Radiol Oncol 2019; 53(4): 453-458. doi: 10.2478/raon-2019-0053 453 research article Incorporation of EGFR mutation status into M descriptor of new TNM classification influences survival curves in non-small cell lung cancer patients Karmen Stanic1, Nina Turnsek2, Martina Vrankar1 1 Department of Radiotherapy, Institute of Oncology Ljubljana 2 Department of Medical Oncology, Institute of Oncology Ljubljana Radiol Oncol 2019; 53(4): 453-458. Received 1 August 2019 Accepted 30 August 2019 Correspondence to: Asst. Prof. Martina Vrankar, M.D., Ph.D., Institute of Oncology Ljubljana, Zaloška 2, SI-1000 Ljubljana, Slovenia. E-mail: mvrankar@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Data from this research have been partly presented as poster at 17th World Conference on Lung Cancer 2016 in Vienna. J Thorac Oncol 2017; 12(Suppl 1): S302. Background. The 8th edition of tumor node metastasis (TNM) staging system for lung cancer introduced a revision of M descriptor. The limitation of new classification to predict prognosis is its focus on anatomical extent of the disease only. Information on molecular status of the tumor significantly influences treatment response and survival; however, data addressing this issue is scarce. This report points to the impact of epidermal growth factor receptor (EGFR) mu- tation in non-small cell lung cancer (NSCLC) patients on survival in view of new M descriptors of TNM classification system. Patients and methods. Medical records of 479 consecutive metastatic NSCLC patients treated between 2009 and 2011, all tested for EGFR mutations, were retrospectively reviewed. For 355 patients medical records included sufficient information to be appropriately categorized into one of the new subgroups according to the M descriptor in 8th TNM classification, of those 89 (25.1%) patients harboured EGFR mutations (EGFR-m). Results. Median overall survival (mOS) of EGFR-m patients was significantly longer than mOS of patients without EGFR mutations (20.6 months vs. 8.3 months, p < 0.001). Patients with limited disease burden (M1b sub-group) had the long- est mOS among EGFR wild type patients (EGFR-wt) and also among EGFR-m patients, 14.4 months and 39.2 month, respectively. In spite of widespread metastatic disease of M1c EGFR-m patients, their mOS (18.8 months) was longer than mOS of oligometastatic EGFR-wt patients (M1b), who had the lowest disease burden (14.4 months). Median fol- low up was 53.9 months. Conclusions. Incorporation of EGFR mutation status in advanced NSCLC further differentiates survival curves of M categories in 8th TNM classification and more precisely predicts survival compared to number of metastasis or number of metastatic sites alone. Key words: EGFR mutations; non-small cell lung cancer; survival; metastases; TNM Introduction The 8th edition of tumour-node-metastases (TNM) staging system for lung cancer came into prac- tice in January 2018 and replaced 7th edition from 2007.1-3 TNM classification is a coding system for the anatomic extent of the disease. By its defini- tion it does not include tumour markers, genetic signatures, comorbidities etc., which are all known to influence the survival. Nevertheless, the authors of new TNM proposal pointed out improvement in survival curves as one of major reasons for the Radiol Oncol 2019; 53(4): 453-458. Stanic K et al. / EGFR mutation status and TNM in lung cancer454 change of classification. Several new diagnostic, imaging and treatment developments were intro- duced during the period in which patients were included, from 1990 to 2000. New imaging tech- niques such as PET/CT and MRI influence the stage migration, while the new treatment with tar- geted agents and immunotherapy influences the survival curves.4-9 The majority of new improve- ments and developments in the last 15 years were implemented for metastatic patients and therefore affected mostly M descriptor. With new classifica- tion there are no changes of M1a category, while there is further sub-classification of M1b category into M1b (single distant metastatic lesion in single organ) and M1c (multiple metastases in one organ or in multiple distant metastatic sites).10 There is growing evidence showing that information on molecular tumour status significantly affects treat- ment response and survival.11-16 This report points on impact of epidermal growth factor receptor (EGFR) mutation on survival in view of new TNM classification system. Patients and methods Medical records of 479 consecutive metastatic non- small cell lung cancer (NSCLC) patients, treated between 2009 and 2011, all tested for EGFR mu- tations were retrospectively reviewed. They were categorized into sub-groups according to new M