Association of molecular status and organs with metastases at diagnosis in patients with non-small cell lung cancer (NSCLC)

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1 Association of molecular status and organs with metastases at diagnosis in patients with non-small cell lung cancer (NSCLC) Chantal Kuijpers* 1,2, Lizza Hendriks 3, Jules Derks 3, Anne-Marie Dingemans 3, Anne van Lindert 1, Michel van den Heuvel 5, Ronald Damhuis 6, Stefan Willems 1,2,7 1. Dept. of Pathology, University Medical Centre Utrecht, Utrecht 2. Foundation PALGA, Houten 3. Dept. of Pulmonary Diseases, GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht 4. Dept. of Respiratory Medicine, University Medical Centre Utrecht, Utrecht 5. Dept. of Lung Disease, Radboudumc, Nijmegen 6. Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht 7. Dept. of Pathology, Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam

2 Disclosure slide This study was partly funded by Roche and Pfizer.

3 Molecular alterations in NSCLC Adenocarcinoma and NSCLC-NOS KRAS mutation 20-25% EGFR mutation 10-15% ALK rearrangement 5% Targetable with TKI EGFR - activating mutations exon 19 del, exon 21 L858R, other uncommon act. mutation - resistance mutations mostly exon 20 mutations

4 Anatomic sites of metastases Most common: bone, brain, liver, adrenal gland, pleura, lung, lymph node 1 Biological predisposition for metastatic organs might differ between molecular subgroups: implications for screening and (prophylactic) treatment Incidence of brain and bone metastases may be higher in EGFR+ patients 2-5 Biological predisposition? What about the other alterations? 1. Hendriks et al. Eur J Cancer (2015) 2. Matsumoto et al. Int J Cancer (2006) 3. Li et al. Clin Exp Metastasis (2016) 4. Guan et al. Med Oncol (2016) 5. Sholl et al. J Thor Oncol (2015)

5 Objective To evaluate the association between molecular status and metastatic organs at diagnosis in a nationwide stage IV non-squamous NSCLC cohort

6 Approach Patient selection Netherlands Cancer Registry (NCR) Dutch Pathology Registry (PALGA) - Identify all stage IV adenoca and NSCLC-NOS (year: 2013) - Exclude: patients with a recent history of cancer ( 5 years) - Age, gender, morphology, TNM stage, metastasis locations ( 3) - Microscopy and conclusion fields - Data extraction on molecular status - Identification mol. subgroups: EGFR+ KRAS+ ALK+ Triple-negative* * Triple-tested or EGFR and KRAS tested

7 Approach - statistical analysis Per metastatic organ: Univariable logistic regression analyses to determine risk factors: - Age (continuous) - Gender - Morphology (adenocarcinoma vs. NSCLC-NOS) - Local disease status ( T2 and N1 vs. T3 or N2) If p-value <0.2: variables included in multivariable analysis Multivariable logistic regression analyses to assess association with: Molecular status: EGFR+, KRAS+ and ALK+ with triple-negative

8 Included patients

9 Organs with metastases - overview Organ N % Organ N % Bone Skin Pleura Spleen Lung Peritoneum Brain Kidney Adrenal gland Thorax Liver Pancreas Extrathoracic lymph nodes Breast Soft tissue Thyroid Heart Meninges Less common metastatic sites (n 6) are not included in the table

10 Association molecular subgroups and metastatic organs

11 Conclusions NSCLC molecular status is associated with organs of metastases. EGFR+ patients had more often bone and pleural metastases, and less often brain and adrenal gland metastases than triple-negative patients. 54% of EGFR+ patients had bone metastases at diagnosis. Screening all EGFR+ patients for bone metastases is worth considering, aiming to prevent skeletal-related events. In contrast to previous studies: EGFR+ less often brain mets at diagnosis probably no biological predisposition for the brain

12 Acknowledgements Funding Lizza Hendriks Ronald Damhuis Jules Derks Marianne van der Mark Anne-Marie Dingemans Stefan Willems Michel van den Heuvel All participating laboratories Anne van Lindert Koos Koole Felix Broekhuizen Ellen de Weger Lucy Overbeek Bert Siebers Rinus Voorham