Background The treatment of lung cancer has made dramatic progress in the past decade, but due to the high cost of drugs, the total pharmaceutical cost has been rising explosively. There are currently no data available in Japan on which regimens are used, to what extent they are used, and what their total cost is.Methods Sixty Japanese centers belonging to the Lung Cancer Study Group of the Japan Clinical Oncology Group were surveyed for information about the first-line treatment for advanced lung cancer in practice from July 2021 to June 2022. Three types of cancer were included: driver gene mutation-negative NSCLC, EGFR mutation-positive NSCLC, and extensive-stage small cell lung cancer (ES-SCLC).Results Recent treatment costs for ICIs or ICI plus chemotherapy were about 20-55 times higher than those for conventional chemotherapy. Of the 3738 patients with driver gene aberration-negative NSCLC, 2573 (68.8%) received treatments with monthly cost of 500 000 Japanese yen (JPY) or more; 2555 (68.4%) received ICI therapy. Of the 1486 patients with EGFR mutation-positive NSCLC, 1290 (86.8%) received treatments with a monthly cost of 500 000 JPY or more; 1207 (81.2%) received osimertinib. ICI treatments with a monthly cost of 500 000 JPY or more were administered to 607 (56.3%) of 1079 patients with ES-SCLC. Elderly NSCLC patients received slightly more high-cost treatment than younger patients.Conclusion Recent treatments cost many times more than conventional chemotherapy. This study revealed that high-cost treatments were widely used in advanced lung cancer and some of high-cost treatments were used despite the lack of clear evidence. Physicians should pay attention to the cost of treatments they use. This study of first-line chemotherapy for advanced lung cancer conducted at sixty Japanese centers revealed the actual use of high-cost treatments.

Background Atezolizumab combined with bevacizumab plus platinum-based chemotherapy is a standard treatment for advanced non-squamous non-small-cell lung cancer (nsNSCLC). We aimed to determine the most effective platinum-based combination, such that future studies with atezolizumab can be conducted to further improve patient outcomes. Methods This phase 2 study enrolled treatment-naïve patients with advanced or recurrent nsNSCLC who were randomly assigned to either cisplatin (75 mg/m2) + pemetrexed (500 mg/m2) + bevacizumab (15 mg/kg) (CisPemBev) followed by maintenance PemBev (N=132) or carboplatin (area under the concentration–time curve of 6 mg/mL/min) + paclitaxel (200 mg/m2) + bevacizumab (15 mg/kg) (CarPacBev) followed by maintenance Bev (N=67). The primary endpoint was progression-free survival (PFS, by central review). Secondary endpoints included overall survival (OS) and overall response rate (ORR). Adverse events (AEs) were evaluated for safety. This study was designed with the point estimate of the hazard ratio (HR) for PFS calculated based on an expected HR <0.830 with a probability ≥80%. Results The HR for PFS (CisPemBev/CarPacBev) was 0.825 [95% confidence interval (CI), 0.600–1.134, median PFS, 7.6 vs. 7.0 months]. Because the observed point estimate of the HR for PFS was <0.830, the primary endpoint was met, and CisPem doublet therapy was deemed to be more effective than CarPac in terms of PFS. Median OS was 23.4 months for CisPemBev and 21.6 months for CarPacBev (HR 0.845; 95% CI, 0.583–1.242). The ORR was 57% for CisPemBev and 55% for CarPacBev. Both CisPemBev and CarPacBev were well tolerated; grade ≥3 AEs were reported in 67% and 82% of patients, respectively. Conclusions CisPem combined with Bev was more effective in improving PFS compared with CarPacBev in patients with advanced nsNSCLC. CisPemBev was also well tolerated by this patient population. A study to evaluate the efficacy of atezolizumab plus CisPemBev is warranted. Trial Registration University hospital Medical Information Network Clinical Trial Registry (ID: UMIN000013354).

