Takaya Ikeda

Analysis of intratumor heterogeneity of EGFR mutations in mixed type lung adenocarcinoma.

BACKGROUND Epidermal growth factor receptor mutations are predictive of the success of EGFR tyrosine kinase inhibitor treatment in patients with advanced non--small-cell lung cancer. As with other solid tumors, lung cancer is thought to be the result of an accumulation of genetic alterations after exposure to carcinogens. The aim of the present study was to clarify the relationship between multistep carcinogenesis and the accumulation of EGFR mutations. PATIENTS AND METHODS The intratumor heterogeneity of EGFR mutations was analyzed in 38 patients with resected mixed-type lung adenocarcinoma according to histological patterns, and the clinical features of the patients harboring intratumor heterogeneity of EGFR mutations were evaluated. RESULTS Intratumor heterogeneity of EGFR mutations was detected in 9 of 38 tumors. EGFR mutations were more common in the bronchioloalveolar (lepidic) carcinoma pattern than in the papillary and acinar patterns, although this difference was not significant. However, there was a significant correlation between intratumor heterogeneity of EGFR mutations and smoking history (P < .043). CONCLUSION Intratumor heterogeneity of EGFR mutations correlates with the distribution of histological subtype in mixed type adenocarcinoma and is associated with smoking history.

Direct comparison of 3 PCR methods in detecting EGFR mutations in patients with advanced non-small-cell lung cancer

BACKGROUND Epidermal growth factor receptor (EGFR) mutations are predictive of response to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. Several methods have been used to detect EGFR mutations; however, it is not clear which is the most suitable for use in the clinic. In this study, we directly compare the clinical sensitivity and specificity of 3 PCR methods. PATIENTS AND METHODS We compared the 3 PCR methods (mutant-enriched PCR, PNA-LNA PCR, and PCR clamp) in patients with advanced NSCLC. A patient who showed sensitive mutations by at least 1 PCR method was treated with gefitinib. A patient who showed no sensitive mutations was treated with chemotherapy with cytotoxic agents. RESULTS Fifty patients with advanced NSCLC previously untreated with EGFR-TKIs were enrolled in this trial. Seventeen patients were harboring EGFR mutations, 5 of whom showed discrepancies between the results of different PCR methods. All 5 patients responded to gefitinib. All patients harboring EGFR mutations received gefitinib treatment and 21 of 33 EGFR-mutation-negative patients received chemotherapy with cytotoxic agents. Median progression-free survival of the gefitinib group and the chemotherapy group were 8.2 and 5.9 months, respectively. CONCLUSION We considered that all the discrepancies might be false negatives because the patients responded to gefitinib. To clarify the reason for the false negatives of each PCR method, and establish the clinical sensitivity and specificity of each PCR method, a large prospective clinical trial is warranted.

Relationship between UGT1A1*27 and UGT1A1*7 polymorphisms and irinotecan-related toxicities in patients with lung cancer

The objective of this study was to evaluate the effects of gene polymorphisms, including UGT1A1*7, *27, and *29, on the safety of irinotecan therapy.

Phase I study of pemetrexed and concurrent radiotherapy for previously untreated elderly patients with locally advanced non-squamous non-small cell lung cancer

Chemoradiotherapy is the standard treatment for locally advanced non‐small cell lung cancer (NSCLC); however, it is disputed whether this treatment is suitable for patients aged ≥75. This study was conducted to determine the maximum tolerated dose (MTD) of pemetrexed for use in concurrent radiotherapy for elderly patients with locally advanced non‐squamous NSCLC.

Adverse renal effects of anaplastic lymphoma kinase inhibitors and the response to alectinib of an ALK+ lung cancer patient with renal dysfunction

A 62-year-old female patient with renal dysfunction and pulmonary adenocarcinoma developed postoperative recurrence and received carboplatin/pemetrexed and maintenance pemetrexed. As an anaplastic lymphoma kinase (ALK) gene translocation was identified, the therapy was changed to crizotinib. However, the patient’s blood creatinine level increased, and her physical status worsened. Alectinib also induced exacerbation of renal dysfunction but was controlled by dose reduction of 140 mg twice daily for 2 weeks treatment and 2 weeks break were repeated, and exhibited a partial response for 16 months. Here, we describe the case in which alectinib treatment had beneficial clinical effects on ALK-positive lung adenocarcinoma, which controlled the adverse renal effects by dose reduction and drug breaks.

Changes in Immunohistochemical Protein Levels in Anaplastic Lymphoma Kinase-positive Lung Adenocarcinoma Possibly due to Chemo-radiotherapy.

To detect the anaplastic lymphoma kinase (ALK) fusion gene in non-small cell lung cancer, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are the standard methods. However, there are discrepancies between them. We herein report a 40-year-old woman with ALK fusion-positive adenocarcinoma that changed from positive to negative in IHC due to chemo-radiotherapy. Recurrence of the disease restored the IHC expression, whereas FISH was positive throughout the entire clinical course. Our experience suggests that we should therefore carefully evaluate samples after chemotherapy and radiotherapy.

