Journal of Thoracic Oncology:
Correlation of Mutation Status and Survival with Predominant Histologic Subtype According to the New IASLC/ATS/ERS Lung Adenocarcinoma Classification in Stage III (N2) Patients
Russell, Prudence A. MBBS, FRCPA*; Barnett, Stephen A. MBBS, FRACS†; Walkiewicz, Marzena MSc‡; Wainer, Zoe BMBS§; Conron, Matthew MBBS, FRACP, MD‖; Wright, Gavin M. MBBS, FRACS¶; Gooi, Julian MBBS, FRACS†; Knight, Simon MBBS, FRACS†; Wynne, Rochelle PhD#; Liew, Danny MBBS, FRACP, PhD**; John, Thomas MBBS, FRACP, PhD‡
*Department of Anatomical Pathology, St Vincent’s Hospital, The University of Melbourne, Melbourne, Australia; †Department of Thoracic Surgery, Austin Health, The University of Melbourne, Melbourne, Australia; ‡Ludwig Institute for Cancer Research, Austin Health, The University of Melbourne, Melbourne, Australia; §The University of Melbourne, Department of Surgery, St Vincent’s Hospital, Melbourne, Australia; ‖Department of Respiratory and Sleep Medicine, St. Vincent’s Hospital, The University of Melbourne, Melbourne, Australia; ¶Department of Thoracic Surgery, St Vincent’s Hospital, The University of Melbourne, Melbourne, Australia; #Melbourne School of Health Sciences, The University of Melbourne, Melbourne, Australia; and **Melbourne EpiCentre, The University of Melbourne and Melbourne Health, Melbourne, Australia.
Disclosure: Dr. T.J. is a Victorian Cancer Agency Fellow and holds a Pfizer Oncology Cancer Research Grant. All other authors declare no conflict of interest. No funding for this work has been received from the National Institutes of Health, Wellcome Trust, and Howard Hughes Medical Institute.
Address for correspondence: Prudence A. Russell MBBS, FRCPA, St. Vincent’s Hospital, 41 Victoria Parade, Fitzroy, 3065, Melbourne, Victoria, Australia. E-mail: firstname.lastname@example.org
Introduction: We investigated the relationship between predominant subtype, according to the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Lung Adenocarcinoma Classification; mutation status; and patient outcome in stage III (N2) lung adenocarcinoma.
Methods: We identified 69 patients with stage III (N2) lung adenocarcinoma operated on with curative intent between 1993 and 2011 who had adequate tumor tissue for molecular analysis and adequate follow-up time for survival analysis. DNA was isolated and tested for mutations using Sequenom’s OncoCarta Panel (v1.0; Sequenom, San Diego, CA).
Results: The majority of tumors were acinar (26 of 69 tumors; 38%), solid (24 of 69 tumors; 35%), and micropapillary predominant (13 of 69 tumors; 19%) subtypes. EGFR and KRAS mutations were identified in 17 of 59 tumors (29%) and 13 of 59 tumors (22%), respectively. EGFR mutations occurred most often in acinar (11 of 25 tumors; 44%) and micropapillary predominant tumors (five of 13 tumors; 38%) (p = 0.009), whereas KRAS mutations occurred most often in solid predominant tumors (nine of 21 tumors; 43%) (p = 0.016). Patients with acinar predominant tumors had significantly improved overall survival compared with those with non-acinar predominant tumors (hazard ratio: 0.45; 95% confidence interval: 0.22–0.91; p = 0.026), which remained significant after adjustment for EGFR status, T-stage, sex, and age. Patients with EGFR-mutant micropapillary predominant tumors had similar survival to those with EGFR-mutant acinar predominant tumors. The predominant subtype in the primary tumor was most often seen in the N2 node in micropapillary and solid predominant tumors but not in acinar predominant tumors.
Conclusions: The predominant subtype in the primary tumor was associated with overall survival in resected stage III (N2) lung adenocarcinoma and was independent of mutation status. Histologic subtyping provides important prognostic information and potentially molecular correlates.