MET exon 14 skipping mutation, observed in 3–4% of non-small cell lung cancer (NSCLC), is emerging as a targetable alteration. In recent years, immune checkpoint inhibitors (ICI) have been effective in treating several NSCLCs. Our research aimed to investigate the characteristics of patients with NSCLCs harboring MET exon 14 mutations and their response to ICI in Japan. Among the 1954 consecutive NSCLCs diagnosed at Saitama Cancer Center between 2010 and 2019, MET exon 14 skipping mutations were detected in 68 (3.5%) NSCLCs. We evaluated their characteristics such as programmed cell death ligand 1 (PD-L1) expression. Median age of patients with NSCLCs harboring MET exon 14 skipping mutations was 73 years. PD-L1 was highly expressed in 17 (70.8%) of the 24 patients examined. Seven patients received ICI monotherapy, and three out of seven had a remarkable treatment response, resulted in objective response rate (ORR) of 42.9% and progression-free survival of 24.7 months. Three patients with donor splice-site mutations showed a long-term treatment response, despite the fact that two with acceptor splice-site mutations demonstrated no response and experienced early disease progression with ICI monotherapy. Our results indicated that patients with NSCLCs harboring MET exon 14 mutations presented with a high rate of positive PD-L1 expression. ICI treatment showed a high ORR and long-term efficacy for NSCLCs harboring MET exon 14 mutations. Variants of MET exon 14 splice-site mutations may be associated with ICI response.

Background: Tuberculosis (TB) is considered to be an adverse effect of treatment with immune checkpoint inhibitors. Methodology & results: Our case was a 75-year-old woman diagnosed with unresectable stage III non-small-cell lung cancer. After radical chemoradiotherapy was completed, durvalumab was initiated as a consolidation therapy. However, since chest CT showed appearances of infiltration shadows scattered in the periphery of the lungs after five doses of immunotherapy, duruvalumab was discontinued. 6 weeks later, the patient was aware of intermittent fever. Chest CT scan showed the appearance of a tree-in-bud pattern in the right lung. Acid-fast bacilli stain of sputum was positive and the PCR test was positive for Mycobacterium tuberculosis. Conclusion: Duruvalumab as PD-L1 blockade may activate TB.

Background The aim of this trial was to evaluate the safety and efficacy of oral hydration as a substitute for intravenous hydration after cisplatin (CDDP) administration. Methods The major eligibility criteria included patients with lung cancer, indications for a CDDP-based regimen at a dose of 60 mg/m2 or higher, an age of between 20 and 74 years and adequate renal function. Antiemetic prophylaxis consisted of an appropriate dose of palonosetron, aprepitant, dexamethasone and magnesium sulfate (8 mEq). Five hundred millilitres of commercially available oral hydration solution (OS-1: Otsuka Pharmaceutical Factory, Tokushima, Japan) was used as a substitute for intravenous posthydration. The planned sample size was 46 to reject a proportion of 70% under an expectation of 88% with a power of 90% and an alpha error of 5%. Results Between May and November 2013, 31 men and 15 women with a median (range) age of 65 (33–74) years were enrolled from three institutions. Of these, five received adjuvant chemotherapy, 17 received definitive chemoradiotherapy and 24 received chemotherapy for advanced diseases. The median (range) number of chemotherapy cycles was 4 (1–5). After the first cycle of CDDP administration, none of the patients experienced a creatinine elevation of grade 2 or higher, thereby meeting the primary endpoint. Of the 46 patients, 45 (97.8%, 95% CI 88.2 to 99.9) completed the CDDP-based chemotherapy without grade 2 or higher renal dysfunction. Conclusion Oral hydration can be used as a safe and convenient substitute for intravenous posthydration for CDDP administration at the standard dose. Trial registration number UMIN000010201.

