- Email: [email protected]
O-123 A prospective study to correlate EGFR mutations with gefitinib response in early stage NSCLC
Oral Sessions/Pathology personalized t]'eatment. The use of gene expression data to preclct the status of oneegenic signaling pathways provides an opportunity to better characterize the oncogenic process, and may provide a path to selecting targeted therapeutics Investigations are underway for EGFR. HEIR2-neu. and VEGF pathways
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prospective study to correlate EGFR mUtaUons with gefltlnlb response In early stags NSCLC
N. Rlzvi. W. Pao. V. Miller. V. Rusch. R. Heelan. M. Ladanyl. P. Ginex. L. Tyson. M. Zakowski. M. Krls. Memorial S/oan Kettenng Cancer Center, New York, USA
$43
CS. 12 in S. Open & close thoracotomies were 4 CS and 6 S. Results wlll be updated for the July 200,5 meeting Conclusions: Early results suggest similar morbidity and mortality when comparing CS to S alone in this population of pts Completeness of resection. an important determinant of survival after resection, was improved with the CS strategy Randomized tTials compabng preop to adjuvant chemotherapy are warranted Supported by SWOG CA30102
Pathology
Background: Retrespect]ve analyses have correlated EGFR tyrosme ~nase domain mutations with response to gefit]nib. In this prospective study we test the bypcthasis that specific mutat]ens in the EGFR gone correlate vath response to gefit]nib. To accomplish this goal. fresh frozen tissue was prrecured on all patients pre~reatment for mutat]enal analysis and the patient population was "ennched" for the presence of EGFR mutations. Methods: Eligible patients have operable and resectable Stage I / II NSCLC with dinieal features that correlate with response to gefrdnib and the presence of EGFR mutations (~<10 pack year sm eking history and/or features of BAC) All patients undergo core biopsy to obtain tumor DNA followed by tTeatment with geftinib for at least 21 days pre-surgery with CT scan !ore- and post~]er~nib. and tumors are assessed for EGFR mutafiens (exons 18 24) Patients with a radiographic response (~>2,5% reduction by bidimensional measurement) to gefltinib preoperat?vely and/or whose tumors contain EGFR mutations continue gefltinib for 2 years post surgery. Patients will be followed for time to recurrence and survival. Results: 10 patients have been enrolled. 7/'10 had a component of BAC and 3/'10 had adenocarclnoma. 5/'10 patients had a less than 10 pack year smoking history. All 10 patients underwent core biopsy for tumor DNA sequenang EGFR mutations were detected in 2/9 patients in preoperative specimens and were confirmed in surgical resection specimens (1 exert 21 L858R mutation. 1 exon 19 deletion) A 22% and ,50% response was observed in these 2 patients 2 patients without evidence of EGFR mutation had a 25% and 43% response No dose limiting texicities were observed 3/4 patients with a response are continuing post-operative gertinib Cone patient developed a rash with postoperative ger~nib and has held treatment) Conduslons: Pree-treatment core biopsy for EGFR mutation stuclas yielded suffioent tumor DNA for EGFR mutational analys~s in all 10 patients. By using clinical charactenst]cs to enrich our patient cohort. 2/9 patients were found to have an EGFR mutation and 4/9 patients demonstrated a radiologic response to preoperative gefit]nib. Responses were observed after only 21 days of gefltinib. 50 patients are planned and accrual continues. [ O ~ 2 ~ $9900: Preliminary "surgical" results e t a phase III trial of surgery
alone or surgery plus preoperative (preop) pactltaxel/carboplatln (PC) chemo~erapy In early stage non-small ceil lung cancer (NSCLC) E. Vallieres ~, K. Pisters 2. J. Crowley~ . K. Chansky ~. P. Bunn 4. D. Gandara ~ I Swe~sh Cancer/'nstJtute, SeatYe, Washington, USA, 2UT M D Anderson Cancer, Houston, USA: 3SWOG Statist/ca~' Center, SeatUe, USA: 4Umvers~ty or Colorado Cancer Center, Denver, USA, ~University of California Davis Cancer Center, Sacramento, USA