Although the overall incidence of lung cancer is falling in Western countries, it remains the biggest cause of cancer mortality.1 Non–small cell lung carcinoma comprises 80% of all lung cancers, of which adenocarcinoma is now the most common subtype.2 Histology has been investigated as an independent prognostic factor, but the evidence for improved outcomes according to broad non–small cell lung carcinoma subtypes remains equivocal. The exception to this is in the context of some individual adenocarcinoma subtypes, with good outcomes approaching 100% 5-year survival in adenocarcinoma in situ, formerly known as bronchioloalveolar carcinoma3–5 and poor outcomes in micropapillary pattern6–8 and solid pattern adenocarcinoma.9,10
In response to these issues, a new lung adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS) has recently been published.11 The importance of the new IASLC/ATS/ERS classification is underscored by its prognostic impact that has been recently reported by three studies,12–14 two of which predominantly examined patients with early-stage disease.12,13
As mutations in the EGFR and KRAS genes are linked almost exclusively to adenocarcinoma histology, it is important to define the associations between these oncogenic drivers and histologic subtype. Furthermore, the presence of activating EGFR mutations has been shown to be prognostic for a more favorable outcome independent of treatment while also predictive for increased responses to tyrosine kinase inhibitor therapy.15–17 Recently, three Asian studies18–20 have reported correlations between predominant subtype in resected lung adenocarcinomas classified according to the new IASLC/ATS/ERS classification and EGFR mutations.
Because recent studies12–14 validating the prognostic impact of the new IASLC/ATS/ERS classification focused predominantly on early-stage disease and those correlating EGFR mutations and the new classification have only been performed in Asian populations,18–20 we sought to examine these relationships in a cohort of predominantly Caucasian patients with locally advanced lung adenocarcinoma, derived from two tertiary Australian centers. To this end, we examined 69 patients who underwent surgical resection with curative intent and were found to have occult pathologic N2 (pN2) lung adenocarcinoma to determine if predominant subtype correlates with somatic mutations and overall survival in more advanced disease. Furthermore, we compared predominant subtypes in the primary tumors with the histologic patterns in the N2 metastases to determine whether it is feasible to determine subtype in nodal tissue and to explore whether some subtypes have a greater propensity to metastasize.
PATIENTS AND METHODS
After approval from the human research ethics boards from the respective institutions, two surgical registries from tertiary academic centers linked to the University of Melbourne, Australia (at St Vincent’s Hospital and Austin Health), were reviewed to identify patients with resected pN2 primary lung adenocarcinoma operated on with curative intent between 1993 and 2011.
All patients had pathologically confirmed adenocarcinoma defined as a malignant epithelial neoplasm with either glandular differentiation or mucin production and histopathologic patterns including lepidic, acinar, papillary, micropapillary, and solid with mucin, according to the IASLC/ATS/ERS classification.11 In addition, all patients had pathologically confirmed N2 nodal disease with metastatic adenocarcinoma in one or more of stations 2 to 9, in accordance with the definitions of the seventh edition of tumor node metastasis classification of lung cancer staging.21
The definition of a never smoker was a person with a lifetime equivalent consumption of fewer than 100 cigarettes. None of the patients had neoadjuvant therapy.
The location, number, and size of tumors were obtained from pathology reports. A pathologist (P.R.), blinded to patient outcome, reviewed all hematoxylin and eosin–stained slides from the 69 cases. An average of six hematoxylin and eosin slides of tumor (range, 2–31) were reviewed per case. In 19 cases, the entire tumor was submitted for histologic examination and in 56 cases, a block of tumor was submitted per centimeter from the largest dimension of tumor. All cases were histologically classified according to the IASLC/ATS/ERS classification,11 with estimation in 5% increments of each histologic subtype present and identification and classification of each tumor according to the predominant subtype, as previously described.13 The lowest limit for the predominant subtype was set at 30%, as previously described.10,11
All hilar and mediastinal lymph nodes included with all 69 cases were examined to assess nodal disease status. All histologic patterns present in the lymph node metastases were recorded as a binary variable, without assigning percentages. It was possible to assign a predominant pattern to the nodal metastases in each case.
Mutational Profiling and EGFR and KRAS Mutational Analysis
Formalin-fixed, paraffin-embedded blocks with adequate tumor tissue was available for 59 cases, from which DNA was isolated. The predominant subtype was circled on a glass slide, and DNA was isolated either from unstained 10-µm-thick sections or by punching a 1.5-mm core from the corresponding formalin–fixed, paraffin-embedded block. The tissue or core was then deparaffinized by serial passages in xylene and alcohol and DNA isolated using DNeasy blood and tissue kits (Qiagen, Melbourne, Australia) and subjected to mutational profiling using Sequenom’s MassArray platform, OncoCarta Panel (v1.0; Sequenom, San Diego, CA), as previously described.22
Follow-up and Outcomes
Of the 69 patients, three patients resected in 2011 were excluded from survival analysis as they had less than 12 months of follow-up, leaving 66 patients for evaluation of overall survival. Each patient was followed up till death or for at least 12 months. One patient died within 30 days of surgery. These patients were not part of a trial protocol; however, most patients were followed up three monthly for the initial 2 years after resection, then six monthly for the subsequent 2 years and annually following this.
