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Supplementary Figure 1 from Identification of a Novel Tumor Suppressor Gene p34 on Human Chromosome 6q25.1

In this study, we observed loss of heterozygosity (LOH) in human chromosomal fragment 6q25.1 in sporadic lung cancer patients. LOH was observed in 65% of the 26 lung tumors examined and was narrowed down to a 2.2-Mb region. Single-nucleotide polymorphism (SNP) analysis of genes located within this region identified a candidate gene, termed p34. This gene, also designated as ZC3H12D, C6orf95, FLJ46041, or dJ281H8.1, carries an A/G nonsynonymous SNP at codon 106, which alters the amino acid from lysine to arginine. Nearly 73% of heterozygous lung cancer tissues with LOH and the A/G SNP also exhibited loss of the A allele. In vitro clonogenic and in vivo nude mouse studies showed that overexpression of the A allele exerts tumor suppressor function compared with the G allele. p34 is located within a recently mapped human lung cancer susceptibility locus, and association of the p34 A/G SNP was tested among these families. No significant association between the less frequent G allele and lung cancer susceptibility was found. Our results suggest that p34 may be a novel tumor suppressor gene involved in sporadic lung cancer but it seems not to be the candidate familial lung cancer susceptibility gene linked to chromosomal region 6q23-25. [Cancer Res 2007;67(1):93–9]

In this study, we observed loss of heterozygosity (LOH) in human chromosomal fragment 6q25.1 in sporadic lung cancer patients. LOH was observed in 65% of the 26 lung tumors examined and was narrowed down to a 2.2-Mb region. Single-nucleotide polymorphism (SNP) analysis of genes located within this region identified a candidate gene, termed p34. This gene, also designated as ZC3H12D, C6orf95, FLJ46041, or dJ281H8.1, carries an A/G nonsynonymous SNP at codon 106, which alters the amino acid from lysine to arginine. Nearly 73% of heterozygous lung cancer tissues with LOH and the A/G SNP also exhibited loss of the A allele. In vitro clonogenic and in vivo nude mouse studies showed that overexpression of the A allele exerts tumor suppressor function compared with the G allele. p34 is located within a recently mapped human lung cancer susceptibility locus, and association of the p34 A/G SNP was tested among these families. No significant association between the less frequent G allele and lung cancer susceptibility was found. Our results suggest that p34 may be a novel tumor suppressor gene involved in sporadic lung cancer but it seems not to be the candidate familial lung cancer susceptibility gene linked to chromosomal region 6q23-25. [Cancer Res 2007;67(1):93–9]

Purpose We conducted a phase II study of carboplatin and irinotecan in patients with advanced non-small cell lung cancer (NSCLC). In addition, we studied the correlation between certain genotypes of enzymes involved in irinotecan metabolism with efficacy and toxicity. Patients and Methods Patients with stage IIIB, IV, or recurrent NSCLC received a combination of irinotecan and carboplatin every 3 weeks at a dose of 200 mg/m2 and area under the curve of 5. Pharmacogenomic analysis was performed on several genes of interest (ABCB1, CYP3A4*1B, ERCC2, GSTP1, UGT1A1*28, and XRCC1). Results Forty-two patients enrolled between December 2001 and January 2004. Six patients achieved partial responses (14%), and 19 (45%) had stable disease. The median progression-free survival was 6.9 months. The median overall survival was 11.7 months, with 1-year overall survival of 42%. The most common toxicities were hematologic; grade 3 or 4 neutropenia was experienced by 26 patients (62%) during treatment, and 15 patients (36%) experienced grade 3 or 4 thrombocytopenia. The homozygous UGT1A1*28 (7/7) genotype was associated with grade 4 neutropenia in three of four patients (75%), but only eight out of 30 (27%) with 6/6 or 6/7 genotypes experienced grade 4 neutropenia ( p = 0.09). None of the 14 patients with the GSTP1 I105V A/A genotype had a partial response, as opposed to five out of 19 (26%) of those with the G/A or G/G genotypes ( p = 0.057). Conclusion The combination of carboplatin and irinotecan is an active combination in NSCLC, with response rates comparable with other platinum-containing doublets. Further studies with irinotecan should incorporate prospective pharmacogenomic analysis to identify markers for response and toxicity.

Purpose Half of all patients with non-small cell lung cancer (NSCLC) are 70 years or older at the time of diagnosis. Surgery is an option for fit elderly patients with early stage disease, but rates of disease recurrence after surgical resection are not well described. We report the outcomes in elderly patients (70 years or older) with stage I NSCLC after surgical resection. Patients and Methods We conducted a retrospective study of patients diagnosed with stage I NSCLC after surgical resection at Washington University School of Medicine-Alvin J. Siteman Cancer Center from 1990 to 2000. Demographic, pathologic, treatment, and follow-up data were collected. Recurrence rates and overall survival were calculated by the Kaplan-Meier method. Multivariate Cox proportional hazards models were used to detect associations between potential prognostic factors and survival and recurrence. Results Of the 715 patients with stage I NSCLC, 286 were 70 years or older at diagnosis. In this elderly cohort, the median age was 74 years (range, 70–89 years) and 140 of them were women (49%). Lobectomy was performed in 237 patients (83%) whereas 43 patients (15%) had a wedge or segmental resection, and six patients (2%) underwent pneumonectomy. Clinical and pathologic characteristics were not statistically different between the elderly and younger cohorts, with the exception that older patients were more likely to be white (90% versus 80%, p = 0.0003) and less likely to be smokers (88% versus 95%, p = 0.019) compared with the younger cohort. With a median follow-up of 4.6 years, the overall 5-year survival rate was 52% with a 5-year recurrence rate of 24%. In comparison, the patients younger than 70 years had a 5-year survival rate of 67% ( p Conclusions Although overall survival was worse in elderly patients, estimated disease recurrence rates after resection were identical.

Objective: There are no reliable markers to predict recurrence in resected Stage I non-small cell lung cancer (NSCLC). A validated clinical model to estimate the risk of recurrence would help select patients for adjuvant therapy. Methods: We reviewed the medical records of 715 patients who had a potentially curative resection for Stage I NSCLC at our institution from 1990 to 2000. Recurrence rates were estimated by the Kaplan-Meier method. A model to estimate risk of recurrence was developed by combining independent risk factors. Results: With a median follow-up of 4.7 years, the 5-year survival rates for Stages IA and IB were 66% and 55% respectively, and 5-year recurrence rates were 19% and 30%, respectively. Four factors were independently associated with tumor recurrence: tumor size >3 cm (hazard ratio [HR] = 2.4), surgery other than lobectomy (HR = 2.0), nonsquamous histology (HR = 1.4), and high-grade cellular differentiation (HR = 1.4). A scoring system for recurrence was developed by assigning 2 points for each major risk factor (tumor size and surgery) and 1 point for each minor risk factor (histologic subtype and cellular grade). Scores were grouped as low (0–1), intermediate (2–3), and high (>3), yielding 5-year estimates of risk of recurrence of 14%, 27%, and 43%, respectively. Conclusion: This model, based upon readily available clinicopathologic characteristics, can estimate the risk of recurrence in Stage I NSCLC, independent of T classification. This model could be used to select patients for adjuvant therapy if validated in independent data sets.

To the EditorSeveral randomized trials utilizing platinum baseddoublet regimens have shown a survival benefit foradjuvant chemotherapy for non-small cell lungcancer (NSCLC) [1 5]. Adjuvant chemotherapy isincreasingly used in the USA following the publica-tions of the above mentioned studies. To our knowl-edge, there have been no reports on delivery andtoxicity of adjuvant chemotherapy for NSCLC out-side the clinical trial setting. We performed an auditof all patients with NSCLC who underwent surgicalresection and received adjuvant chemotherapy atWashington University School of Medicine betweenJanuary 2003 and December 2005. A total of 40patients were identified to have received adjuvantchemotherapy for NSCLC. The median age in thisgroup was 57 years (range 40 73). The majority ofpatients (68%) were Caucasian with African Amer-icans representing 27% of the population. Men andwomen were represented in equal proportions. Over90% of the patients had a favorable (0 1) Adultcomorbidity evaluation score-27 (ACE-27) at thetime of surgery. The median time from surgery tothe start of cycle 1 of chemotherapy was 49 (range16 118) days. Cisplatin with docetaxel was the mostfrequently used (43%) adjuvant chemotherapy regi-men during the study period followed by carboplatinand paclitaxel (17%), carboplatin and docetaxel(17%), and carboplatin and gemcitabine (15%).Of the 40 patients, 16 (40%) had received theintended dose (all the scheduled cycles without anydose modifications or delays). Seven patients (18%)did not receive the planned cycles of chemotherapywhile 21 (53%) patients had dose reductions and3 (8%) had dose delays (Table I). Adjuvant therapywas discontinued without completion of the sched-uled number of cycles due to toxicities in 6 (15%).Seventeen patients (42%) reported grade 3/4 toxi-cities, most commonly neutropenia and fatigue.Neutropenic fever occurred in two patients. Therewere no deaths resulting from adjuvant chemo-therapy.Most of the current data regarding delivery andtolerability of adjuvant chemotherapy for NSCLCare obtained from prospective studies [4,6 9] cis-platin and docetaxel, 11 (65%) received full doses ofchemotherapy without dose reduction, delays oromission. Grade 3/4 neutropenia in our studyoccurred in 25% of the patients as opposed to 36%in the CALGB 9633 trial, 17.5% (grade 4 alone) inthe IALT trial and 85% in the ANITA trial [2,4,7].This report provides the first ‘‘real life’’ experienceregarding the chemotherapy delivery and toxicity inpatients with resected non-small cell lung canceroutside the context of clinical trials.

We conducted a phase II study of carboplatin and irinotecan in patients with advanced non-small cell lung cancer (NSCLC). In addition, we studied the correlation between certain genotypes of enzymes involved in irinotecan metabolism with efficacy and toxicity.Patients with stage IIIB, IV, or recurrent NSCLC received a combination of irinotecan and carboplatin every 3 weeks at a dose of 200 mg/m2 and area under the curve of 5. Pharmacogenomic analysis was performed on several genes of interest (ABCB1, CYP3A4*1B, ERCC2, GSTP1, UGT1A1*28, and XRCC1).Forty-two patients enrolled between December 2001 and January 2004. Six patients achieved partial responses (14%), and 19 (45%) had stable disease. The median progression-free survival was 6.9 months. The median overall survival was 11.7 months, with 1-year overall survival of 42%. The most common toxicities were hematologic; grade 3 or 4 neutropenia was experienced by 26 patients (62%) during treatment, and 15 patients (36%) experienced grade 3 or 4 thrombocytopenia. The homozygous UGT1A1*28 (7/7) genotype was associated with grade 4 neutropenia in three of four patients (75%), but only eight out of 30 (27%) with 6/6 or 6/7 genotypes experienced grade 4 neutropenia (p = 0.09). None of the 14 patients with the GSTP1 I105V A/A genotype had a partial response, as opposed to five out of 19 (26%) of those with the G/A or G/G genotypes (p = 0.057).The combination of carboplatin and irinotecan is an active combination in NSCLC, with response rates comparable with other platinum-containing doublets. Further studies with irinotecan should incorporate prospective pharmacogenomic analysis to identify markers for response and toxicity.

18555 Background: Lung cancer is the most common cause of cancer related death in the United States. Non-small cell lung cancer (NSCLC) accounts for over 80% of all new cases of lung cancer. Lung cancer is a disease of the elderly. There are only limited data available on NSCLC in octogenarians. Methods: From our institutional tumor registry, we identified all patients with NSCLC from 1995 to 2002 who were 80 years or older at the time of initial presentation. Data regarding overall stage, histology, date and extent of surgery, and co-morbidities were analyzed. Co-morbidity determination was based on the Adult Co-morbidity Evaluation (ACE-27) test, which ranges from 0 to 3 depending on severity of co-existing conditions. Results: At the time of initial presentation with NSCLC, 236 pts were 80 years or older. The distribution of stages were: stage I in 93 pts (39.5%), stage II in 15 pts (6.5%), stage III in 66 pts (28%) and stage IV in 62 pts (26%). Of the 236 patients the co-morbidity score was known for 223 pts. The distribution of the known scores was: 0, 39 pts (17.5%); 1, 79 pts (35%); 2, 68 pts (30.5%); and 3, 37 pts (17%). Only 35 patients in this cohort underwent surgery. Conclusions: 1. Despite a high proportion (46%) of early stage NSCLC, only a few elderly patients 80 years or older undergo surgical resection, likely because of co-morbid conditions. 2. Innovative non-surgical local modalities of therapy need to be studied in this population. No significant financial relationships to disclose.

7224 Background: Lung cancer is the leading cause of cancer-related mortality in both men and women in the United States. Over 80% of patients are diagnosed with non-small cell lung cancer (NSCLC) and approximately 30% of patients with NSCLC present with resectable disease. Nearly 40–50% of patients with resected stage I NSCLC develop recurrent disease. Currently there are no clinical, radiological, or molecular markers to predict outcomes following surgery in early stage NSCLC. Positron emission tomography (PET) with 2-[18F] fluoro-2-deoxy-D-glucose (FDG-PET) is used commonly in the staging work up of NSCLC. The standardized uptake value (SUV) is a semiquantitive measure of FDG uptake that correlates with tumor doubling time. We studied the relationship between the maximum preoperative tumor SUV (SUVmax) for FDG and disease-free survival (DFS) in patients with resected stage I NSCLC. Methods: We identified 153 consecutive patients diagnosed with stage I NSCLC between 1999 and 2003 who had undergone FDG-PET before curative surgical resection. Data were collected regarding stage distribution, histology, recurrence and survival. No patient in this cohort received adjuvant chemotherapy or radiotherapy. SUVmax above and below the median was correlated with DFS. Results: Of 153 patients with stage I NSCLC, 90 (59%) had T1 and 63 (41%) had T2 tumors. The mean and median follow-up time for the cohort was 2.9 and 3.1 years respectively. The mean and median SUVs were 7.0 and 6.0 respectively. The 5-year DFS categorized by SUVmax < 6 vs. SUVmax ≥ 6 was 62% vs. 46 (p = 0.0036) for the entire cohort; 64% vs. 54% (p = 0.20) for the T1 subset; and 60% vs. 40% (p = 0.07) for the T2 subset. Conclusions: High SUVmax (≥ 6) on preoperative FDG-PET is a predictor of poor outcome in resectable stage I NSCLC. [Table: see text]

6058 Background: Despite recent advances in the treatment of pts with thoracic malignancies, the outcome continues to be poor. Only about 3% of all adult oncology pts enroll in clinical trials compared to approximately 50% of pediatric pts. The proportion of adult pts enrolled in clinical trials is low, even in tertiary cancer centers. It is critical to understand the barriers for accrual to clinical trials. Methods: We reviewed the outpatient charts of all pts with thoracic malignancies (non-small cell lung cancer [NSCLC], small cell lung cancer, and esophageal cancer) referred to the thoracic medical oncology group at our institution from 11/1/2004 to 10/31/2005. Available and appropriate clinical trials are presented to the pts routinely and reasons for non-enrollment are documented. We collected information on histology, stage, performance status (PS) and co-morbid conditions. Appropriate studies at the time of initial consultation were noted from database. Results: Of 284 consecutive patient charts reviewed, 13 pts (4.6%) did not require therapy, 6 pts (2.1%) were deemed to have a non-thoracic primary on review, and 15 pts (5.3%) had already initiated therapy at the time of consultation. Of the remaining 250 evaluable pts, 88 pts (35.2%) were not enrolled because of lack of available appropriate clinical trials at the time of initial consultation. The most common categories were adjuvant therapy for early stage NSCLC and advanced esophageal cancer. Twenty-one pts (8.4%) enrolled onto a clinical trial. The most common reasons for not participating in a clinical trial include: ineligibility due to PS (28 pts, 11.2%), geographic issues (23 pts, 9.2%), patient refusal (16 pts, 6.4%) and co-morbid conditions (9 pts, 3.6%). Ten pts (4.0%) were lost to follow up. Conclusions: 1. Lack of appropriate and available clinical trials and poor PS are the two most common reasons for lack of patient enrollment in clinical trials at our institution. 2. It is critical to develop innovative clinical trials for pts with advanced esophageal cancer, adjuvant therapy in early stage NSCLC, and poor PS. 3. More work is needed to understand patient perception about clinical trials. [Table: see text]

