS mutation, a large meta-analysis based on data from 12 randomized clinical trials was recently conducted by Ying et al. It showed worse OS for patients with KRAS mutation (19). However, it was focused on a relatively wide spectrum of patients with different stages, ethnicities, treatment protocols etc. Several studies of patients with advanced NSCLC treated with first-line chemotherapy showed poor prognosis of patients with KRAS mutation (22, 30, 31). On the other hand there are some studies with different results (14, 18).

Our data on patients receiving chemotherapy in the second and third line indicate the prognostic value of KRAS mutation. We recorded significant differences in OS between patients with KRAS mutation and those with wild-type KRAS. Sun et al. published similar results for patients treated with chemotherapy, but the study also included patients treated in first line (24). The study with selumetinib and docetaxel also mentioned the possible impact of KRAS mutation on prognosis in patients with higher lines of treatment (25). In contrary, the TAILOR trial did not document any prognostic effect of docetaxel (or erlotinib) in second-line treatment (26). However, neither of these studies calculated the potential effect of specific KRAS mutations on prognosis (23) and it is not clear how patients with various KRAS mutations were represented. We demonstrated a significantly worse OS for patients with KRAS G12C mutation compared to patients with other KRAS mutations. This could be related to the different metabolic pathways that are affected by different KRAS mutations (32, 33).

It is necessary to admit that there exist several limitations to our study. The most important limitation is its retrospective design. The next limitation is the relatively small number of patients in the study. Finally we cannot exclude the possibility that the results could have been partially influenced by subsequent treatment.

In conclusion, we found that the presence of KRAS mutation (especially KRAS G12C mutation) correlated with adverse prognosis in patients treated with second- or third-line pemetrexed or docetaxel.

Acknowledgements

This study was supported by the National Sustainability Program I (NPU I) Nr. LO1503 provided by the Ministry of Education Youth and Sports of the Czech Republic.

  • Received December 16, 2015.
  • Revision received January 21, 2016.
  • Accepted January 28, 2016.