Secondary EML4–ALK-positive Lung Adenocarcinoma in a Patient Previously Treated for Acute Lymphoblastic Leukemia in Childhood: A Case Report

It is widely recognized that the risk of secondary neoplasms increases as childhood cancer survivors progress through adulthood. These are mainly hematological malignancies, and recurrent chromosome translocations are commonly detected in such cases. On the other hand, while secondary epithelial malignancies have sometimes been reported, chromosome translocations in these epithelial malignancies have not. A 33-year-old man who had been diagnosed with acute lymphoblastic leukemia and treated with chemotherapy almost 20 years earlier was diagnosed with lung adenocarcinoma. After chromosomal rearrangement of echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene was detected in this adenocarcinoma, he responded to treatment with crizotinib. It was therefore concluded that this echinoderm microtubule-associated protein-like 4 gene-anaplastic lymphoma kinase gene-positive lung adenocarcinoma was a secondary epithelial malignancy.

Diffuse alveolar hemorrhage with pseudoprogression during nivolumab therapy in a patient with malignant melanoma: Alveolar hemorrhage in nivolumab therapy

Nivolumab, an anti‐PD‐1 antibody, has been shown to be effective in many cancers, such as malignant melanoma and lung cancer; however, nivolumab therapy can result in pseudoprogression. Diffuse alveolar hemorrhage (DAH) is persistent or recurrent pulmonary hemorrhage as a result of drugs, autoimmune diseases, or infections. DAH with pseudoprogression during nivolumab administration has rarely been reported. Herein, we describe our experience with one such case. A 41‐year‐old woman exhibited bloody sputum and ground glass opacities in the lungs along with tumor growth during nivolumab therapy for multiple lung metastases of malignant melanoma. We diagnosed DAH with pseudoprogression as a result of nivolumab and administered steroid therapy. The DAH subsequently improved and the tumor shrank. This case illustrates that nivolumab can cause DAH with pseudoprogression, which can be controlled by steroid therapy. Thus, if bloody sputum and ground glass opacities in the lungs are observed with tumor growth during nivolumab administration, steroid therapy should be considered to control DAH with pseudoprogression.

Abstract 5032: The relationship between theUGT1A1*27andUGT1A1*7genetic polymorphisms and irinotecan-related toxicities in patients with lung cancer

Background: Genetic polymorphisms in the UDP-glucuronosyltransferase 1A1 (UGT1A1), UGT1A7, and UGT1A9 genes are associated with interindividual differences in irinotecan toxicities. The UGT1A1*7, *27, and *29 gene polymorphisms occur within the common exons of UGT1A1 isoforms and cause substantial reductions in their functional activity; however, few clinical studies have examined the effects of these polymorphisms. Purpose: To evaluate the effects of gene polymorphisms, including UGT1A1*7, *27, and *29, on the safety of irinotecan therapy. Patients and methods: The eligibility criteria were as follows: lung cancer patients who were scheduled to undergo irinotecan therapy, aged ≥20 years, and had a performance status of 0-2. After informed consent had been obtained, patients were enrolled, and their blood was collected and used to examine the frequency of the UGT1A1*6, *7, *27, *28, and *29 polymorphisms and the drug concentrations of irinotecan, SN-38, and SN-38G after irinotecan therapy. Results: Thirty-one patients were enrolled. The patients’ characteristics were as follows: male/female = 25/6, median age (range) = 71 (55-84), stage IIB/IIIA/IIIB/IV = 2/6/11/12, and Ad/Sq/Sm/Oth = 14/10/3/4. The -/-, *6/-, *7/-, *27/-, *28/-, and *29/- UGT1A1 gene polymorphisms were observed in 10 (32%), 10 (32%), 2 (6%), 2 (6%), 7 (23%), and 0 (0%) cases, respectively. There were no homozygous or complex heterozygous polymorphisms. The UGT1A1*27 polymorphism occurred separately from the UGT1A1*28 polymorphism. The lowest leukocyte counts of the patients with the UGT1A1*27 and UGT1A1*6 gene polymorphisms were lower than those seen in the wild-type patients. SN-38 tended to remain in the blood for a prolonged period after the infusion of irinotecan in patients with the UGT1A1*27 or UGT1A1*28 polymorphism. No severe myelotoxicity was seen in the patients with UGT1A1*7. Conclusions: UGT1A1*27 and UGT1A1*7 are both rare gene polymorphisms. UGT1A1*27 can occur separately from UGT1A1*28 in some circumstances and is related to leukopenia during irinotecan treatment. UGT1A1*7 is less relevant to irinotecan-induced toxicities, and UGT1A1*29 seems to have little clinical impact. Citation Format: Minoru Fukuda, Manabu Okumura, Tomomi Iwakiri, Arimori Kazuhiko, Shinnosuke Takemoto, Takaya Ikeda, Takuya Honda, Hiroyuki Yamaguchi, Katsumi Nakatomi, Kazuma Kobayashi, Mitsuko Masutani, Mikio Oka, Kazuto Ashizawa, Hiroshi Mukae. The relationship between the UGT1A1*27 and UGT1A1*7 genetic polymorphisms and irinotecan-related toxicities in patients with lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5032. doi:10.1158/1538-7445.AM2017-5032

Analysis of the EGFR mutations in non-small cell lung cancer patients after EGFR-TKI treatment.

e18065 Background: Gefitinib and erlotinib are the epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) that have the dramatically effects in selective patients with non-small ce...