17044 Background: Approximately 10% of patients (pts) with lung cancer do not have a history of tobacco smoking. The clinical presentation and outcomes of pts with LCINS have not been well characterized in the Western population. Methods: We reviewed our institutional tumor registry to identify patients with lung cancer from 1992 to 2002. Data regarding tobacco smoking, stage, histology and survival were collected. Results: Of the 5417 consecutive pts diagnosed with lung cancer, 254 were determined to be never-smokers with confirmed pathologic diagnosis of non-small cell lung cancer (NSCLC). The table below describes the patient demographics. The five-year survival for the entire population with LCINS was 22.56%, with 37 pts surviving beyond five years. The median overall survival for women was 21.08 months (95% CI 14.03–23.37) and for men 13.5 months (95% CI 8.5–32.492); p = 0.73. Among the different histologic subtypes, broncho-alveolar carcinoma was associated with better median overall survival of 61.67 months (p < 0.0001). The median overall survival by TNM stage: I (71 months), II (32 months), III (15 months), and IV (6 months). Conclusions: 1. LCINS affects predominantly women. 2. Adenocarcinoma is the most common histological type. 3. Brain and bone are the most common sites of metastases. [Table: see text] No significant financial relationships to disclose.

7298 Background: With the established benefit of second-line chemotherapy for advanced stage NSCLC and the availability of new agents, an increasing number of patients receive third-line chemothera...

8027 Background: Nearly 30% of pts with lung cancer are 70 years or older at the time of diagnosis. Surgery is an option for fit elderly pts with early stage NSCLC. We studied the outcomes of 280 p...

7198 Background: The five year survival rates for patients with stage I NSCLC treated with surgery alone range from 55% to 75%. Adjuvant chemotherapy improves survival in resected stage I NSCLC. Th...

Non-small cell lung cancer (NSCLC) is the commonest cause of cancer mortality worldwide. Growth factor receptor signalling pathways constitute an important mediator for tumor growth and proliferation. PTEN and pAKT play important roles in regulating signal transduction along this pathway. Separate cohorts of stage I (n=25) and stage IV (n=34) NSCLC were examined by immunohistochemistry for PTEN and pAKT expression. There was no correlation between PTEN expression and pAKT expression and neither were associated with age, sex or smoking status. Patients with stage IV disease who overexpressed pAKT (at least 2+) or were PTEN-null had poorer overall survival and progression-free survival. This suggests that PTEN-null or pAKT-positive tumors constitute more aggressive tumors whose clinical course is not altered by therapy. There was no difference in the clinical outcome for stage I disease by PTEN or pAKT expression. A greater proportion of the stage IV patients had PTEN-null disease compared to the stage I cohort, suggesting that loss of PTEN is important in the tumor biology of advanced disease. Loss of PTEN or overexpression of pAKT predicts for an aggressive subset of lung tumors that have a poor prognosis. This will allow identification of a poor prognosis subset that can be targeted with novel treatments that either restore PTEN function or target activated AKT, mTOR and other downstream signal transduction molecules.