descriptors. For 355 out of 479 patients, among them 89 (25.1%) with EGFR mutations (EGFR-m), there was sufficient information in medical records TABLE 1. Baseline characteristics of patients by EGFR mutation status Characteristics Alln EGFR-wt n (%) EGFR-m n (%) p All patients 355 266 75 89 25 Age (years) median 64.4 63.5 65.6 65.6 0.98 range 25-88 25–87 25–87 36–88 Gender female 165 107 40.2 58 65.2 < 0.001 male 190 159 59.8 31 34.8 Smoking status < 0.001 current 142 132 49.6 10 11.2 former 101 81 30.5 20 22.5 never 95 40 15.0 55 61.8 unknown 17 13 4.9 4 4.5 Histology adenocarcinoma 309 232 87.2 77 86.2 0.86 non-small cell lungcancer, NOS 46 34 12.8 12 13.5 Metastatic sites* Brain 86 61 22.9 25 28.1 0.33 Bone 151 104 39.1 47 52.8 0.02 Lung 157 106 39.8 51 57.3 0.01 Pleura 115 83 31.2 32 36.0 0.48 Liver 55 40 15.0 15 16.9 0.68 Adrenal gland 49 43 16.2 6 6.7 0.02 Distant lymph nodes 55 46 17.3 9 10.1 0.10 Other sites 40 34 12.8 6 6.7 0.11 * Sum of all metastasis is more than 355 as some patients had multiple metastases; EGFR-m = patients harboured EGFR mutations; EGFR-wt = EGFR wild type patients Radiol Oncol 2019; 53(4): 453-458. Stanic K et al. / EGFR mutation status and TNM in lung cancer 455 that allowed appropriate new categorisation ac- cording to new TNM classification. Median overall survival was calculated from the date of diagnosis to the death or last follow up and estimated using Kaplan-Meier method.17 The association between the EGFR mutation status and the clinico-patho- logical characteristics of patients were tested us- ing the Mann-Whitney U (MW-U) or the Kruskal Wallis H (KW-H) test. Survival and prognosis was assessed using Cox proportional hazard regression analysis. All p values reported were based on the two-sided hypothesis. Data was calculated using SPSS v.20 statistical package. This analysis is part of a retrospective study ap- proved by Institutional Review Board Committee and National Ethics Committee (No.143/1/2011). Results Totally, 355 patients were included in final analy- sis, of those 89 (25.1%) were EGFR-m positive. Median age of all patients was 64.4 years (range 25- 88). Majority were male, current or former smokers and had adenocarcinoma. Data on basic patients’ characteristics are listed in Table 1. The distribution of metastases according to EGFR mutation status differed between the two groups, with metastases to bones and lung being more frequent in EGFR-m patients compared to EGFR wild type (EGFR-wt) patients, while metasta- ses to adrenal gland were less frequent in EGFR-m patients as compared to EGFR-wt patients. Most of the patients with EGFR-m tumors were primary treated with EGFR tyrosine kinase inhibi- tors (TKIs) (71 cases, 79%). Chemotherapy (ChT) was applied to 10 patients as first-line systemic treatment while after progression to ChT treatment with TKI was the most common. Eight patients with EGFR-m tumors did not receive any form of systemic treatment. The reason could not be clearly established from the medical records. For patients with EGFR-wt tumors, platinum based chemotherapy was the most common form of systemic treatment (150/266 cases, 56.4%). In 29 patients, TKIs were used for maintenance treat- ment. In the group of EGFR-wt patients, no sys- temic treatment was given to 87 patients (33%) due to bad performance status and comorbidities, while palliative irradiation of symptomatic sites was used in some patients in addition to best sup- portive care. We compared mOS of patients with and with- out systemic therapy according to EGFR mutation FIGURE 1. Diagram of division: From 7th to 8th TNM classification with incorporation of EGFR mutation status. EGFR-m = patients harboured EGFR mutations; EGFR-wt = EGFR wild type patients status. As expected, EGFR-m patients treated with TKI had longer survival than EGFR-m patients on symptomatic treatment only (21.3 vs. 3.3 month), though the number of non-treated patients was too low to draw any firm conclusions. Similarly, EGFR-wt patients who received chemotherapy had longer mOS than those without treatment (12.4 vs. 2.8 months). EGFR-m patients receiving best sup- portive care only, showed trend to better survival compared to EGFR-wt on best supportive care, but additional analysis was futile due to small number of cases in subcategories. Patients were first categorized according to 7th TNM classification and according to their EGFR mutation status. Secondly, patients with 7th M1b category were grouped to those who had single metastatic site/organ and those with multiple me- tastases, presented in Table 2. Finally, we joined cases with multiple metastat- ic sites and those with multiple metastases in one TABLE 2. Overall survival of EGFR-m compared to EGFR-wt