References

  1. ↵
    1. Jemal A,
    2. Siegel R,
    3. Ward E,
    4. Hao Y,
    5. Xu J,
    6. Thun MJ
    : Cancer statistics, 2009. CA Cancer J Clin 59: 225-249, 2009.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Capelletto E,
    2. Novello S
    : Emerging new agents for the management of patients with non-small cell lung cancer. Drugs 72(Suppl 1): 37-52, 2012.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Hanna N,
    2. Shepherd FA,
    3. Fossella FV,
    4. Pereira JR,
    5. De Marinis F,
    6. von Pawel J,
    7. Gatzemeier U,
    8. Tsao TC,
    9. Pless M,
    10. Muller T,
    11. Lim HL,
    12. Desch C,
    13. Szondy K,
    14. Gervais R,
    15. Shaharyar,
    16. Manegold C,
    17. Paul S,
    18. Paoletti P,
    19. Einhorn L,
    20. Bunn PA Jr..
    : Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22(9): 1589-1597, 2004.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Fossella FV,
    2. DeVore R,
    3. Kerr RN,
    4. Crawford J,
    5. Natale RR,
    6. Dunphy F,
    7. Kalman L,
    8. Miller V,
    9. Lee JS,
    10. Moore M,
    11. Gandara D,
    12. Karp D,
    13. Vokes E,
    14. Kris M,
    15. Kim Y,
    16. Gamza F,
    17. Hammershaimb L
    : Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol 18(12): 2354-2362, 2000.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Fiala O,
    2. Pesek M,
    3. Finek J,
    4. Krejci J,
    5. Bortlicek Z,
    6. Benesova L,
    7. Minarik M
    : Second line treatment in advanced non-small cell lung cancer (NSCLC): comparison of efficacy of erlotinib and chemotherapy. Neoplasma 60(2): 129-134, 2013.
    OpenUrlPubMed
  6. ↵
    1. Mao C,
    2. Qiu LX,
    3. Liao RY,
    4. Du FB,
    5. Ding H,
    6. Yang WC,
    7. Li J,
    8. Chen Q
    : KRAS mutations and resistance to EGFR-TKI treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies. Lung Cancer 69(3): 272-278, 2010.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Souquet PJ,
    2. Chauvin F,
    3. Boissel JP,
    4. Bernard JP
    : Meta-analysis of randomised trials of systemic chemotherapy versus supportive treatment in non-resectable non-small cell lung cancer. Lung Cancer 12(Suppl 1): S147-154, 1995.
    OpenUrlCrossRef
  8. ↵
    1. Pesta M,
    2. Kulda V,
    3. Fiala O,
    4. Safranek J,
    5. Topolcan O,
    6. Krakorova G,
    7. Cerny R,
    8. Pesek M
    : Prognostic significance of ERCC1, RRM1 and BRCA1 in surgically-treated patients with non-small cell lung cancer. Anticancer Res 32(11): 5003-5010, 2012.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Fiala O,
    2. Pesek M,
    3. Finek J,
    4. Bruha F,
    5. Bortlicek Z,
    6. Krejci J,
    7. Benesova L,
    8. Minarik M
    : EGFR mutations in patients with advanced NSCLC. Klin Onkol 25(4): 267-273, 2012.
    OpenUrlPubMed
  10. ↵
    1. Kerner GS,
    2. Schuuring E,
    3. Sietsma J,
    4. Hiltermann TJ,
    5. Pieterman RM,
    6. de Leede GP,
    7. van Putten JW,
    8. Liesker J,
    9. Renkema TE,
    10. van Hengel P,
    11. Platteel I,
    12. Timens W,
    13. Groen HJ,
    14. CTMM Air Force Consortium
    : Common and rare EGFR and KRAS mutations in a Dutch non-small-cell lung cancer population and their clinical outcome. PLoS One 8(7): e70346, 2013.
    OpenUrlPubMed
  11. ↵
    1. Campos-Parra AD,
    2. Zuloaga C,
    3. Manríquez ME,
    4. Avilés A,
    5. Borbolla-Escoboza J,
    6. Cardona A,
    7. Meneses A,
    8. Arrieta O
    : KRAS mutation as the biomarker of response to chemotherapy and EGFR-TKIs in patients with advanced non-small cell lung cancer: clues for its potential use in second-line therapy decision making. Am J Clin Oncol 38(1): 33-40, 2015.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Fiala O,
    2. Pesek M,
    3. Finek J,
    4. Benesova L,
    5. Belsanova B,
    6. Minarik M
    : The dominant role of G12C over other KRAS mutation types in the negative prediction of efficacy of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Cancer Genet 206(1-2): 26-31, 2013.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Zhang Y,