Background: Malignant mesothelioma (MM) is an aggressive disease with a poor prognosis, and the mainstay of treatment is systemic chemotherapy (Cx). Given its rarity, little information is available on its clinical courses in daily practice, especially regarding peritoneal MM. Methods: This retrospective analysis included 40 patients (pts) with MM (peritoneal, n = 8 and pleural, n = 32) from Jan. 2005 to Dec. 2016 in our hospital. The diagnosis of MM should be supplemented by immunohistochemistry, including 2 or more positive markers (eg, calretinin, CK 5/6, WT1) and 1 or more negative markers (eg, CEA, BerEP, TTF-1). We focused on clinical outcomes of pts with peritoneal (pe-MM) and pleural MM (pl-MM) who underwent Cx. Results: The median age was 65.5 y.o., and 31 (77.5%) were male. 3 (37.5%) pts with pe-MM and 4 (12.5%) pts with pl-MM received only best supportive care (BSC) after their diagnoses. Four pts (12.5%) with pl-MM received surgery as their 1st treatment. The rest of 29 pts (pe-MM, n = 8 and pl-MM n = 32) received 1st line Cx (26 pts with pemetrexed and platinum, 1 pt with pemetrexed monotherapy and 2 with gemcitabine and cisplatin). Pts with pe-MM had tendency to have poorer performance status (PS). Meanwhile, all the patients with pl-MM could start Cx with PS 0 or 1 after 23 (95.8%) of them received initial thoracentesis or pleurodesis. After the 1st line regimen, all the pts with pe-MM received BSC, while 46 % of pts with pl-MM transferred to the 2nd line Cx. The median overall survival was 10.3 months in total. Survival did not show statistical difference depending on the origin (pe-MM vs pl-MM, 1.7 vs 11.0 months, p = 0.33). Conclusion: In our analysis, pts with pe-MM had more tendencies to drop out of Cx than pts with pl-MM. Proactive ascites management to maintain better PS might improve their continuum of care.

After the development of EGFR tyrosine kinase inhibitors (TKIs), genetic testing of EGFR became required for effective treatment of lung cancer. Initially, the testing was conducted separately for each mutated region. However, many EGFR mutations have since been identified that determine the efficacy of EGFR-TKIs. Therefore, genetic testing of EGFR by next generation sequencing (NGS) may be a suitable strategy for lung cancer. Here we examined the applicability of the NGS method in regard to sensitivity, time and cost. A total of 939 specimens were obtained from 686 lung cancer patients at our hospital. DNA and RNA were simultaneously extracted from specimens derived from surgery, bronchoscopy, and fluid aspiration. Specimens included cerebrospinal fluid, pleural effusion, abdominal fluid, and pericardial effusion. From RNA, target regions (EGFR, KRAS, ALK fusion and RET fusion) were enriched by RT-PCR and sequenced with MiSeq. From DNA, PCR or PCR-RFLP conventional methods were performed. NGS and conventional methods were carried out routinely per week. Among the total 939 specimens, 38 specimens could not be examined with NGS. Among these, 34 specimens were analyzed by conventional testing with simultaneously extracted DNA. The remaining four specimens could not be tested with either method. Compared with the conventional method, the concordance rate of mutations was 99% (892/901), excluding specimens with NGS failure. The time period required from processing of specimens to results was 4 days, and the cost per sample was sufficiently low. In conclusion, the genetic testing with NGS method was useful for lung cancer treatment. The cost, sensitivity and time were able to tolerate routine examinations.