The association between the predominant subtype, demographic factors and molecular status was first compared with the Fisher’s exact test. Survival analysis was undertaken with stratification by predominant subtype/variant according to the new IASLC/ATS/ERS classification using the Kaplan–Meier method by calculating the time from resection to death or date of last follow-up. Hazard ratios (HRs) were derived using Cox regression analyses, and adjustment was made for mutation status, pathologic seventh edition tumor node metastasis stage, sex, age, T-stage, and adjuvant chemotherapy.
Patient and Tumor Characteristics
This data set of 69 patients with resected pN2 lung adenocarcinoma comprised 38 women (55%), with a median age of 65.3 years (range, 29–85 years), and 16 current, 34 former, and 19 never smokers. Median tumor size was 35 mm (range, 10–110 mm) (Table 1). Sixty-three patients (91%) underwent surgical lobectomy, five underwent pneumonectomy, and one had a segmentectomy, with all undergoing mediastinal lymph node dissection. Pathologic stage was stage IIIA in 68 patients and stage IIIB in one patient.
Predominant subtype in 69 primary tumors was as follows: 26 of 69 acinar (38%), 24 of 69 solid (35%), 13 of 69 micropapillary (19%), four of 69 papillary (6%), and two of 69 colloid (2%) tumors (Table 1). There were no lepidic predominant tumors.
Correlation of Mutational Profile and Predominant Subtype
Mutational profiles were available for 59 patients. EGFR and KRAS mutations were identified in 17 of 59 tumors (29%) and 13 of 59 tumors (22%), respectively (Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/JTO/A381). EGFR mutations occurred most often in acinar predominant (11 of 25 [44%]) and micropapillary predominant tumors (five of 13 [38%]) compared with solid predominant tumors (one of 21 [5%]) (p = 0.009) (Table 1). In contrast, KRAS mutations occurred most often in solid predominant tumors (nine of 21 [43%]) compared with acinar predominant (three of 25 [12%]) and micropapillary predominant tumors (one of 13 [8%]) (p = 0.016) (Table 1).
Correlation of Predominant Subtype and Patterns in Primary Tumor and Corresponding N2 Metastases
For 69 patients, the N2 metastases showed an admixture of histologic patterns (Fig. 1). Although a predominant pattern could be identified in all the cases, it was not possible to semiquantify each histologic pattern as a percentage. As evident from Table 2, the predominant subtype in a primary tumor was most often seen in the N2 metastases in micropapillary and solid predominant primary tumors, though, for two of 24 (8%) solid predominant primary tumors, the N2 metastases showed predominantly micropapillary pattern tumor. For 11 of 26 acinar predominant primary tumors (42%), the N2 metastases showed predominantly acinar tumor, but for the remaining 15 of 26 acinar predominant primary tumors (58%), the N2 metastases contained predominantly micropapillary (eight of 15) or solid (seven of 15) pattern tumor. In most cases, if the predominant pattern in the lymph node was discordant from the predominant subtype in the primary tumor, the predominant pattern in the lymph node consisted of a secondary pattern present in the primary tumor. Both solid predominant primary tumors with predominantly micropapillary tumor in the N2 metastases showed micropapillary tumor as a secondary pattern in the primary tumors (Table 3). Similarly, all eight acinar predominant primary tumors with predominantly micropapillary tumor in the N2 metastases showed micropapillary tumor as a secondary pattern in the primary tumors (Table 3). Likewise, six of seven acinar predominant primary tumors with predominantly solid tumor in the N2 metastases showed solid tumor as a secondary pattern in the primary tumors, whereas one did not. This latter tumor was 40 mm and comprised 80% acinar and 20% papillary patterns, with only three blocks submitted for histologic examination. Furthermore, in all four papillary predominant primary tumors, the N2 metastases contained predominantly micropapillary tumor, with micropapillary pattern present as a secondary pattern in all four tumors, and in two colloid predominant primary tumors, the N2 metastases contained mostly acinar tumor, with acinar pattern present as a secondary pattern in both primary tumors (Table 3).
