Clinical and toxicity predictors of response and progression to temsirolimus in women with recurrent or metastatic endometrial cancer.
OBJECTIVE
Temsirolimus (TEM) has recently shown activity (NCIC CTG phase II trial) in endometrial cancer (EC). Despite EC having a high rate of PTEN mutation, in this trial activity was independent of PTEN and other molecular markers. We explored whether treatment related toxicity occurring in cycle one was predictive of outcomes.


METHODS
Patients were those enrolled on two sequential phase II studies of the NCIC CTG that evaluated single agent TEM in women with recurrent or metastatic chemotherapy naïve or treated EC. An exploratory landmark analysis examined the relationship between early treatment related toxicities as well as prior chemotherapy and efficacy outcomes (response, progression, and tumor size shrinkage) in univariate and multivariate analyses. The relationship between molecular markers and outcomes was also reexamined in patients.


RESULTS
Mucositis, diarrhea, decreased absolute neutrophil count, as well as elevated glucose, or cholesterol were not independent predictors of response or progression. Highest fasting triglyceride predicted for a 3.5% tumor shrinkage from baseline. Women previously treated with chemotherapy were at 7.37 times greater risk of progression and experienced 20.9% increased tumor growth compared to chemotherapy naïve women. Molecular markers were not predictors of response or progression.


CONCLUSIONS
Except for elevation in fasting triglyceride being associated with minimal tumor shrinkage, no other relationship between efficacy and TEM induced adverse events was found. mTOR inhibition activity in EC seems greatest in chemo-naïve patients. Future studies of mTOR inhibitors in EC should focus on women without prior chemotherapy while continuing to explore molecular mechanisms of benefit.
Ottawa Hospital Research Institute, University of Ottawa, 501 Smyth Road, Ottawa, Ontario K1H 5L3, Canada. Electronic address: rgoodwin@toh.on.ca.
Rachel A
RA
Goodwin
Rahima
R
Jamal
Dongsheng
D
Tu
Wendy
W
Walsh
Janet
J
Dancey
Amit M
AM
Oza
Laurie
L
Elit
Elizabeth A
EA
Eisenhauer
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism; D018196:Carcinoma, Adenosquamous / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D004334:Drug Administration Schedule; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012189:Retrospective Studies; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C401859:temsirolimus; D020123:Sirolimus
Endometrial cancer; Predictors of response; Temsirolimus; mTOR inhibitors