P-633 Non-small cell lung cancer (NSCLC) patients with undetectable epidermal growth factor receptor (EGFR) expression respond poorly to ZD1839 (Iressa)

S252

Poster Session I/Pathology

Methods: We retrospectively reviewed the history of NSCLC patients who had MBLs and had ever taken ZD1839. Patients were divided into 3 groups, group A: ZD1839 was the only treatment after MBLs were found; group B: patients with MBLs had been treated with brain radiotherapy or systemic chemotherapy before ZD1839 treatment; and group C: new MBL(s) developed during ZD1839 treatment. Patients who started to take ZD1839 within 2 months after completion of brain radiotherapy were excluded. Tumor response was evaluated separately in MBLs and extra-brain lesions (EBLs). Results: A total of 57 patients received ZD1839 250mg daily for treatment of advanced NSCLC. Sixteen patients had MBLs and were eligible in this study. ZD1839 was used as the 1st (n=l), 2nd (r-1=8), 3rd (n=4), or 4th (n=3) lines therapy in these patients. There were13 patients whose tumors were evaluable for response. The RR was 56.3% (9 PR, 1 SD, 3 PD), comparing with 42.1% in all patients. In group A (n=6), there were 2 PR, 3 SD, 1 PD in MBLs. RRs of MBLs and EBLs were 33% and 67%, respectively. Accordingly, one patient showed PR in both MBLs and EBLs, two had PR in EBLs but SD in MBLs, one with multiple MBLs showed SD in EBLs but PR in MBLs, and one had PD in both MBLs and EBLs. In group B (n=7), the EBLs showed 4PR, ISD 2PD. The MBLs were all in SD. There was no patient in group C. Conclusions: ZD1839 has active effect on MBLs in patients with advanced NSCLC and it is feasible to design a prospective study on this issue. Role of ZD 1839 in Patients Affected by Metastatic NSCLC ElP 632 Laura Lombardo’, Federico Cappuzzo’, Vanesa Gregorc?, Katia Bruna Bencardino4, Anna Spreafico 3, Stefalia Bartolini5, Stefano Schipani3, Irene Florianis, Giovanni Luca Ceresoli’, Lucia Grin??, Eugenio Villa3. ’ Division of Radiochemofherapy, scientific institute University Hospital San Raffaele, Milano, Italy; 2 Division of medical Oncology, Be//aria hbspita/, Bologna, Italy; 3 Division of Radiochemotherapy, Scientific institute University San Raffaele Hospital, Milano, Italy; 4 Division of Radiochemofherapy Scientific lnsfifute University San Raffaele Hospital, Milano, Italy; 5 Division of Medical Oncology, Be//aria Hospifal, Bologna, Italy; 6 Deparfment lstifuto Mario Negri, Milano, Italy; ‘Division of Radiochemotherapy, Scientific lnsfitute University San Raffaele Hospital Milan, ltaly Background: ZD1839 is an oral EGFR inhibitor that has shown to be active in NSCLC criteria in calization available. of overall advanced

patients. Brain metastases (BM) have been considered an exclusion phase ll/lll trials, due to the poorer prognosis of pts with brain loNo data regarding the activity of ZD1839 in this population are yet The aim of this study was to evaluate efficacy of ZD 1839, in terms response rate (RR) and time to progression (TTP), in patients with NSCLC, also with BM. Patients and methods: From January 2001, 114 consecutive pts with metastatic NSCLC, who progressed after I-2 lines of chemotherapy, were treated on compassionate bases with 250 mg of ZD 1839 until disease progression, unacceptable toxicity or refusal. Thirty pts (26%) had BM; M/F: 71/43; mean age 62 years (range 31-90); ECOG Performance Status O/1/2: 35/65/14; adenocarcinoma/bronchiolar-alveolar/squamous/unspecified NSCLC: 65/12/18/19; ZD1839 as lst/2nd/3th-line therapy: g/34/71; 22 of 30 pts with BM received brain RT treatment, whole brain/radiosurgery: 20/2. Treatment was well tolerated with pts reported only mild side effects. Results: Response to treatment has been evaluated in 101 pts. The overall clinical benefit was: 50%, median TTP of the whole group was: 3 months (range: I-18 months). In the group of pts with BM, we observed 5 (18%) partial response (PR), 9 (32%) stable disease (SD), for an overall clinical benefit of 50%; in the group of pts without BM was observed 8 PR (11%) and 29 SD (40%) for an overall clinical benefit of 51%. Median TTP was 4 months (range: 1-14 months) for pts with BM and 3 months (range: 1-18 months) for pts without BM (HR: 1.22, 95%CI: 0.74-2.00, p
I P 633

Non-small cell lung cancer (NSCLC) patients with undetectable epiclermal growth factor receptor (EGFR) expression respond poorly to ZD1839 (Iressa)