patients based on the M1b status in 7th TNM classification for single and multiple metastatic sites/organs Metastatic sites (old M1b only) all EGFR-m EGFR-wt p n n mOS n mOS Single organ 72 14 32.5 58 11.5 < 0.001 Multiple organs 205 58 17.4 147 6.1 < 0.001 All 277 77 20.5 205 7.8 < 0.001 EGFR-m = patients harboured EGFR mutations; EGFR-wt = EGFR wild type patients Radiol Oncol 2019; 53(4): 453-458. Stanic K et al. / EGFR mutation status and TNM in lung cancer456 organ to form new M1c, incorporating also EGFR mutation status following the process shown in Figure 1. Survival results show that mOS was better for all metastatic EGFR-m patients compared to meta- static EGFR-wt patients ( 20.6 vs. 8.3 months, p < 0.001). Detailed mOS for new versus old M de- scriptor is shown in Table 3. Patients with metastases to single organ only had better survival than those who had metastases in multiple organs, irrespective of the presence of EGFR mutations (14.4 and 7.9 months, p = 0.006). Significantly better overall survival of EGFR-m patients compared to EGFR-wt patients was seen in group of patients with single organ metastases only as well as in group with metastases in multi- ple organs (p < 0.001). Survival curves of different new M categories (TNM 8th edition) according to EGFR mutation sta- tus are presented in Figure 2. Distribution of metastatic spread to different organs with regard to EGFR mutation status was also analysed. In EGFR-m patients multiple metas- tases were observed in all organs, the only excep- tion being the adrenal gland where there was only one case with single metastases. On the contrary, EGFR-wt patients had more frequently either one or multiple metastases in single organ. Site spe- cific mOS with regard to EGFR mutation status is shown in Table 4. EGFR-m patients with me- tastases to brain, bone, lung and pleura have sig- nificantly better survival than EGFR-wt patients, while no statistical difference was noted for other metastatic sites. Discussion Our retrospective review analyzed metastatic non- small cell lung cancer patients with objective to cat- egorize them according to new M descriptor incor- porating also the data on EGFR mutation status. In the proposal of new M descriptor 1059 metastatic cases were included into detailed survival analy- sis.10 Since the patients were diagnosed between 1999 and 2012, not all could have had EGFR muta- tion testing, as this was not a routine procedure be- fore the year 2004.18 Their main purpose was anal- ysis of expected change in survival curves due to stage migration, incorporating new diagnostic pro- cedures (PET/CT) and new treatment options with local approaches, especially irradiation of oligo- metastatic sites as well as improvement in systemic treatment, mainly molecular targeted agents.19 In TABLE 3. M descriptors for 7th and 8th TNM classification according to EGFR mutation status and their median overall survival (mOS) in months 7th TNM classification M descriptor EGFR-m EGFR-wt n n mOS n mOS p M1a 78 17 22.4 61 10.7 0.025 M1b 252 72 18.8 205 7.9 < 0.001 All 355 89 20.6 266 8.3 < 0.001 8th TNM classification EGFR-m EGFR-wt M1a 78 17 22.4 61 10.7 0.025 M1b 37 5 39.2 32 14.4 0.082 M1c 240 67 18.8 173 6.6 < 0.001 All 355 89 20.6 266 8.3 < 0.001 EGFR-m = patients harboured EGFR mutations; EGFR-wt = EGFR wild type patients TABLE 4. Site specific median overall survival (mOS) according to EGFR mutation status Metastatic site Patients mOS n all EGFR-m EGFR-wt p Brain 86 8.1 14.9 7.1 0.003 Bone 151 9.4 21.3 6.7 < 0.001 Lung 157 11.9 20.2 8.3 0.002 Pleura 115 8.8 20.6 6.5 < 0.001 Liver 55 5.6 10.4 5.5 0.245 Adrenal gland 49 5.2 4.9 5.5 0.595 Distant lymph nodes 55 6.2 13.0 5.5 0.237 Other sites 40 8.9 14.9 8.4 0.156 EGFR-m = patients harboured EGFR mutations; EGFR-wt = EGFR wild type patients FIGURE 2. Survival curves of different M categories according to EGFR mutation status based on 8th TNM classification. EGFR-m = patients harboured EGFR mutations; EGFR-wt = EGFR wild type patients Radiol Oncol 2019; 53(4): 453-458. Stanic K et al. / EGFR mutation status and TNM in lung cancer 457 our single institution analysis 355 patients were in- cluded, which represent one third (35.5%) of cases published in a paper that is proposing and justify- ing the classification changes. In further detailed analysis of distribution pat- tern of metastatic spread according to EGFR muta- tion status, we first divided patients by organ/site they metastasized to rather than number of metas- tasis in a single organ. As shown in this analysis and known also from clinical practice and previ- ous studies, patients with single metastatic site (or- gan) have better prognosis than those with multi- ple metastatic