Background: Prepp PC was shown to be feasible, safe and seemed to improve survival over histoncsl contTclS in a large phase II tTial in early stage NSCLC (BLOT) $g950 was undertaken to determine whether 3 cycles of prepperafive PC could improve survival compared to surgery alone Secondary endpoints included a compabson of operative morbicity and mortality in the 2 study arms ACOSOG. ECOG. NCIC. NCCTG and RTOG also participated Methods: Consenting pts with clinical stage T2N0. T1 2N1. and T3N0 1 NSCLC were stratified by clinical stage IB/IIA vs IIB/'IIIA and randomized to preop PC every 3 weeks for 3 cycles 9 (CS) or surgery alone iS). Eligible pts had performance status 0-1. age ~>18years (yrs). predicted post4"asect]on FEV1 ~> 1.0L. Surgical resection was at least a Iobectomy and meclastinal lymph node sampling. This study was a prospective, randomized, stratified phase III thai. Current median follow4Jp is 24 months (range 1-60) Results: $9900 was dosed prematurely in 07;04 based on the reported positive adjuvant data. At the time of study dcsure. 354 pts had been entered. 174 pts were randomized to S and 180 to CS Pt characteristics: median age 64yrs. 66% male. 36% PS 1.63% T2N0. ,5% T1NI. 19% T2NI. 10% T3N0 At ti"is stage, morbidity data is available on 282 pts (128 pts CS. 154 pts S) There were 5 deaths in the CS arm. 3 in the S arm (NS) Operative morbidity was very similar in between the 2 groups lout there was a non-stafiseally significant tTend for more events in the CS arm Post-operative Coostop) infections (pneumonia. wound infection and empyema) occurred in 13 CS pts. in 7 S pts (p 0 07) Cardiovascular events (MI. DVT. PE and CVA) ocourred in 5 CS pts and in 2 S lots. (p= 0.16R) Respiratory failure occurred in 9 and 7 lots respectively and 2 pts requred tracheostomy in the CS arm. 3 in the S arm. Status of resection is available in 289 pts. (133 CS. 156 S pts) R0 resection were achieved in 95% of CS. 88% of S. Co= 0.03) Only 2 pts had R1/'IR2 in
Histopathological entities and molecular profiles
Tuesday, 5 July 2005 ~Gene
14:30-16:30
expression profiling distinguishes large ceil lung cancer associated with disparate clinical outcomes
R. Battafarano. J. Lewls. J. Ritter. B. Mayers. J. Cooper. G. Patterson. M. Watson. WaShington Untverstty tn St. Louts, St. Louts, Mtsoun, USA
Background: Large coil neuroendoalne ca~nomas (LCNEC) of the lung cisplay immunohistochemical characteristics common to neureendocnne tumors, but share histologlsal features of uncifferent]ated large coil ca~nomas (LILCC) We have recently shown that survival for patients with LCNEC was significantly lower than that observed in patients with ULCC (30 2% vs 71 3%. p 0 013). even in patients with stage I disease (32 1% vs 80 0%. p 0 008) The objec0ve of this study was to identify patterns of gene expression that could cifferenfiate between these two variants of NSCLC. toward the development of clinically useful molecular biomarkers and a better understancing of the molecular biology associated with their disparate clinical outcomes Methods: Snap frozen tumor tissue from cases of LCNEC i n = 9) and ULCC i n = 5) were collected under IRB approval, sect]ened and histologically reviewed to confirm neoplastic coil content, and utilized for RNA isolation. Biotinylated cRNA targets were generated from each IRNA sample, and these in turn ware hybridized to AffymetTix U133Plus2 human GeneChip ® microarrays using standard protocols Signal data from approximately 54.000 probe pair sequences was normalized and filtered for invanant and non
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Expression profiling of matrix mstalloprotslnases (MMPs) and Inhlbltors reveals a novel prognostic role for MMP-19 In paUents with non-small cell lung cancer
F. Black~all < . M. Pint]lie 2. N. L i J . C. Pemington 4. C. Zhu 3. F. Shepherd. D Edwards 4. M Tsao ~ lChrist]e Hospital NHS Trust, Manchester, UI~ 2University Health Network-Princess Margaret Hospital, Toronto, Canada, 3Ontario Cancer lnsbtute/Pnncess Margaret Hospital, Umverslty Health Network and Department ot Laboretory Me~cme and Patho~ologg Uruverslty Toronto, Canada, 4School of Biological Sciences, University of East Angtia, Not~ch, UK
Background: MaITIx metallopretelnases (MMPs). and their endogenous inhlbltors (TIMP) and RECK are believed to be crlt]eal for angiogenesis and tumour invasion but there are conflicting reports for thedr importance in non small coil lung cancer (NSCLC). Also. clinical ~als to evaluate MMP inhlbltors
~0~A
prospective study to correlate EGFR mUtaUons with gefltlnlb response In early stags NSCLC
N. Rlzvi. W. Pao. V. Miller. V. Rusch. R. Heelan. M. Ladanyl. P. Ginex. L. Tyson. M. Zakowski. M. Krls. Memorial S/oan Kettenng Cancer Center, New York, USA
$43
CS. 12 in S. Open & close thoracotomies were 4 CS and 6 S. Results wlll be updated for the July 200,5 meeting Conclusions: Early results suggest similar morbidity and mortality when comparing CS to S alone in this population of pts Completeness of resection. an important determinant of survival after resection, was improved with the CS strategy Randomized tTials compabng preop to adjuvant chemotherapy are warranted Supported by SWOG CA30102
Pathology
Background: Retrespect]ve analyses have correlated EGFR tyrosme ~nase domain mutations with response to gefit]nib. In this prospective study we test the bypcthasis that specific mutat]ens in the EGFR gone correlate vath response to gefit]nib. To accomplish this goal. fresh frozen tissue was prrecured on all patients pre~reatment for mutat]enal analysis and the patient population was "ennched" for the presence of EGFR mutations. Methods: Eligible patients have operable and resectable Stage I / II NSCLC with dinieal features that correlate with response to gefrdnib and the presence of EGFR mutations (~<10 pack year sm eking history and/or features of BAC) All patients undergo core biopsy to obtain tumor DNA followed by tTeatment with geftinib for at least 21 days pre-surgery with CT scan !ore- and post~]er~nib. and tumors are assessed for EGFR mutafiens (exons 18 24) Patients with a radiographic response (~>2,5% reduction by bidimensional measurement) to gefltinib preoperat?vely and/or whose tumors contain EGFR mutations continue gefltinib for 2 years post surgery. Patients will be followed for time to recurrence and survival. Results: 10 patients have been enrolled. 7/'10 had a component of BAC and 3/'10 had adenocarclnoma. 5/'10 patients had a less than 10 pack year smoking history. All 10 patients underwent core biopsy for tumor DNA sequenang EGFR mutations were detected in 2/9 patients in preoperative specimens and were confirmed in surgical resection specimens (1 exert 21 L858R mutation. 1 exon 19 deletion) A 22% and ,50% response was observed in these 2 patients 2 patients without evidence of EGFR mutation had a 25% and 43% response No dose limiting texicities were observed 3/4 patients with a response are continuing post-operative gertinib Cone patient developed a rash with postoperative ger~nib and has held treatment) Conduslons: Pree-treatment core biopsy for EGFR mutation stuclas yielded suffioent tumor DNA for EGFR mutational analys~s in all 10 patients. By using clinical charactenst]cs to enrich our patient cohort. 2/9 patients were found to have an EGFR mutation and 4/9 patients demonstrated a radiologic response to preoperative gefit]nib. Responses were observed after only 21 days of gefltinib. 50 patients are planned and accrual continues. [ O ~ 2 ~ $9900: Preliminary "surgical" results e t a phase III trial of surgery
alone or surgery plus preoperative (preop) pactltaxel/carboplatln (PC) chemo~erapy In early stage non-small ceil lung cancer (NSCLC) E. Vallieres ~, K. Pisters 2. J. Crowley~ . K. Chansky ~. P. Bunn 4. D. Gandara ~ I Swe~sh Cancer/'nstJtute, SeatYe, Washington, USA, 2UT M D Anderson Cancer, Houston, USA: 3SWOG Statist/ca~' Center, SeatUe, USA: 4Umvers~ty or Colorado Cancer Center, Denver, USA, ~University of California Davis Cancer Center, Sacramento, USA