Concurrent chemoradiation therapy (CRT) is standard for stage III non-small cell lung cancer (NSCLC). In our institute, patients undergo surgery after CRT if possible. We aimed to assess the efficacy and adverse event of CRT in patients with stage III NSCLC and investigate the risk of radiation pneumonitis (RP). Two hundred fifty seven patients received CRT for newly diagnosed stage III NSCLC from 2003 to 2013. Patient characteristics were as follows: 87.2% male; median age, 67 years; 55.6% stage IIIA; and 44.4% IIIB. CRT was prescribed, with 40Gy to the primary tumor and mediastinum and a boost of 20Gy to all gross disease. All patients also received platinum based doublet regimen concurrently. After CRT, the patients were re-evaluated in the resectability and underwent surgery. We analyzed tumor volume reduction ratio near the end of radiation therapy. All patients were classified by their lung condition about emphysematous and interstitial changes with CT images before treatment into three degree (slight / moderate / severe). Patients with grade 2 or worse RP were ebaluated with their Dose-Volume Histofram(DVH) parameteres of both lungs. The median follow up time was 73.9 months. The 3-year and 5-year overall survival rates were 44.8% and 33.0% in all patients, and 74.7% and 64.7% in patients with CRT followed by surgery. The 3-year and 5-year local control rates were 68.8% and 49.0%, respectively, in all patients. More than 50 % volume reduction was observed in 73.2 % of patients surviving over 2-years, but 32.3% of these good responder had local failure. Grade 2 or worse RP were observed in 70 patients (27%), grade3 in 11 patients (4%), grade 5 in 3 patients (1%). The median of V5Gy, V10Gy, V20Gy, V40Gy, and mean dose of group with grade 2 or worse RP were 32.1, 27.5, 22.5, 16.5 %, and 13.5Gy, respectively, and with grade 3 to 5 RP were 31.5, 27.9, 23.9, 19.0 %, and 12.8Gy, respectively. In patients with grade 3 to 5 RP, 8 of 14 patients had severe emphysematous lung and moderate or severe interstitial change, or had over 30 % lung V20Gy. CRT for stage III NSCLC was effective with acceptable toxicities. Even though patients had good early response to CRT, local control was not sufficient. Grade 3 or worse RP may relate not only to DVH parameters, but also pulmonary complication before CRT.

Background: The epidermal growth factor receptor (EGFR) T790M mutation is considered the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations. Although chemotherapy is commonly used for those patients under the condition without T790M-targeted therapy, the clinical outcomes are poorly defined. Therefore, we aimed to reveal the treatment patterns and clinical outcomes in patients with T790M-positive NSCLC.Methods: We conducted a retrospective observational study at 23 sites in Japan, and 141 patients with T790M-positive advanced/recurrent NSCLC were identified from January 2008 to December 2014. Their records were studied to understand treatment patterns after detection of a T790M mutation and to assess the objective response rate (ORR) and median survival time (MST) to specific treatment modalities.Results: Of 141 patients, 24 had de novo T790M-positive tumors and 117 had acquired T790M-positive tumors, with MSTs (95% CI) of 21.4 (12.4-36.7) and 9.1 (6.4-13.9) months, respectively. The most common regimen was platinum-based doublet chemotherapy +/- bevacizumab, which was associated with an ORR/MST of 25.0%/29.1 months, respectively, in patients with de novo T790M mutations, and 22.2%/15.3 months, respectively, in patients with acquired T790M mutations.Conclusions: This study reveals the treatment patterns and outcomes of NSCLC patients in Japan after detection of the T790M mutation. The most common treatment following detection of the T790M mutation was platinum-based doublet chemotherapy +/- bevacizumab. Platinum-based doublet chemotherapy +/- bevacizumab was moderately effective, indicating the need for targeted therapies for patients with T790M mutation-positive NSCLC.

ObjectiveDisease progression because of acquired resistance is common in advanced or metastatic epidermal growth factor receptor (EGFR)-mutation positive non-small cell lung cancer (NSCLC), despite initial response to EGFR-tyrosine kinase inhibitors (TKIs). In Japan, transbronchial tissue biopsy is the most common sampling method used for re-biopsy to identify patients eligible for treatment. We aimed to investigate the success rate of re-biopsy and re-biopsy status of patients with advanced or metastatic NSCLC completing first-line EGFR-TKI therapy.Patients and methodsThis was a retrospective, multi-center, Japanese study. The target patients in the study were EGFR mutation-positive NSCLC patients. The primary endpoint was the success rate (number of cases in which tumor cells were detected/total number of re-biopsies performed×100). Secondary endpoints included differences between the status of the first biopsy and that of the re-biopsy in the same patient population, and the details of cases in which re-biopsy could not be carried out. Re-biopsy-associated complications were also assessed.ResultsOverall, 395 patients were evaluated (median age 63 years), with adenocarcinoma being the most common tumor type. Re-biopsy was successful in 314 patients (79.5%). Compared with the sampling method at first biopsy, at re-biopsy, the surgical resection rate increased from 1.8% to 7.8%, and percutaneous tissue biopsy increased from 7.6% to 29.1%, suggesting the difficulty of performing re-biopsy. Approximately half of the patients had T790M mutations, which involved a Del19 mutation in 55.6% of patients and an L858R mutation in 43.0%. Twenty-three patients (5.8%) had re-biopsy- associated complications, most commonly pneumothorax.ConclusionsSuccess rate for re-biopsy in this study was approximately 80%. Our study sheds light on the re-biopsy status after disease progression in patients with advanced or metastatic NSCLC. This information is important to improve the selection of patients who may benefit from third-generation TKIs.