Correlation of Predominant Subtype, Mutational Profile, and Overall Survival
The median survival on the basis of predominant subtype was as follows: 65.5 months for acinar predominant tumors, 27 months for micropapillary predominant tumors, 23.9 months for solid predominant tumors, 14 months for the three patients with papillary predominant tumors, and 10.1 months for the two patients with colloid predominant tumors (Fig. 2A). The relationship between overall survival and individual predominant subtype/variant did not reach statistical significance, most likely due to limited patient numbers. Each previous study investigating the prognostic impact of the IASLC/ATS/ERS classification combined predominant subtypes with similar survival into three groups, increasing their power of analysis.12–14 Hence, we combined patients with micropapillary, solid, papillary, and colloid predominant tumors into one group on the basis of similar poor survival relative to survival in patients with acinar predominant tumors. The overall survival of patients with acinar predominant tumors was significantly improved compared with those with non-acinar predominant tumors (HR: 0.45; 95% confidence intervals: 0.22–0.91; p = 0.026) (Fig. 2B). This remained significant after adjustment for T-stage, sex and age, and EGFR mutation status, a known favorable prognostic factor in advanced disease. When adjuvant chemotherapy was included in the model, the direction of effect toward improved outcome in acinar predominant tumors remained; however, it lacked statistical significance (HR: 0.71, 95% confidence intervals: 0.23–1.05; p = 0.066).
Given the differences in survival observed on the basis the predominant subtype in the primary tumor, we investigated whether the predominant pattern in the N2 node influenced survival. No significant differences were seen on the basis of the N2 nodal predominant pattern, indicating that the predominant subtype in the primary tumor was the main determinant of outcome.
As both acinar and micropapillary predominant subtypes displayed divergent prognosis yet harbored EGFR mutations at similar rates, we sought to determine whether survival in these subgroups was influenced by the presence of mutations. Although limited numbers restricted our analyses, patients with EGFR-mutant micropapillary predominant tumors had similar survival to EGFR-mutant acinar predominant tumors, suggesting a less aggressive phenotype in these patients (Fig. 3; Supplementary Table 2, Supplemental Digital Content 2, http://links.lww.com/JTO/A382).
These data demonstrate a significant correlation between overall survival and predominant subtype according to the new IASLC/ATS/ERS lung adenocarcinoma classification11 in a cohort of patients with advanced-stage lung adenocarcinoma. The survival benefit in acinar predominant tumors versus non–acinar predominant tumors was observed after adjustment for mutation status but not for adjuvant chemotherapy.
We confirm that EGFR-mutant tumors were more likely to be either acinar or micropapillary predominant subtypes, whereas KRAS-mutant tumors were more often of solid predominant subtype. When the predominant subtype in the primary tumor was compared with that in the N2 metastases, less than half acinar predominant primary tumors showed predominantly acinar pattern in the N2 nodes. However, micropapillary and solid predominant primary tumors were associated with the same predominant pattern in the N2 metastases in almost all cases. Despite these differences in metastatic potential, the predominant subtype in the primary tumor dictated survival differences, not the predominant pattern in the N2 metastases.
Of the three recent studies12–14 validating the prognostic impact of the new IASLC/ATS/ERS classification, the one from Warth et al.14 includes the largest patient numbers with advanced-stage disease. They examined 205 stage I, 105 stage II, 162 stage III, and 15 stage IV patients, with 141 stage III patients with pN2 disease. Predominant subtype in the 141 pN2 tumors included two lepidic predominant (1.4%), 57 acinar predominant (40.4%), 53 solid predominant (37.6%), eight papillary predominant (5.7%), and 21 micropapillary predominant (14.9%) tumors. In this larger cohort, the percentage of patients with each predominant subtype was similar to ours; however, we did not observe any pN2 lepidic predominant tumors. Overall survival for 141 pN2 patients was 40.5 months in the study by Warth et al. and 26.2 months in our study. Warth et al.14 do not provide survival analyses for 141 pN2 patients according to each separate predominant subtype, and it is unclear which patients received adjuvant chemotherapy, although they report 71 of 106 stage III/IV patients received chemotherapy.
