Abstract:
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Background: Gefitinib (GEF) may act by
inhibiting anti-apoptotic signals transduced by mutant EGFR kinase
(Science 305:1163,04). Cell culture assays with cell death endpoints
could be informative for GEF activity. Methods: We tested 568
biopsies of fresh human tumors (TUM) with 2 concentrations of GEF (22
and 11 µg/ml) for 96 hrs, each with 2 separate cell death
endpoints
(DISC and MTT), detailed methods http://weisenthal.org/w_ovarian_cp.pdf.
Results classified as resistant (RES), intermediate (INT), or sensitive
(SEN) based on means and standard deviations of training set data (ref
ibid), reported prospectively to 3 different physicians: surgeon,
pathologist, and oncologist. Assay evaluability rate > 90%. Results:
Based on overall % control cell death, the following
TUM showed (on average) no greater RES or SEN than the universe of 568
assays: NSCLC (n = 72), colon (33), breast (106), ovarian (109),
melanoma (23), pancreatic (20), endometrial (12). The following showed
(on avg) significantly greater RES: soft tissue sarcomas (n = 24),
carcinoid/islet (16), renal (15), and mesothelioma (8). For NSCLC,
there was no avg difference between female (32) vs male (35) or
untreated (34) vs previously treated (38). For 32 unRxd pts with
survival data, there was no significant difference in overall surv for
20 pts with prospectively reported GEF RES (GR) assays vs 12 pts with
SEN or INT (GSI) assays. For 31 pts with prior chemoRx (med surv = 155
days), there was significant survival disadvantage for 14 pts with
prospectively reported GR vs 17 pts with GSI (median 85 vs 380 days, P2
< 0.0001, HR 3.7; 95% C.I. 2.6-19) (Click here to see Kaplan-Meier
Curves). For pts with known post-assay Rx, there were 7 pts with
GSI subsequently receiving GEF or erlotinib (ERLOT), with med surv =
485 days; 9 pts with GSI not receiving GEF or ERLOT, med surv = 135
days; 10 pts with GR not receiving GEF or ERLOT, med surv = 76 days,
and 3 pts with GR receiving GEF or ERLOT, med surv = 75 days. Survival
of group of 7 pts was significantly greater than those of groups of 9,
10, and 3 pts (P2 = 0.037, P2 < 0.0001, and P2 = 0.0008,
respectively, click here to
see
Kaplan-Meier Curves). Conclusions: GEF-induced cell death
in cultures of fresh TUM from prev-treated NSCLC pts may identify pts
with favorable prognosis, particularly when treated with GEF or ERLOT.
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