Abstract We have already found that a nuclear receptor PXR can modulate the cytotoxicity of CDDP for cancer cells, and ketoconazole, a PXT antagonist, can be an agent enhancing the antitumor activity of CDDP due to increase of the intracellular platinum content as the mechanism. However, nuclear receptor ligands have a variety of functions, and there is a possibility that PXR antagonist may enhance the cytotoxicity of CDDP through the mechanism other than the inhibition of transporter-mediated efflux of CDDP. The goal of this study was to compare the enhancing ability of three PXR antagonists, ketoconazole (KTZ), phenethyl isothiocyanate (PEITC) and metformin (MFM), for the antitumor effect of CDDP and clarify the contribution of inhibition of the efflux transporter as the mechanism of PXR antagonist. Cell lines used in this study were human hepatoma cell line HepG2. Changes in mRNA expression were assessed by real-time RT-PCR, and the ability of apoptosis induction was assessed as caspase-3 activity. Total intracellular platinum contents were determined by ICP-AES. When HepG2 cells were treated for 24 hr with 10 μM of CDDP, no change of caspase-3 activity was observed when compared to control cells. Also, 30 μM of KTZ, 30 μM of PEITC or 5 mM of MFM had no affect on the caspase-3 activity in treated cells compared with control cells. When KTZ, PEITC or MFM was exposed to HepG2 cells from 24 hr before treatment and during 24-hr treatment with 10 μM of CDDP, the caspase-3 activity was significantly increased to 461%, 355% and 326% of the control, respectively, in comparison with that in CDDP alone. When HepG2 cells were treated for 8 hr with 25 μM of CDDP, the intracellular platinum content was 110 ng/mg protein. On the other hand when KTZ, PEITC or MFM was exposed to HepG2 cells from 24 hr before treatment and during 8-hr treatment with 25 μM of CDDP, the intracellular platinum content was apparently increased to 227%, 491% and 161% of CDDP alone, respectively. Three PXR antagonists resulted in an increase in the intracellular platinum content that seems to be due to inhibition of the platinum efflux transporter, but there is no correlation between increase in intracellular platinum content and enhancement of antitumor activity by PXR antagonists. These results concluded that PXR antagonist can be an agent enhancing the antitumor activity of CDDP, but the ability of PXR antagonist for enhancing antitumor activity of CDDP can not be determined from only the increase in the intracellular platinum content. Citation Format: Shuichi Kishimoto, Megumi Yasuda, Megumi Tomita, Yuki Yamane, Ryosuke Suzuki, Shoji Fukushima. Comparison of enhancement of the antitumor effect of CDDP by PXR antagonists. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4742.