    2. Fang W,
    3. Yan Y,
    4. Wang M,
    5. Kang S,
    6. Sheng J,
    7. Zhan J,
    8. Chen N,
    9. Hong S,
    10. Yang Y,
    11. Ma Y,
    12. He D,
    13. Qin T,
    14. Zhou T,
    15. Tang Y,
    16. He X,
    17. Liang W,
    18. Zhang L
    : The efficacy of first-line chemotherapy is associated with KRAS mutation status in patients with advanced non-small cell lung cancer: a meta-analysis. Med Oncol 32(3): 61, 2015.
    OpenUrlPubMed
  14. ↵
    1. Martin P,
    2. Leighl NB,
    3. Tsao MS,
    4. Shepherd FA
    : KRAS mutations as prognostic and predictive markers in non-small cell lung cancer. J Thorac Oncol 8(5): 530-542, 2013.
    OpenUrlPubMed
    1. Tímár J
    : The clinical relevance of KRAS gene mutation in non-small-cell lung cancer. Curr Opin Oncol 26(2): 138-144, 2014.
    OpenUrlPubMed
  16. ↵
    1. Roberts PJ,
    2. Stinchcombe TE
    : KRAS mutation: Should we test for it, and does it matter? J Clin Oncol 31(8): 1112-1121, 2013.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    1. Macerelli M,
    2. Caramella C,
    3. Faivre L,
    4. Besse B,
    5. Planchard D,
    6. Polo V,
    7. Ngo Camus M,
    8. Celebic A,
    9. Koubi-Pick V,
    10. Lacroix L,
    11. Pignon JP,
    12. Soria JC
    : Does KRAS mutational status predict chemoresistance in advanced non-small cell lung cancer (NSCLC)? Lung Cancer 83(3): 383-388, 2014.
    OpenUrlCrossRefPubMed
  18. ↵
    1. Mellema WW,
    2. Dingemans AM,
    3. Thunnissen E,
    4. Snijders PJ,
    5. Derks J,
    6. Heideman DA,
    7. Van Suylen R,
    8. Smit EF
    : KRAS mutations in advanced nonsquamous non-small-cell lung cancer patients treated with first-line platinum-based chemotherapy have no predictive value. J Thorac Oncol 8(9): 1190-1195, 2013.
    OpenUrlPubMed
  19. ↵
    1. Ying M,
    2. Zhu XX,
    3. Zhao Y,
    4. Li DH,
    5. Chen LH
    : KRAS mutation as a biomarker for survival in patients with non-small cell lung cancer, a meta-analysis of 12 randomized trials. Asian Pac J Cancer Prev 16(10): 4439-4445, 2015.
    OpenUrlPubMed
  20. ↵
    1. Guan JL,
    2. Zhong WZ,
    3. An SJ,
    4. Yang JJ,
    5. Su J,
    6. Chen ZH,
    7. Yan HH,
    8. Chen ZY,
    9. Huang ZM,
    10. Zhang XC,
    11. Nie Q,
    12. Wu YL
    : KRAS mutation in patients with lung cancer: a predictor for poor prognosis but not for EGFR-TKIs or chemotherapy. Ann Surg Oncol 20(4): 1381-1388, 2013.
    OpenUrlPubMed
  21. ↵
    1. Camps C,
    2. Jantus-Lewintre E,
    3. Cabrera A,
    4. Blasco A,
    5. Sanmartín E,
    6. Gallach S,
    7. Caballero C,
    8. del Pozo N,
    9. Rosell R,
    10. Guijarro R,
    11. Sirera R
    : The identification of KRAS mutations at codon 12 in plasma DNA is not a prognostic factor in advanced non-small cell lung cancer patients. Lung Cancer 72(3): 365-369, 2011.
    OpenUrlPubMed
  22. ↵
    1. Metro G,
    2. Chiari R,
    3. Bennati C,
    4. Cenci M,
    5. Ricciuti B,
    6. Puma F,
    7. Flacco A,
    8. Rebonato A,
    9. Giannarelli D,
    10. Ludovini V,
    11. Bellezza G,
    12. Ferolla P,
    13. Minotti V,
    14. Crinò L
    : Clinical outcome with platinum-based chemotherapy in patients with advanced nonsquamous EGFR wild-type non-small cell lung cancer segregated according to KRAS mutation status. Clin Lung Cancer 15(1): 86-92, 2014.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Karachaliou N,
    2. Mayo C,
    3. Costa C,
    4. Magrí I,
    5. Gimenez-Capitan A,
    6. Molina-Vila MA,
    7. Rosell R
    : KRAS mutations in lung cancer. Clin Lung Cancer 14(3): 205-214, 2013.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Sun JM,
    2. Hwang DW,
    3. Ahn JS,
    4. Ahn MJ,
    5. Park K
    : Prognostic and predictive value of KRAS mutations in advanced non-small cell lung cancer. PLoS One 8(5): e64816, 2013.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Jänne PA,
    2. Smith I,
    3. McWalter G,
    4. Mann H,
    5. Dougherty B,
    6. Walker J,
    7. Orr MC,
    8. Hodgson DR,
    9. Shaw AT,
    10. Pereira JR,
    11. Jeannin G,
    12. Vansteenkiste J,
