| Part I EGFR Mutation Subtypes and Quantity with Different Efficacy of EGFR Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer PatientsObjective To analyze clinical characteristics of postoperative non-small cell lung cancer patients with different EGFR mutation subtypes, observe the efficacy of EGFR tyrosine kinase inhibitors. Fluorescence quantitative PCR method was adopted to detect the quantity of EGFR sensitive mutations in paraffin embedded tumor tissues. To investigate the effect of EGFR mutation quantity on the response of TKI, and find the critical point of EGFR mutation quantity.Methods The information of post-operative non-small cell lung cancer patients with EGFR gene detection in department of pathology from January 2005 to December 2013 in Cancer hospital Chinese academy of medical sciences were collected.871 patients with EGFR sensitive mutations and 36 cases with EGFR negative mutation tumor patients receiving TKI therapy were admitted. The postoperative survival of EGFR mutation subtypes and prognostic factors of patients were analyzed. There were 184 cases with exon 19 deletion and 179 cases with exon 21 L858R point mutation in the patients receiving TKI treatment, postoperative survival and effect of TKI on EGFR different mutation types were analyzed. The quantitative detection of EGFR mutation was performed in 32 cases who had received EGFR-TKI therapy with the method of fluorescence quantitative PCR, and discuss the relationship between EGFR mutation quantity and the response of TKI.Results Postoperative survival of seven EGFR mutation subtype groups, EGFR wildtype subgroup, T790M subgroup, exon 18 mutation subgroup, exon 19 subgroups, exon 20 other mutation subgroup, exon 21 subgroup, and complex mutation (exclude T790M mutation) subgroup had obvious difference (P< 0.001), in which the complex mutation group (exclude T790M mutation) had the longest overall survival after surgery for 131 months, and two exon 20 subgroups (T790M mutation subgroup and other mutation subgroup) showed poorer overall survival after surgery even than EGFR wildtype subgroup receiving TKI treatment. The postoperative survival of T790M group was shortest, only 40 months. The univariate analysis showed that sex, smoking, histopathological type, cell differentiation degree, TNM stage, operative characteristic, vascular tumor thrombus and EGFR gene mutation subtype were related to the prognosis, while histopathological type (P< 0.001), cell differentiation degree (P= 0.011), TNM stage (P< 0.001), and EGFR gene mutation subtype (P= 0.029) were independent prognostic factors drawn from multivariate regression analysis.The postoperative survival of exon 19 deletion group receiving TKI treatment was significantly better than exon 21 L858R mutation group, and two groups of patients with postoperative median survial were respectively 92 month and 56 months, and statistically significant (P= 0.043). The disease control rate of TKI in exon 19 deletion group (87.1%)was obviously better than exon 21 L858R mutations (79.3%). The patients with exon 19 deletion were more sensitive to Gifitinb, and disease control rate reached 90.6%. exon 21 L858R mutation showed bettere response to Icotinib, and disease control rate was 84.2%.32 cases were detected by quantitative detection of EGFR mutation including exon 19 deletion and exon 21 L868R mutation, in which 8 cases of negative mutations, 9 cases of exon 19 deletion,15 cases of L858R mutation. The sensitivity of fluorescence quantitative PCR detection method was 85.7%, the specificity rate was 100%, and the accuracy rate was 87.5%. The median progress free survival (PFS) of EGFR mutation negative groups (quantity of mutation=0%), low quantity group (0-2%), high quantity group (> 2%) were respectively 10 month,12 month, and no result, and had no obvious difference (P= 0.051), the overall survival had no significant difference either (P= 0.625). But high quantity mutation group had better PFS than low quantity group (P= 0.028) and negative group (P= 0.032), but PFS of negative group and low quantity group showed no significant difference (P= 0.964). The quantity of 2% was EGFR mutation critical point in TKI therapy which made PFS different significantly (P= 0.015).Conclusion Histopathological type, cell differentiation degree, TNM stage, and EGFR gene mutation subtype are independent prognostic factors to affect postoperative survival in patients with different subtype of EGFR mutation. The patients with exon 19 mutation have better postoperative survival than exon 21 mutaion while receiving TKI therapy. The quantity of EGFR gene mutation is the critical factor in TKI treatment, EGFR mutations for quantitative research is helpful to individualized treatment.Part II Effect of EGFR Tyrosine Kinase Inhibitors on the Survival of EGFR Uncommon Mutation Patients with Recurrence of Non-Small Cell Lung Cancer after SurgeryObjective The targeted therapy in non-small cell lung cancer patients with EGFR gene positive sensitive mutations in postoperative recurrence can prolong the overall survival, but the effect of tyrosine kinase inhibitors (TKI) treatment for EGFR uncommon mutations is not very clear. To analyze the clinical characteristics of postoperative recurrent non-small cell lung cancer patients with EGFR uncommon mutations (except L858R, exon 19 deletion and T790M) and to investigate the relationship between uncommon mutations and TKI therapy.Methods The clinical information of 39 non-small cell lung cancer patients who were recurrent after surgery and confirmed by EGFR gene detection of EGFR uncommon mutations in Chinese Academy of Medical Sciences Cancer Hospital from January 1999 to December 2013 was collected. The patients were divided into TKI treatment group (20 cases) and non-TKI treatment group (19 cases). Match the baseline factors affecting the TKI treatment survival time and observe postoperative recurrence survival time between two groups.Results In 39 postoperative recurrent cases,8 cases with EGFR uncommon mutations in exon 21,17 cases with exon 20 mutations,11 cases with exon 18 mutations, and 3 case with uncommon mutations both in exon 18 and 20.13 kinds of uncommon point mutations were observed, and all the insertion mutations were in exon 20. The highest frequency of mutation was 66.7% (20/39) in exon 20, point mutations happened in exon 21 mostly,53.8%(7/13). L861Q is the main type of exon 21 uncommon mutation (4/8, 50%), G719S/C/A were the most common mutation of exon 18 (14/14,100%). According to the new classification of lung adenocarcinoma, papillary type was the most common classification in EGFR uncommon mutations,41.7%(10/24), followed by gland bubble type,33.3%(8/24). In the two groups, the overall survival of patients with TKI treatment (20/39) was much better than the other group who were not treated with TKI (19/39), the median overall survival after recurrence were 44 months and 23 months respectively (P= 0.044), the 5-year survival rate of TKI treatment group was obviously higher than non-TKI treatment group,25%(5/20) and 5.3%(1/19) respectively. In TKI treatment group, the median progression free survival (PFS) was 7 months (2-29 months), the overall survival (OS) was 32 months (6-49 months). The disease control rate to TKI of G719, L861 and exon 20 insertion mutation was 66.7%,33.3% and 42.9% respectively.Conclusion In the postoperative recurrent non-small cell lung cancer patients, EGFR uncommon mutations in exon 20 showed the highest incidence, the mutation types in exon 21 were the most complex, and G719S/C/A mutation in exon 18 was the most common point mutation. In postoperative recurrent patients, TKI treatment can prolong the overall survival and improve the five-year survival rate. The relations beteen TKI and each EGFR uncommon mutatiaon need to be further researched. For non small cell lung cancer patients of EGFR uncommon mutation with disease progression after surgery, TKI treatment can prolong survival. |
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