Objective: We studied the relation between hematologic toxicity and demographic characteristics in patients who received Amrubicin (AMR). Methods: From 2008 through 2014, we retrospectively studied clinical characteristics, treatment course, hematologic toxicity, and other factors in 108 patients who received AMR for the treatment of recurrent small-cell lung cancer. Results: The study group comprised 88 men and 20 women, with a median age of 69 years. The performance status at the start of treatment with AMR was 0 in 18 patients, 1 in 58, 2 in 21, and 3 in 11. Previous treatment was received once in 68 patients, twice in 34, and 3 times in 6. At the time of starting treatment with AMR, 29 patients had bone metastasis, 5 had grade 2 liver disease, and 23 had a history of chest irradiation. The starting dose of AMR was 25 mg/m2 in 7 patients, 30 mg/m2 in 20, 35 mg/m2 in 60, 40 mg/m2 in 19, and 45 mg/m2 in 2. The median number of treatment cycles was 3, the response rate was 27%, and PFS was 103 days. The incidence of grade 3 or 4 hematologic toxicity was 48% for neutropenia, 8% for decreased hemoglobin concentrations, 6% for thrombocytopenia, and 26% for febrile neutropenia. Four patients died of treatment-related infections. All deaths were associated with a poor performance status or liver dysfunction at the start of treatment. The incidences of hematologic toxicity and febrile neutropenia increased in a dose-dependent manner. Conclusions: AMR has relatively mild nonhematologic toxicity and is a key drug for the management of recurrent small-cell lung cancer. However, caution is required because hematologic toxicity and febrile neutropenia increase in a dose-dependent manner. Particular caution should be exercised in patients with a poor performance status or severe liver dysfunction, and the starting dose of AMR should be reduced depending on background characteristics.

We analyzed whole-exome sequencing data from 97 Japanese lung adenocarcinoma patients and identified several putative cancer-related genes and pathways. Particularly, we observed that cancer-related mutation patterns were significantly different between different ethnic groups. As previously reported, mutations in the EGFR gene were characteristic to Japanese, while those in the KRAS gene were more frequent in Caucasians. Furthermore, during the course of this analysis, we found that cancer-specific somatic mutations can be detected without sequencing normal tissue counterparts. 64% of the germline variants could be excluded using a total of 217 external Japanese exome datasets. We also show that a similar approach may be used for other three ethnic groups, although the discriminative power depends on the ethnic group. We demonstrate that the ATM gene and the PAPPA2 gene could be identified as cancer prognosis related genes. By bypassing the sequencing of normal tissue counterparts, this approach provides a useful means of not only reducing the time and cost of sequencing but also analyzing archive samples, for which normal tissue counterparts are not available.

1552 Background: The frequencies of known driver mutation in lung adenocarcinoma from patients in the United States have been reported by the NCI’s Lung Cancer Mutation Consortium (LCMC), indicating driver mutations were detected in 54% (280/516) of tumors. In this report, mutations found: EGFR 17%, KRAS 22%, HER2 0.6%, PIK3CA 1.2%, BRAF 2%, MET amplification 0.6%, MAP2K1 0.4%, NRAS 0.4%, AKT 0%, ALK rearrangements 7%. However little is known about ethnic difference of driver mutation frequencies and correlations between driver mutations and histological subtypes in lung adenocarcinoma. Methods: Known driver mutations in tumors from 97 Japanese patients with lung adenocarcinoma who underwent surgical resection between 1999 and 2003 in National Cancer Center Hospital East were analyzed by next-generation sequencing and confirmed by Sanger sequencing. Correlations between driver mutations and histological subtypes were also assessed. Results: Driver mutations were detected in 72% of tumors. Mutations found: EGFR 57%, KRAS9%, HER2 2%, PIK3CA 2%, BRAF 1%, MET amplification 1%, MAP2K1 0%, NRAS 0%, AKT 0%. Due to the limitation of rearrangement detection by exon-sequencing, ALK rearrangements were not analyzed. Compared with the report by LCMC, the frequency of EGFR mutations was high and that of KRAS mutations was low in the present study. All mutations were mutually exclusive. The number of predominant histological subtypes of tumors harbored EGFR mutations were papillary 28, acinar 3, solid 5, lepidic 19. That with KRAS mutations showed papillary 2, acinar 2, solid 2, lepidic 3, and HER2 mutations showed papillary 1 and acinar 1. Two tumors harbored PIK3CA mutations showed both histological acinar pattern. Each of BRAF mutation and MET amplification showed lepidic and papillary pattern, respectively. Conclusions: It was suggested that there should be ethnic difference of driver mutation frequencies in lung adenocarcinoma between Asian and non-Asian patients, although the details of ethnic distribution included in LCMC study has not been opened. In addition, each driver mutations did not correspond to specific histological subtypes of lung adenocarcinoma.

