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Poster display session

3215 - TP53 mutation predicts sensitivity to adjuvant gemcitabine in pancreatic cancer: results from the CONKO-001 study

Date

09 Sep 2017

Session

Poster display session

Topics

Cytotoxic Therapy;  Translational Research;  Pancreatic Cancer

Presenters

Marianne Sinn

Citation

Annals of Oncology (2017) 28 (suppl_5): v209-v268. 10.1093/annonc/mdx369

Authors

M. Sinn1, J. Budczies2, F. Damm1, P. Lohneis2, R. Schmuck3, D. Treue2, J.K. Striefler1, M. Bahra3, U. Pelzer1, A. Jühling1, H. Bläker2, S. Bischoff1, H. Oettle4, C. Denkert5, H. Riess1, B. Sinn2

Author affiliations

  • 1 Medical Oncology, Charite Universitätsmedizin Berlin, 13353 - Berlin/DE
  • 2 Institute Of Pathology, Charite Universitätsmedizin Berlin, 10117 - Berlin/DE
  • 3 Surgery, Charite Universitätsmedizin Berlin, 13353 - Berlin/DE
  • 4 Hematology/oncology, Medical practice - Helmut Oettle, 88045 - Friedrichshafen/DE
  • 5 Institut Of Pathology, Charite Universtitätsmedizin Berlin, German Cancer Consortium (DKTK) Partner Site Berlin, 13353 - Berlin/DE
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Resources

Abstract 3215

Background

Pancreatic adenocarcinoma (PDAC) is a molecular heterogeneous disease, but clinically relevant genetic biomarkers are still missing. There are no data from prospective studies after curatively intended surgery and adjuvant chemotherapy so far.

Methods

CONKO-001, was a prospective randomized phase III study and investigated the role of adjuvant gemcitabine (Gem) as compared to observation (Obs). Formaline-fixed paraffin-embedded tissue samples of 187 patients (pts) could be collected, of which 97 could be analysed after DNA-extraction by targeted next generation sequencing (NGS), using a predefined sequencing panel including mutation hotspot regions of 36 genes (ACTN4, ACVR1B, APC, ARID1A, ARID1B, ARID2, ATM, BRAF, CDK6, CDKN2A, CNDP2, CREBBP, CTNNB1, ERBB2, FGFR1, GATA6, KDM6A, KMT2C, KMT2D, KRAS, MAP2K4, MET, MYC. PBRM1, PIK3CA, PREX2, RNF43, RPA1, SF3B1, SMAD4, SMARCA2, SMARCA4, SOX9, STK11, TGFBR2, TP53). Mutational status was correlated with survival by fitting a cox proportional hazard model.

Results

Patient’s characteristics were balanced between Gem (n = 49) and Obs (n = 48) group. KRAS, TP53, SMAD4 mutation was found in 73% (Gem/Obs n = 33/38), 59% (n = 28/29), 8% (n = 4/4) of patients. KRAS/SMAD4 mutation status was not associated with (treatment-related) survival. TP53 mutation was identified as a negative prognostic factor for untreated patients: hazard ratio (HR) for disease free-survival (DFS) TP53 mutant vs TP53 wildtype 2.90 (95% CI 1.55 -5.41). Furthermore, TP53 mutation was found to be a positive predictive factor for Gem: HR for DFS Gem vs Obs in TP53 wildtype patients was 0.87 (95% CI 0.46-1.66) in comparison to TP53 mutated patients with a HR of 0.22 (95% CI 0.12-0.39). Test of TP53-by-treatment-interaction was statistically significant; p = 0.002.

Conclusions

To the best of our knowledge, we present the first NGS data from a prospective clinical study in PDAC. In contrast to previous data, we could not identify KRAS or SMAD4 mutation as clinically relevant factors in primarily resectable PDAC. In CONKO-001, TP53 mutated patients had an unfavorable prognosis when randomized to Obs and profited strongly from adjuvant Gem, while adjuvant treatment did not significantly prolong DFS in TP53 wildtype patients.

Clinical trial identification

ISRCTN34802808.

Legal entity responsible for the study

Charite Universitätsmedizin Berlin, CONKO-study group.

Funding

Charite Forschungsförderung, German Cancer Consortium (DKTK), Rahel-Hirsch grant.

Disclosure

M. Sinn: Honoraria, Advisory board: Baxalta. Research funding: Leo Pharma. Travel support: Amgen. All other authors have declared no conflicts of interest.

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