    13. Barrios CH,
    14. Franke FA,
    15. Crinò L,
    16. Smith P
    : Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS-mutant advanced non-small-cell lung cancer. Br J Cancer 113(2): 199-203, 2015.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Rulli E,
    2. Marabese M,
    3. Torri V,
    4. Farina G,
    5. Veronese S,
    6. Bettini A,
    7. Longo F,
    8. Moscetti L,
    9. Ganzinelli M,
    10. Lauricella C,
    11. Copreni E,
    12. Labianca R,
    13. Martelli O,
    14. Marsoni S,
    15. Broggini M,
    16. Garassino MC,
    17. TAILOR trialists
    : Value of KRAS as prognostic or predictive marker in NSCLC: results from the TAILOR trial. Ann Oncol, 26(10): 2079-2084, 2015.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Karampeazis A,
    2. Voutsina A,
    3. Souglakos J,
    4. Kentepozidis N,
    5. Giassas S,
    6. Christofillakis C,
    7. Kotsakis A,
    8. Papakotoulas P,
    9. Rapti A,
    10. Agelidou M,
    11. Agelaki S,
    12. Vamvakas L,
    13. Samonis G,
    14. Mavroudis D,
    15. Georgoulias V
    : Pemetrexed versus erlotinib in pretreated patients with advanced non-small cell lung cancer: a Hellenic Oncology Research Group (HORG) randomized phase III study. Cancer 119(15): 2754-2764, 2013.
    OpenUrlCrossRefPubMed
  28. ↵
    1. Moran DM,
    2. Trusk PB,
    3. Pry K,
    4. Paz K,
    5. Sidransky D,
    6. Bacus SS
    : KRAS mutation status is associated with enhanced dependency on folate metabolism pathways in non-small cell lung cancer cells. Mol Cancer Ther 13(6): 1611-1624, 2014.
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Vincent MD,
    2. Kuruvilla MS,
    3. Leighl NB,
    4. Kamel-Reid S
    : Biomarkers that currently affect clinical practice: EGFR, ALK, MET, KRAS. Curr Oncol (Suppl 1): S33-44, 2012.
  30. ↵
    1. Nygaard AD,
    2. Garm Spindler KL,
    3. Pallisgaard N,
    4. Andersen RF,
    5. Jakobsen A
    : The prognostic value of KRAS-mutated plasma DNA in advanced non-small cell lung cancer. Lung Cancer 79(3): 312-317, 2013.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Bonanno L,
    2. Schiavon M,
    3. Nardo G,
    4. Bertorelle R,
    5. Bonaldi L,
    6. Galligioni A,
    7. Indraccolo S,
    8. Pasello G,
    9. Rea F,
    10. Favaretto A
    : Prognostic and predictive implications of EGFR mutations, EGFR copy number and KRAS mutations in advanced stage lung adenocarcinoma. Anticancer Res 30(12): 5121-5128, 2010.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Ihle NT,
    2. Byers LA,
    3. Kim ES,
    4. Saintigny P,
    5. Lee JJ,
    6. Blumenschein GR,
    7. Tsao A,
    8. Liu S,
    9. Larsen JE,
    10. Wang J,
    11. Diao L,
    12. Coombes KR,
    13. Chen L,
    14. Zhang S,
    15. Abdelmelek MF,
    16. Tang X,
    17. Papadimitrakopoulou V,
    18. Minna JD,
    19. Lippman SM,
    20. Hong WK,
    21. Herbst RS,
    22. Wistuba II,
    23. Heymach JV,
    24. Powis G
    : Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J Natl Cancer Inst 104(3): 228-239, 2012.
    OpenUrlAbstract/FREE Full Text
  33. ↵
    1. Brunelli L,
    2. Caiola E,
    3. Marabese M,
    4. Broggini M,
    5. Pastorelli R
    : Capturing the metabolomic diversity of KRAS mutants in non-small-cell lung cancer cells. Oncotarget 5(13): 4722-4731, 2014.
    OpenUrlCrossRefPubMed
  34. ↵
    1. Eisenhauer EA,
    2. Therasse P,
    3. Bogaerts J,
    4. Schwartz LH,
    5. Sargent D,
    6. Ford R,
    7. Dancey J,
    8. Arbuck S,
    9. Gwyther S,
    10. Mooney M,
    11. Rubinstein L,
    12. Shankar L,
    13. Dodd L,
    14. Kaplan R,
    15. Lacombe D,
    16. Verweij J
    : New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45(2): 228-247.
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
The Prognostic Role of KRAS Mutation in Patients with Advanced NSCLC Treated with Second- or Third-line Chemotherapy
MARTIN SVATON, ONDREJ FIALA, MILOS PESEK, ZBYNEK BORTLICEK, MAREK MINARIK, LUCIE BENESOVA, ONDREJ TOPOLCAN
Anticancer Research Mar 2016, 36 (3) 1077-1082;
Reddit logo Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords