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Pathologic heterogeneity of lung adenocarcinomas: A novel pathologic index predicts survival.

ABSTRACT: Although the most predominant subtype of invasive lung adenocarcinoma has been reported to have clinical significance, a major limitation of this concept is that most tumors are mixed-subtype. Therefore, we aimed to determine the individual prognostic significance of each subtype and also attempted to establish a pathologic index that reflects the pathologic subtypes and overall heterogeneity of lung adenocarcinomas and evaluated its prognostic significance. The individual prognostic impact of each subtype was assessed from the development cohort using the disease-free survival (DFS) curve of a previous large-scale study. Hazard ratios (HRs) from the development cohort were 1, 1.025, 1.059, 1.495, and 1.160 for the lepidic, acinar, papillary, micropapillary, and solid pattern subtype, respectively. Based on the calculated HR of each subtype, four indices representing pathologic heterogeneity were developed. The first and second indices were defined as the sum of the proportions of each subtype multiplied by their HRs, with the addition of either entropy or Gini coefficient, respectively. The third index was calculated as the sum of all subtype percentages multiplied by their HRs. To emphasize heterogeneity, the fourth index was defined as the simple arithmetic sum of the scores of the subtypes multiplied by their HRs. Each subtype was assigned a score of 0 if the subtype was absent and a score of 1 if the subtype was present in a binary fashion. We applied these four pathologic indices to a validation group of 148 patients with comprehensive histologic subtyping for completely resected lung adenocarcinomas. DFS curves were plotted and predictive ability of each pathologic index was evaluated. Among the four pathologic indices, only pathologic index 3 enabled significant patient stratification in the validation cohort according to DFS (P = 0.004) and showed the highest Harrell's C index of 0.691 of all four pathologic indices. In conclusion, we estimated the HR of each subtype and generated four pathologic indices that reflect heterogeneity. One of these, index 3, the pathologic heterogeneity index based on the sum of all subtype percentages multiplied by their HR, possesses good prognostic ability for predicting survival in patients with lung adenocarcinoma.

SUBMITTER: Lee G

PROVIDER: S-EPMC5342557 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Pathologic heterogeneity of lung adenocarcinomas: A novel pathologic index predicts survival.

Lee Geewon G Choi E-Ryung ER Lee Ho Yun HY Jeong Ji Yun JY Ahn Joong Hyun JH Kim Seonwoo S Bae Jungmin J Kim Hong Kwan HK Choi Yong Soo YS Kim Jhingook J Zo Jaeil J Lee Kyung Soo KS Shim Young Mog YM

Oncotarget 20161001 43

Although the most predominant subtype of invasive lung adenocarcinoma has been reported to have clinical significance, a major limitation of this concept is that most tumors are mixed-subtype. Therefore, we aimed to determine the individual prognostic significance of each subtype and also attempted to establish a pathologic index that reflects the pathologic subtypes and overall heterogeneity of lung adenocarcinomas and evaluated its prognostic significance. The individual prognostic impact of e ...[more]

PMID: 27612421

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Project description:ImportanceIntratumoral heterogeneity has been recognized as a significant barrier in successfully developing targetable biomarkers for gastroesophageal adenocarcinoma (GEA) and may affect neoadjuvant precision medicine approaches.ObjectiveTo describe intratumoral spatial heterogeneity of tumor cell populations in nonmetastatic GEA and its association with survival.Design, setting, and participantsThis case series retrospectively identified 41 patients with GEA who underwent up-front surgical resection at a tertiary referral cancer center from January 1, 1989, through December 31, 2013. Survival was calculated from date of surgery to date of death through June 1, 2017. Data were analyzed from June 2, 2017, to March 1, 2019.Main outcomes and measuresOverall survival, intratumoral clonal composition determined by genomic single-nucleotide variation array and bioinformatic analysis, and intercellular tumoral distances determined by multiprobe fluorescence in situ hybridization.ResultsAmong the 41 patients included in the analysis (22 men [54%]; mean [SD] age, 63 [12] years), a high proportion (19 [46%]) presented with tumors possessing high intratumoral heterogeneity. Kaplan-Meier analysis demonstrated that cases with an intratumoral clonal composition count of at least 2 exhibited worse survival compared with cases with a clonal composition count of 0 to 1 (univariate hazard ratio, 3.92; 95% CI, 1.27-12.08; P = .02). This finding remained significant on multivariate analysis controlling for stage, Lauren histologic subtype, receipt of adjuvant therapy, and age (multivariate hazard ratio, 4.55; 95% CI, 1.09-19.04; P = .04). Multiprobe fluorescence in situ hybridization demonstrated intratumoral clonal populations coexisting at submillimeter distances with differing relevant oncogenic copy number alterations, such as EGFR, JAK2, FGFR2, MET, CCND1, KRAS, MYC, PIK3CA, CD274, and PDCD1LG2.Conclusions and relevanceThis study found that spatial intratumoral heterogeneity of oncogenic copy number alterations exists before metastatic dissemination, and increased heterogeneity was associated with worse outcomes in resected GEA. Baseline heterogeneity illustrates the challenges in GEA targeted therapy. Further study may offer insight into strategies on combinatorial and/or sequential targeted and immunotherapeutic approaches.

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Pathologic heterogeneity of lung adenocarcinomas: A novel pathologic index predicts survival.

Publications

Pathologic heterogeneity of lung adenocarcinomas: A novel pathologic index predicts survival.

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