Before the publication of the new IASLC/ATS/ERS classification, several studies10,23–25 examined relationships between EGFR and KRAS mutations and histologic pattern, each study using modifications of the 2004 World Health Organization classification2 to classify tumors. Significant associations between papillary10 and micropapillary patterns10,23 and EGFR mutations were reported by two groups, whereas a third group 24 reported that in a series of 15 micropapillary pattern adenocarcinomas, a disproportionately high rate of mutations was present, in comparison to results of all histologic subtypes from their institution.25
Since the publication of the new IASLC/ATS/ERS classification, the relationship between EGFR and KRAS mutations and predominant subtype has been examined by two Korean studies investigating EGFR mutations and a Chinese study examining EGFR, KRAS, HER2, and BRAF mutations (Table 4). Shim et al.18 examined 107 resected lung adenocarcinomas finding EGFR mutations in 50.5% including 10 of 12 micropapillary predominant and five of eight lepidic predominant tumors, with significant associations found between EGFR mutations and micropapillary predominant tumors (p = 0.02) and the presence of any amount of lepidic pattern (p = 0.02). Sun et al.19 examined 249 resected lung adenocarcinomas and found EGFR mutations in 55.4%, including 98 of 173 acinar predominant, 21 of 30 papillary predominant, and two of four micropapillary predominant tumors, but the relationship between acinar and micropapillary predominant tumors and EGFR mutations did not reach statistical significance (p = 0.06). Zhang et al.20 investigated 349 never-smoking female lung adenocarcinoma cases and found EGFR mutations in 76.2%, including 152 of 183 acinar predominant tumors, with a significant association between EGFR mutations and acinar predominant histology (p = 0.002). Overall, the results from these three Asian studies are similar to our own; however, we found EGFR mutations in 29% of tumors. These data suggest that in white populations, the predominant subtype enriches for specific genotypes.
The significant association between KRAS mutations and solid predominant histology is in contrast to the results of Zhang et al., who reported a significant association between KRAS mutations and invasive mucinous adenocarcinomas (p = 0.028), and Motoi et al.10, who did not find any significant associations between histologic subtype and KRAS mutations. However, our findings are in line with the results from a North American cohort of 82 resected lung adenocarcinomas in which 27 of 82 tumors harbored KRAS mutations, with 16 of 25 KRAS-mutant (64%) showing solid predominant histology in comparison to 11 of 57 KRAS-mutant tumors (19%) with non–solid predominant histology (p = 0.0002).26 In fact, it appears that the frequency of KRAS and indeed EGFR mutations in solid predominant histology differs in Asian and Caucasian populations. This is supported by reports of Asian patients showing significant numbers of EGFR mutations in solid predominant tumors including 60% of solid predominant tumors in the series from Zhang et al.20 and nine of 12 tumors (75%) in a series from Sholl et al.27, who examined 65 never-smoking Taiwanese women with resected lung adenocarcinoma.
Because of differences in survival between acinar predominant and micropapillary predominant subtypes but similar frequencies of EGFR mutations, we examined survival in these two EGFR-mutant histologic subtypes. Patients with EGFR-mutant micropapillary predominant tumors had similar survival as those with EGFR-mutant acinar predominant tumors. These findings suggest that acinar predominant tumors, although being more likely to harbor EGFR mutations, are associated with improved survival regardless of mutation status, whereas EGFR wild-type micropapillary predominant tumors have the poorest clinical outcome. Therefore, EGFR mutations within the micropapillary predominant subtype determined a markedly different clinical subgroup compared with EGFR wild-type micropapillary predominant tumors that were universally associated with poorer outcome.
Comparison of the predominant subtype in the primary tumor and histologic patterns in the N2 metastases showed that both micropapillary and solid patterns were more likely to be present in the N2 metastases, despite being present as a small percentage in the primary tumor. These findings suggest that different metastatic potential exists among adenocarcinoma subtypes, as proposed by Sica et al.28, who examined 73 patients with resected lung adenocarcinoma and N1, N2, and brain metastases, and also noted that the rates of concordance between predominant subtypes in the primary tumors and N2 metastases suggested differing metastatic potential. On the basis of this, we concur that the acinar pattern is of intermediate metastatic potential, whereas micropapillary and solid patterns are of high metastatic potential.
In conclusion, we report a significant relationship between the predominant subtype in the primary tumor, as defined by new IASLC/ATS/ERS lung adenocarcinoma classification, and overall survival in 66 patients with resected stage III pN2 lung adenocarcinoma. Athough EGFR mutations occurred more frequently in acinar predominant tumors, the improvement in survival occurred independent of mutation status. These findings indicate that the predominant subtype in the primary tumor determines outcome in pN2 disease but not the predominant pattern in the lymph node or mutation status. Subtyping tumors based on the new IASLC/ATS/ERS classification provides important prognostic information and potentially molecular correlates. Subtyping could be used to better personalize treatments toward subgroups most likely to derive benefit, a strategy that warrants further investigation in prospective studies.
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Adenocarcinoma subtype; Mutation status; Survival
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