Abstract B29: Ki67 proliferation index score paradoxical increase after neoadjuvant therapy in resected NSCLC.
Authors: Weiss Glen J. , Moldvay Judit , Dome Balazs , Fabian Katalin , Podmaniczky Eszter , Papay Judit , Gyulai Marton , Furak Jozsef , Szirtes Ildiko , Ai Jizhou , McCabe Ryan , LoBello Janine , Hegedus Balazs 
Published: August 2014

Abstract
Background: Neoadjuvant chemotherapy is used to help downstage cancer, and is widely used in locally-advanced breast cancer. Studies of Ki67 proliferation index in breast cancer have been fairly extensively evaluated. Comparison of core and surgical specimens in breast cancers without exposure to chemo- or radiotherapy revealed technical variation of up to 20% in the Ki67 index score. In non-small cell lung cancer (NSCLC), however, little is known about the association of rate of change of Ki67 after neoadjuvant chemotherapy +/- radiotherapy with radiographic response and clinical outcomes. We surveyed NSCLC from patients treated with neoadjuvant chemotherapy +/- radiotherapy.
Methods: NSCLC patients treated with neoadjuvant chemotherapy were identified from 3 Hungarian hospitals and 1 community hospital in the United States. Matched pre-chemotherapy and post-surgical resection formalin-fixed, paraffin-embedded (FFPE) tumor specimens were collected and the Ki67 index was scored under an IRB exemption. We set an absolute difference of 20% between pre-chemotherapy and post-resection Ki67 scores as “meaningful” to avoid possible technical variation reported in the literature (1). Radiographic response to neoadjuvant chemotherapy by RECIST 1.0 criteria was also measured. Fisher's exact test was used to measure the relationship between gender, histology, and type of chemo with “meaningful” Ki67 index. Logistic regression was used to test the relationship between Ki67 index decline rate and outcome subgroup (response/no response). Decline rate was defined as a ratio of decrease of Ki67 to its level at baseline. For univariate analysis, Kaplan-Meier method was used to estimate the survival probability and the log rank test was used to assess the difference in survival between groups. For multivariate analysis, the Cox proportional hazards regression was used. P-values were adjusted for multiple comparison.
Results: 63 matched cases were identified. 46 cases were analyzable for pre-chemotherapy and post-operative Ki67, and chemotherapy regimen; 40 cases also had response criteria by RECIST (Table I). Of the 46 cases, the median patient age was 59 years (range 40-77), 24 were men, and 30 of 34 had a smoking history. There were 24 adenocarcinomas and 22 squamous cell carcinomas. Stages I, II, III, and IV were 2, 9, 31, and 4; respectively. All but two patients received a platinum-doublet, with 24 containing gemcitabine. 5 patients also received neoadjuvant radiotherapy. 22 are deceased as of last follow-up. Median overall survival (OS) is 28.5 months (range 7.4-107.7 months). The mean Ki67 index scores were 35% (range 1-100%) pre-chemotherapy and 32% (0-100%) post-resection (see representative example in Figure 1). 9 patients (19.6%) had a paradoxical “meaningful” increase in Ki67 index after neoadjuvant chemotherapy. Of the 40 patients with RECIST response data, there was 1 complete response, 34 partial responses, 4 stable diseases, and 1 disease progression. There were no statistically significant differences between gender, histology subtype, or type of platinum doublet administered associated with this paradoxical increase. There was no statistically significant difference in Ki67 decline rate between responders and non-responders. Additionally, there was no statistically significant association by univariate or multivariate analysis with gender, histology, chemo type (gemcitabine vs. other), paradoxical Ki67 increase, or RECIST response and OS.
Conclusion: In this cohort of patients, there was a paradoxical “meaningful” increase in Ki67 index after neoadjuvant chemotherapy in ~20% of patients, without a clear association between histology or platinum doublet administered. For patients receiving neoadjuvant chemotherapy, the Ki67 index decline rate was not associated with radiographic response or OS. Approximately 1/5 of NSCLC may have selection of tumor cells for a higher proliferative index when undergoing neoadjuvant platinum-based chemotherapy, though this does not appear to impact OS.
Citation Format: Glen J. Weiss, Judit Moldvay, Balazs Dome, Katalin Fabian, Eszter Podmaniczky, Judit Papay, Marton Gyulai, Jozsef Furak, Ildiko Szirtes, Jizhou Ai, Ryan McCabe, Janine LoBello, Balazs Hegedus. Ki67 proliferation index score paradoxical increase after neoadjuvant therapy in resected NSCLC. [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr B29.