1567 Background: Epidermal growth factor receptor (EGFR) mutation plays a key role in the carcinogenesis of lung adenocarcinoma. However little is known about the environmental and life style factors, in particular dietary habits, influencing EGFR mutations. Methods: Between July 1999 and July 2004, 1995 consecutive patients with lung cancer were prospectively assessed on dietary habits using the semiquantitative Food Frequency Questionnaire (FFQ) which contains questions regarding 138 foods in National Cancer Center Hospital East. EGFR mutations (exon 19 deletion and exon 21 L858R) were examined in 298 adenocarcinomas of whom by direct sequence method. The intake of nutrients was calculated with standard tables of food composition in Japan, 5th revised and enlarged edition. The differences of consumption of 22 food groups and 45 nutrients (energy-adjusted values using the residual method) between EGFR mutations positive (156 patients) and negative (142 patients) were investigated by multivariate logistic regression model adjusted for gender, age, smoking status and body mass index, regarding patients without EGFR mutations as control cases. Results: The grain and carbohydrate consumption of patients with EGFR mutations was significantly lower than patients without EGFR mutations. The multivariate-adjusted odds ratios and 95% confidence intervals for the third tertile of grain and carbohydrate consumption of patients with EGFR mutations in comparison with the first tertile were 0.46 (0.24-0.87) (p for trend =0.021) and 0.44 (0.23-0.85) (p for trend =0.016), respectively. Conclusions: In the present study, it was suggested that the lower consumption of grain and carbohydrate correlated with EGFR mutations. Further research to investigate the influence of these dietary components and habits on carcinogenesis of lung adenocarcinoma with EGFR mutations is warranted.

7544 Background: The frequency of EGFR gene minor mutations, which are mutation other than exon 19 deletions or exon 21 L858R, have been reported about 5-10% of lung cancer with EGFR gene mutations. Little is known about clinicopathologic differences between lung cancer with EGFR gene major and other minor mutations. Methods: In National Cancer Center Hospital East, EGFR gene mutations were examined in 593 lung cancer patients between November 2005 and July 2009, and 31 patients with minor mutations (16% of all patients with EGFR gene mutations) were identified. EGFR gene mutations were analyzed by direct sequence or PCR-Invader method. Results: Thirty patients had point mutations in exon 18-21 and one had deletion in exon 18. Eleven patients had both minor and major mutations (7 with exon 19 deletions and 4 with exon 21 L858R). There were 19 males and 12 females, 22 smokers and 9 non-smokers, and 24 with adenocarcinomas and 7 with non-adenocarcinomas. The proportion of males (61%), smokers (71%), non-adenocarcinomas (23%) was significantly higher than that with major mutations. Gefitinib was administered to 9 patients with these minor mutations and only 3 patients, all had both minor and major mutations, showed clinical responses. Other 6 patients were not responded to gefitinib. Conclusions: The lung cancer patients with EGFR gene minor mutations had apparently different clinicopathologic characteristics from those with major mutations and it is possible that the minor mutation is associated with resistance to EGFR-TKI. No significant financial relationships to disclose.

Background Histopathological evaluation method for predicting the outcome of non-small cell lung cancer (NSCLC) treated by neoadjuvant therapy has not been fully assessed. The purpose of this study was to assess a novel histopathological evaluation method for predicting the outcome of NSCLC treated by neoadjuvant therapy. Methods We reviewed the histopathology of the tumors of 53 NSCLC treated by neoadjuvant chemotherapy, chemoradiotherapy, or radiotherapy followed by complete resection and identified the histologic features produced by neoadjuvant therapy by comparing them with the histologic features of the tumors in 138 NSCLC cases treated by surgery without neoadjuvant therapy. We also measured the area of residual tumor (ART) on the maximum cut surface of the tumors and analyzed the relationships between the histologic features, ART, and the outcome. Results The proportions of cases with the histologic features "cholesterin clefts," "foreign body reactive giant cells," "stromal hyalinosis," and "bizarre nucleus in more than 50% of the cancer cells" were significantly higher in the neoadjuvant therapy group than in the surgery alone group. However, the presence of none of these features had any significant effect on survival. Although pathologic T factor and N factor had no significant effect on overall survival, smaller ART (≤400 mm2) and absence of pleural invasion (p [−]) were predictors of a outcome (p = 0.014 and p = 0.003, respectively). Conclusions Smaller ART and p (−) predict a better outcome of NSCLC treated by neoadjuvant therapy. We concluded that ART is a novel histopathological evaluation method for predicting the outcome of NSCLC treated by neoadjuvant therapy.

Recent molecular biological studies have identified podoplanin as a candidate cancer stem cell (CSC) marker in squamous cell carcinoma (SqCC). The purpose of this study was to examine the expression pattern of podoplanin, and the other stem cell markers CD44 and p63, and their relationship to clinico‐pathological features including survival in pulmonary SqCC. We examined histologically the expression of podoplanin, CD44, and p63 in 162 consecutive SqCC by immunostaining. Podoplanin expression was observed in 107 (66%) tumors, CD44 in 145 (89.5%), and p63 in 151 (93.2%), respectively. In 95.3% of the podoplanin‐positive tumors, tumor cells showing strong expression were localized in the periphery of the tumor nests. However, this peripheral localization was observed in only 55.9% of the CD44‐positive and 43% of p63‐positive tumors. In 88.8% of the podoplanin‐positive tumors, positive cells were localized more peripherally in the tumor nests than CD44‐ or p63‐positive cells and when CD44 and p63 expressions were compared in these podoplanin‐positive tumors, p63‐positive layers in the periphery of the tumor nests were broader compared to CD44‐positive layers. These findings suggest tumor cells are aligned in the “hierarchical distribution pattern” according to the expression of these three markers. Patients who had podoplanin‐positive tumors with the “hierarchical pattern” resulted in significantly better overall survival than those who had podoplanin‐negative tumors (P = 0.043). These results suggest that podoplanin expression would reflect the most immature status in the differentiation process of SqCC, and SqCC with hierarchical expression would be a well‐organized tumor group with lower biological aggressiveness based on the CSC concept. (Cancer Sci 2009)

e11574 Background: Chemotherapy, chemoradiotherapy, or radiotherapy is sometimes used to treat non-small cell lung cancer (NSCLC) before surgical resection (neoadjuvant therapy). However, no histopathological evaluation method for predicting the outcome of NSCLC treated by neoadjuvant therapy has been fully assessed. The purpose of this study was to assess a novel histopathological evaluation method for predicting the outcome of NSCLC patients who received neoadjuvant therapy followed by surgical resection.METHODSWe reviewed the histopathology of the tumors of 61 NSCLC patients who received neoadjuvant chemotherapy, chemoradiotherapy, or radiotherapy and identified the histological features produced by neoadjuvant therapy by comparing them with the histopathological features of the tumors in 138 NSCLC cases treated by surgery without neoadjuvant therapy. We also measured the area of residual tumor (ART) on the maximum cut surface of the tumors and analyzed the relationships between the histological features, ART, and the outcome.RESULTSThe proportions of cases with the histological features "cholesterin clefts," "foreign body reactive giant cells," "stromal hyalinosis," and "cancer cells more than 50% of which contained a bizarre nucleus" were significantly higher in the neoadjuvant therapy group than in the surgery alone group. However, the presence of none of these features except "stromal hyalinosis" had any significant effect on survival in the neoadjuvant therapy group. Although pathological T factor (ypT) and N factor (ypN) had no significant effect on overall survival, smaller ART (≤400 mm2) and absence of pleural invasion (p(-)) were predictors of a outcome (p=0.004 and p=0.001, respectively).CONCLUSIONSSmaller ART (≤400 mm2) and p(-) predict a better outcome of NSCLC in patients who receive neoadjuvant therapy. We concluded that ART is a novel histopathological parameter for predicting the outcome of NSCLC patients who receive neoadjuvant therapy followed by surgical resection. No significant financial relationships to disclose.