sites.20 Patients with low number of metastatic sites are known to have oligometastatic disease, though the definitions differ and current guidelines propose modified treatment.21-23 The new M descriptor does not define oligometastatic disease in a way that would help clinicians make decision about the treatment. For example, treat- ment and prognosis of patients with one metas- tasis in the brain (M1b) might be the same as of three small metastases (M1c).24 Similarly, treatment of one metastasis in the liver (M1b) will prob- ably be the same as for multiple metastases (M1c). One special situation is metastasis to the adrenal gland. Therapeutic options for metastasis to the adrenal gland as a single metastatic site are local treatments, either irradiation or operation.25,26 No cases with more than one metastasis in a single adrenal gland were observed in the current analy- sis. Patients with metastases in the adrenal gland, which are often affected on both sides, have bad prognosis and survival. According to our analysis, patients with metastases to adrenal gland have the worst survival regardless of EGFR-m status. In ad- dition, other researchers noticed that patients with adrenal gland metastasis showed impaired surviv- al.10 However, based on their data they concluded that the site of metastasis is not prognostic for sin- gle or multiple lesions within the single organ. It is questionable whether one or more metastases in a single organ really influence survival. On the con- trary, current analysis suggests that the number of metastatic sites might be more important prognos- tic factor than number of metastatic lesions in one organ. Even though large number of patients was in- cluded in our series, only 5 patients with EGFR mutations were sub-classified into M1b category. It seems that once EGFR-m tumors metastasize they do it in aggressive and widespread way. For the first time we have shown that not only have EGFR-m patients better mOS than EGFR-wt pa- tients but also better mOS in each sub-category of M descriptor. This analysis showed that in spite of widespread metastatic disease (M1c) and high tumor burden, EGFR-m patients treated with TKI had longer mOS (18.8 months) than EGFR- wt patients with only one metastasis (M1b) (14.4 months). Likely, EGFR-m status has greater impact on survival curves than different sub-categories of M descriptor. We are aware of the need for simple and predict- able system for classification in prognostic groups of patients with lung cancer. However, according to our survival data it seems that TNM classification is inadequate for relevant prediction of survival, because in some cases, as we show for EGFR muta- tions, molecular feature is more important than an- atomical distribution of malignant disease. Maybe we should consider adding the new descriptor to TNM classification that labels molecular feature of tumor. Recently, investigators from University of California published an article on how integration of molecular prognostic classifier into TNM system might improve identification of high-risk patients and predict survival in non-metastatic NSCLC. They used 11 cancer-related target genes; howev- er, they did not include current biomarkers such as EGFR, KRAS ALK, which was recognized as an important drawback of their study.27 There are some important limitations to the current analysis. It was not possible to find reli- able metastatic information for about 25% of cases in our database, which could not be included in the analysis. It should be recognized that due to small number of series those might be the cases that could influence the results and represent the potential bias. There were also more patients with symptomatic treatment among EGFR-wt patients than EGFR-m patients, reflecting real clinical situa- tion. However, this is not surprising as majority of EGFR-m patients are nonsmokers and have less co- morbidities. Also, in contrast to EGFR-wt patients who can receive chemotherapy only in good per- formance status (PS) 0-2, EGFR-m patients may al- so receive TKI in poor PS (3-4). Due to retrospective nature of the study not all metastatic sites rather symptomatic ones were diagnosed and collected in routine clinical practice. Conclusions Number of metastatic sites might be more impor- tant predictive survival factor than number of met- astatic lesions in single organ, though both fall into M1c category. Incorporation of EGFR mutation sta- Radiol Oncol 2019; 53(4): 453-458. Stanic K et al. / EGFR mutation status and TNM in lung cancer458 tus seem to predict survival more reliably than the number of metastasis or number of metastatic sites in NSCLC. 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