Clavton R. Polowy’ , John S. Coon’, William T. Leslie’, Lucia DiNunno’ , lvanka Lukic’ , Gina Kanevsky’ , Meryl Gale’, Larry E. Morrisons, Steven A. Seelig’, Philip Bonomi’ ’ Rush Medical College, Chicago, USA; p Vysis, Chicago, USA Phase II studies have shown that ZD1839 produces approximately a 10% response rate in previously treated NSCLC patients (pts). There is relatively little known about the relationship between molecular profiles and NSCLC response to ZD1839. The goal of this study was to assess immunohistochemistry

and Molecular Taxonomy (IHC) and flourescence-in-situ-hybridization (FISH) as predictors of response to ZD1839. A total of 104 consecutive pts were enrolled in the Expanded Access Trial; seven pts died of progressive disease prior to starting ZD1839. Ninetyseven pts (53 female, 44 male; median age 68 years: 48 adenocarcinomas vs. 49 other histologies) received ZDI 839, 500 mg po on Day 1, then 250 mg po daily. Pts were evaluated monthly and had CT scans every 2 months; the median follow-up was 170 days. Overall response rate was 6.2% (ICR, 5PR), and 16 pts (16.5%) had stable disease (SD). Median Kaplan-Meier survival and progression-free interval (PFI) were 180 and 59 days, respectively. The Fisher’s Exact test was used to evaluate associations. A greater proportion of pts with adenocarcinoma responded or had SD (pi.05). of the 97 pts treated, 44 had tissue available for molecular profiles. None of the 27 pts who lacked expression of EGFR by IHC responded to ZD1839, compared to 1 complete and 3 partial responses in pts with EGFR positive tumors (p<.O2); the level of expression was insignificant. Median Kaplan-Meier PFI for pts with and without EGFR expression was 201 and 68 days, respectively (p<.Ol). For 1 l/42 pts with both EGFR expression and chromosome copy number (FISH) >2.5, four (36%) responded (CR+PR) compared to 0% of the other pts (p<.OO3). Nine pts had EGFR amplification by FISH (ratio>l.5, Vysis SpectrumOrange-LSI EGFR probe) which was associated with EGFR expression (p<.O2), female sex (Pc.04) and adenocarcinoma histology (pc.04). Defining the molecular profile for response to ZD1839 is still at an early stage, but it appears that detectable EGFR expression and chromosome 7 copy number may have predictive value for response and PFI in pts on ZD1839.

THURSDAY, 14 AUGUST 2003

Pathology I.P

634

and Molecular

Taxonomy

Evaluation of the Carcinogenic Risk of Depleted Uranium rn the Lungs of Gulf War Veterans

Asaf Durakovic’, Len Dietz”, Isaac Zimmerman3. ‘Uranium Medical Research Centre, Washington, USA; ’ Uranium Medical Research Centre, Niskayuna, USA; 3 Uranium Medical Research Centre, Waterport, USA The aim of this work was to determine the burden of inhaled depleted uranium (DU) oxide particles in the lungs of British, Canadian, and US Gulf War I veterans at time-zero of exposure. In a group of thirteen veterans whose urine was quantitatively analyzed for DU isotopes by thermal ionization mass spectrometry (TIMS) nine years after exposure, five tested positive for the presence of DU. Our method presents a new, non-invasive technique for calculating a cumulative alpha-particle radiation dose from DU isotopes in the lungs of exposed veterans We have utilized a method of determining the minimum biological half-life of DU from the derivation of the Battelle Model of simulated interstitial lung fluid. The values of the minimum biological half-life determined the total inhalational exposure to DU isotopes at time-zero. The integration of the total number of alpha particle events from time-zero to ten years after exposure has been calculated as a radiation dose. The average of 24-hour urine specimens of veterans containing 3.89 x IO-’ micrograms (kg) of DU corresponds to inhalational exposure of 0.34 milligrams (mg) of DU at time-zero with an alpha radiation dose to the lungs of 1.14 milliSieverts (mSv) during the first year and a total of 5.77 mSv over ten years. The determined values slightly exceed the maximum permissible inhalational dose of uranium and suggest a need for additional research on metabolic pathways, biological half-life, and DU induced risk of malignant alterations in the respiratory system of the exposed population.

I

P 635

Chromosomal Instability Detected by Fluorescence in Situ Hybridization in Surgical Specimens of Non-small Cell Lung Cancer Is Associated with Poor Survival

Haruhiko Nakamura, Hisashi Saji, Akihiko Ogata, ldiris Aute, Takamoto Saijo, Harubumi Kato. Dept. of Surgery Tokyo Medical University, Tokyo, Japan Chromosomal instability (CIN) in non-small cell lung cancer (NSCLC) has yet to be well studied. We examined the relationship between CIN detected by fluorescence in situ hybridization (FISH) and survival in patients with NSCLC. Touch preparations from 50 surgical specimens of NSCLC were studied. Tumors included 34 adenocarcinomas, 15 squamous cell carcinomas, and 1 large cell carcinoma. The pathologic stage was IA in 14, IB in 17, II9 in 8, IIIA in 9, and IIIB in 2 cases. Enumeration of chromosomes 3, IO, 11, and 17 was used to determine which tumors carried CIN. The association between CIN and survival also was analyzed. Disomy was most common, but tetrasomy and trisomy of the examined chromosomes were seen frequently. Fourteen tumors (28%) showed heterogeneity of all four chromosomes examined and were judged to