Background: Prepp PC was shown to be feasible, safe and seemed to improve survival over histoncsl contTclS in a large phase II tTial in early stage NSCLC (BLOT) $g950 was undertaken to determine whether 3 cycles of prepperafive PC could improve survival compared to surgery alone Secondary endpoints included a compabson of operative morbicity and mortality in the 2 study arms ACOSOG. ECOG. NCIC. NCCTG and RTOG also participated Methods: Consenting pts with clinical stage T2N0. T1 2N1. and T3N0 1 NSCLC were stratified by clinical stage IB/IIA vs IIB/'IIIA and randomized to preop PC every 3 weeks for 3 cycles 9 (CS) or surgery alone iS). Eligible pts had performance status 0-1. age ~>18years (yrs). predicted post4"asect]on FEV1 ~> 1.0L. Surgical resection was at least a Iobectomy and meclastinal lymph node sampling. This study was a prospective, randomized, stratified phase III thai. Current median follow4Jp is 24 months (range 1-60) Results: $9900 was dosed prematurely in 07;04 based on the reported positive adjuvant data. At the time of study dcsure. 354 pts had been entered. 174 pts were randomized to S and 180 to CS Pt characteristics: median age 64yrs. 66% male. 36% PS 1.63% T2N0. ,5% T1NI. 19% T2NI. 10% T3N0 At ti"is stage, morbidity data is available on 282 pts (128 pts CS. 154 pts S) There were 5 deaths in the CS arm. 3 in the S arm (NS) Operative morbidity was very similar in between the 2 groups lout there was a non-stafiseally significant tTend for more events in the CS arm Post-operative Coostop) infections (pneumonia. wound infection and empyema) occurred in 13 CS pts. in 7 S pts (p 0 07) Cardiovascular events (MI. DVT. PE and CVA) ocourred in 5 CS pts and in 2 S lots. (p= 0.16R) Respiratory failure occurred in 9 and 7 lots respectively and 2 pts requred tracheostomy in the CS arm. 3 in the S arm. Status of resection is available in 289 pts. (133 CS. 156 S pts) R0 resection were achieved in 95% of CS. 88% of S. Co= 0.03) Only 2 pts had R1/'IR2 in
Histopathological entities and molecular profiles
Tuesday, 5 July 2005 ~Gene
14:30-16:30
expression profiling distinguishes large ceil lung cancer associated with disparate clinical outcomes
R. Battafarano. J. Lewls. J. Ritter. B. Mayers. J. Cooper. G. Patterson. M. Watson. WaShington Untverstty tn St. Louts, St. Louts, Mtsoun, USA
Background: Large coil neuroendoalne ca~nomas (LCNEC) of the lung cisplay immunohistochemical characteristics common to neureendocnne tumors, but share histologlsal features of uncifferent]ated large coil ca~nomas (LILCC) We have recently shown that survival for patients with LCNEC was significantly lower than that observed in patients with ULCC (30 2% vs 71 3%. p 0 013). even in patients with stage I disease (32 1% vs 80 0%. p 0 008) The objec0ve of this study was to identify patterns of gene expression that could cifferenfiate between these two variants of NSCLC. toward the development of clinically useful molecular biomarkers and a better understancing of the molecular biology associated with their disparate clinical outcomes Methods: Snap frozen tumor tissue from cases of LCNEC i n = 9) and ULCC i n = 5) were collected under IRB approval, sect]ened and histologically reviewed to confirm neoplastic coil content, and utilized for RNA isolation. Biotinylated cRNA targets were generated from each IRNA sample, and these in turn ware hybridized to AffymetTix U133Plus2 human GeneChip ® microarrays using standard protocols Signal data from approximately 54.000 probe pair sequences was normalized and filtered for invanant and non
~0~
Expression profiling of matrix mstalloprotslnases (MMPs) and Inhlbltors reveals a novel prognostic role for MMP-19 In paUents with non-small cell lung cancer
F. Black~all < . M. Pint]lie 2. N. L i J . C. Pemington 4. C. Zhu 3. F. Shepherd. D Edwards 4. M Tsao ~ lChrist]e Hospital NHS Trust, Manchester, UI~ 2University Health Network-Princess Margaret Hospital, Toronto, Canada, 3Ontario Cancer lnsbtute/Pnncess Margaret Hospital, Umverslty Health Network and Department ot Laboretory Me~cme and Patho~ologg Uruverslty Toronto, Canada, 4School of Biological Sciences, University of East Angtia, Not~ch, UK
Background: MaITIx metallopretelnases (MMPs). and their endogenous inhlbltors (TIMP) and RECK are believed to be crlt]eal for angiogenesis and tumour invasion but there are conflicting reports for thedr importance in non small coil lung cancer (NSCLC). Also. clinical ~als to evaluate MMP inhlbltors