Tumour cell proliferation (Ki-67) in non-small cell lung cancer: a critical reappraisal of its prognostic role

Abstract

Background:Uncontrolled proliferation is a hallmark of malignant tumour growth. Its prognostic role in non-small cell lung cancer (NSCLC) has been investigated in numerous studies with controversial results. We aimed to resolve these controversies by assessing the Ki-67 proliferation index (PI) in three large, independent NSCLC cohorts.Methods:Proliferation index was retrospectively analysed by immunohistochemistry in a cohort of 1065 NSCLC and correlated with clinicopathological data including outcome and therapy. Results were validated in two independent cohorts of 233 squamous cell carcinomas (SQCC) and 184 adenocarcinomas (ADC).Results:Proliferation index (overall mean: 40.7%) differed significantly according to histologic subtypes with SQCC showing a mean PI (52.8%) twice as high as ADC (25.8%). In ADC PI was tightly linked to growth patterns. In SQCC and ADC opposing effects of PI on overall (OS), disease-specific and disease-free survival were evident, in ADC high PI (optimised validated cut-off: 25%) was a stage-independent negative prognosticator (hazard ratio, HR OS: 1.56, P=0.004). This prognostic effect was largely attenuated by adjuvant radio-/chemotherapy. In SQCC high PI (optimised validated cut-off: 50%) was associated with better survival (HR OS: 0.65, P=0.007).Conclusions:Our data demonstrate that PI is a clinically meaningful biomarker in NSCLC with entity-dependent cut-off values that allow reliable estimation of prognosis and may potentially stratify ADC patients for the need of adjuvant therapy.

Ex Vivo Explant Cultures of Non–Small Cell Lung Carcinoma Enable Evaluation of Primary Tumor Responses to Anticancer Therapy

“…1A). These observations are consistent with several previous reports (28)(29)(30). With regard to cPARP staining, the majority of samples showed less than 20% of staining, indicating low levels of intrinsic cell death ( Fig.…”

Ki-67 expression in pulmonary tumors

“…However, the informative value of the vast majority of studies on this issue is limited by the small sample numbers investigated, different Ki-67 clones used in different studies, and the use of various Ki-67 cutoff points for defining a tumor positive or negative (25). Moreover, subgroup analyses of different NSCLC histologies demonstrate that the prognostic impact of Ki-67 PI depends on the NSCLC type (26) and studies of NSCLC cohorts with mixed histologies will not lead to meaningful results. Despite the large number of published analyses exploring the prognostic role in NSCLC, Ki-67 is still not considered an established factor for routine use in clinical practice.…”

“…Despite the large number of published analyses exploring the prognostic role in NSCLC, Ki-67 is still not considered an established factor for routine use in clinical practice. A recent study investigated the Ki-67 PI in three large, independent NSCLC cohorts and found the need for use of different cutoff values for each histologic NSCLC type (26). Ki-67 PI was a highly significant and independent predictor for DFS for lung adenocarcinoma and adenosquamous carcinoma, in both the test and validation cohorts, but not for OS and disease-specific survival (DSS) (26).…”

“…A recent study investigated the Ki-67 PI in three large, independent NSCLC cohorts and found the need for use of different cutoff values for each histologic NSCLC type (26). Ki-67 PI was a highly significant and independent predictor for DFS for lung adenocarcinoma and adenosquamous carcinoma, in both the test and validation cohorts, but not for OS and disease-specific survival (DSS) (26). Interestingly, the authors found that in squamous cell carcinoma a high PI was reversely correlated with a better OS (cut-off value of 50%; HR =0.65; P=0.007).…”

Correlation of diffusion MRI with the Ki-67 index in non-small cell lung cancer

“…[13][14][15][16][17][18][19] The Ki-67 index has also been used routinely in the evaluation of lung tumours and has been shown to be an important prognostic factor for lung cancer. 3,6,[20][21][22][23][24][25][26][27] Although a few studies have evaluated the association of ADC with Ki-67 index in lung tumours 3,6 , no study has previously investigated differences in the ADC/Ki 67 correlation in different tumour subtypes.…”