The Effect of Gene Alterations and Tyrosine Kinase Inhibition on Survival and Cause of Death in Patients With Adenocarcinoma of the Lung and Brain Metastases.
Lung cancer remains the most common cause of both cancer mortality and brain metastases (BM). The purpose of this study was to assess the effect of gene alterations and tyrosine kinase inhibition (TKI) on median survival (MS) and cause of death (CoD) in patients with BM from lung adenocarcinoma (L-adeno).



A multi-institutional retrospective database of patients with L-adeno and newly diagnosed BM between 2006 and 2014 was created. Demographics, gene alterations, treatment, MS, and CoD were analyzed. The treatment patterns and outcomes were compared with those in prior trials.



Of 1521 L-adeno patients, 816 (54%) had known alteration status. The gene alteration rates were 29%, 10%, and 26% for EGFR, ALK, and KRAS, respectively. The time from primary diagnosis to BM for EGFR-/+ was 10/15 months (P=.02) and for ALK-/+ was 10/20 months (P<.01), respectively. The MS for the group overall (n=1521) was 15 months. The MS from first treatment for BM for EGFR and ALK-, EGFR+, ALK+ were 14, 23 (P<.01), and 45 (P<.0001) months, respectively. The MS after BM for EGFR+ patients who did/did not receive TKI before BM was 17/30 months (P<.01), respectively, but the risk of death was not statistically different between TKI-naïve patients who did/did not receive TKI after the diagnosis of BM (EGFR/ALK hazard ratios: 1.06 [P=.84]/1.60 [P=.45], respectively). The CoD was nonneurologic in 82% of patients with known CoD.



EGFR and ALK gene alterations are associated with delayed onset of BM and longer MS relative to patients without these alterations. The CoD was overwhelmingly nonneurologic in patients with known CoD.
Minneapolis Radiation Oncology and University of Minnesota Gamma Knife Center, Minneapolis, Minnesota. Electronic address: psperduto@mropa.com.
Paul W
PW
Sperduto
Sloan Kettering Cancer Center, New York, New York.
T Jonathan
TJ
Yang
Sloan Kettering Cancer Center, New York, New York.
Kathryn
K
Beal
MD Anderson Cancer Center, Houston, Texas.
Hubert
H
Pan
MD Anderson Cancer Center, Houston, Texas.
Paul D
PD
Brown
University of Minnesota, Masonic Cancer Center, Biostatistics, Minneapolis, Minnesota.
Ananta
A
Bangdiwala
University of Minnesota, Masonic Cancer Center, Biostatistics, Minneapolis, Minnesota.
Ryan
R
Shanley
University of Colorado-Denver, Denver, Colorado.
Norman
N
Yeh
University of Colorado-Denver, Denver, Colorado.
Laurie E
LE
Gaspar
University of California-San Francisco, San Francisco, California.
Steve
S
Braunstein
University of California-San Francisco, San Francisco, California.
Penny
P
Sneed
Duke University, Durham, North Carolina.
John
J
Boyle
Duke University, Durham, North Carolina.
John P
JP
Kirkpatrick
Massachusetts General Hospital, Boston, Massachusetts.
Kimberley S
KS
Mak
Massachusetts General Hospital, Boston, Massachusetts.
Helen A
HA
Shih
University of Maryland, Baltimore, Maryland.
Alex
A
Engelman
CHUM, University of Montreal, Montreal, Quebec, Canada.
David
D
Roberge
Dana Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.
Nils D
ND
Arvold
Dana Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.
Brian
B
Alexander
Dana Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.
Mark M
MM
Awad
Yale University, New Haven, Connecticut.
Joseph
J
Contessa
Yale University, New Haven, Connecticut.
Veronica
V
Chiang
Mayo Clinic, Rochester, New York.
John
J
Hardie
Mayo Clinic, Rochester, New York.
Daniel
D
Ma
University of Minnesota, Department of Hematology Oncology, Minneapolis, Minnesota.
Emil
E
Lou
Duke University, Durham, North Carolina.
William
W
Sperduto
University of Maryland, Baltimore, Maryland.
Minesh P
MP
Mehta
D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000556:secondary*; D000368:Aged; D000369:Aged, 80 and over; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D015994:Incidence; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015995:Prevalence; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D014481:United States / Q000453:epidemiology
D000970:Antineoplastic Agents; D005819:Genetic Markers; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases