Association between new-onset hypothyroidism and clinical response in patients treated with tyrosine kinase inhibitor therapy in phase I clinical trials.
Tyrosine kinase inhibitor (TKI)-induced thyroid dysfunction has been identified as an important but manageable adverse effect of targeted therapy. Several studies have suggested that patients who develop hypothyroidism respond better to TKIs, but this relationship is not well elucidated. We evaluated the relationship between new-onset hypothyroidism and clinical response in patients with advanced cancers treated with TKIs at our institution.



We retrospectively reviewed records for patients from four clinical trials that included at least one TKI  therapy between January 2006 and December 2011. Patients with preexisting thyroid disease, including thyroid cancer, hypothyroidism, or hyperthyroidism, were excluded. Analysis of 197 patients was performed. Response was determined using RECIST 1.0. Clinical benefit was described as complete response, partial response, or stable disease greater than 4 months. Multivariable logistic regression analysis was performed to correlate patient characteristics with clinical response.



The median age for the 197 patients was 58 years (range, 13-85 years), and 56 % were female. Of the 197 patients, 52 (26 %) developed hypothyroidism after therapy. Clinical benefit rates were 50 % in patients with new-onset hypothyroidism versus 34 % in patients without hypothyroidism. In the univariate model, the odds ratio (OR) for new-onset hypothyroidism was 1.9 [95 % confidence interval (CI) (1.0, 3.6) and p = 0.05]. We grouped tumor types into six categories (breast, colorectal carcinoma, melanoma, non-small cell lung cancer, pancreas, and other). When adjusted for tumor type, age (>50 years) and sex, the OR was 2.9 [95 % CI (1.3, 6.5) and p = 0.012] for new-onset hypothyroidism.



New-onset hypothyroidism was associated with favorable clinical response in patients who received TKI treatment.
Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mehmet Asim
MA
Bilen
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 455, Houston, TX, 77030, USA.
Amy
A
Patel
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Kenneth R
KR
Hess
Department of Hematology/Oncology, Banner MD Anderson Cancer Center, Gilbert, AR, USA.
Javier
J
Munoz
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Naifa L
NL
Busaidy
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 455, Houston, TX, 77030, USA.
Jennifer J
JJ
Wheler
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 455, Houston, TX, 77030, USA.
Filip
F
Janku
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 455, Houston, TX, 77030, USA.
Gerald S
GS
Falchook
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 455, Houston, TX, 77030, USA.
David S
DS
Hong
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 455, Houston, TX, 77030, USA.|Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Funda
F
Meric-Bernstam
Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mouhammed Amir
MA
Habra
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 455, Houston, TX, 77030, USA. anaing@mdanderson.org.
Aung
A
Naing
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017321:Clinical Trials, Phase I as Topic; D005260:Female; D006801:Humans; D007037:Hypothyroidism / Q000139:chemically induced* / Q000453:epidemiology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases
Clinical response; Hypothyroidism; Phase I; Toxicity; Tyrosine kinase inhibitor