Endocrine therapy is a crucial treatment for estrogen receptor-positive (ER+) breast cancer, with proven clinical benefits. However, adaptive mechanisms emerge in the tumor, causing resistance to endocrine therapy. A better understanding of resistance mechanisms is needed to overcome this problem and to develop new, precise treatment strategies. Accumulating genetic and cancer biological studies demonstrate the importance of understanding the PI3K/Akt/mTOR and CDK4/6/RB pathways in ER+ HER2- breast cancer. PIK3CA (which encodes phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit α) is frequently mutated in breast cancer, and 30% of advanced ER+ HER2- breast cancers have an activating PIK3CA mutation. AKT1 mutations (E17K) have been found in 1.4-8% of breast cancer patients. ER+ breast cancer patients preferentially demonstrate gain of CCND1 (cyclin D1; 58% in luminal B vs. 29% in luminal A) and CDK4 (25% in luminal B vs. 14% in luminal A) and loss of CDKN2A (p16) and CDKN2C (p18), which are negatively regulated with the cell cycle and are correlated with the CDK4/6/RB pathway. Abnormalities in PI3K/Akt/mTOR and CDK4/6/RB pathways due to genetic alterations result in deregulated kinase activity and malignant transformation. This review focuses on the recent reports of the essential role of PI3K/Akt/mTOR and CDK4/6/RB pathways in ER+ HER2- breast cancer.

Squamous cell carcinoma of the lung can be divided into two types according to the location of the primary site: the central type and the peripheral type. The clinicopathologic factors in the peripheral type of lung squamous cell carcinoma have not yet been fully evaluated. A total of 204 surgically resected lung squamous cell carcinomas were reviewed with special reference to their location, histologic characteristics based on tumor growth patterns, and clinicopathologic factors. The central type and the peripheral type accounted for 95 and 109 cases, respectively. Although the patient population of the peripheral type was older, with a lower pathologic stage, lower lymphatic vessel involvement, and lymph node metastasis, the Kaplan-Meier survival proportions did not differ significantly between these two groups. Based on the histologic growth pattern, the peripheral type was classified under three subgroups as follows: 1). the alveolar space-filling type, 2). the expanding type, and 3). the combined type. Among these three types, the alveolar space-filling type showed neither lymphatic vessel invasion nor lymph node metastasis and had the most favorable prognosis. The central and peripheral types of lung squamous cell carcinoma have different clinicopathologic characteristics and should be classified under respectively different categories.

Sorafenib is a novel oral multikinase inhibitor that targets Raf serine/threonine and receptor tyrosine kinases, and inhibits tumor cell proliferation and angiogenesis. We have conducted a phase I study of sorafenib to determine the safety, tolerability, pharmacokinetics, and potential efficacy of this agent in 31 Japanese patients with advanced refractory solid tumors. Sorafenib (100-600 mg) was given as a single dose followed by a 7-day wash-out period, and then administrated twice daily (bid). The most frequent drug-related adverse events were rash/desquamation (61%), hand-foot skin reactions (39%), diarrhea (36%), and elevations of serum lipase (36%) and amylase (26%) levels. Dose-limiting toxicities (DLTs) were grade 3 diarrhea at 200 mg bid and grade 3 fatigue at 600 mg bid. Grade 3 and 4 pancreatic enzyme elevations were observed at 200-600 mg bid, but they were not deemed dose-limiting because they were asymptomatic and were not associated with pancreatitis or chronic damage to the pancreas. The AUC and C max of sorafenib increased linearly with dose up to 400 mg bid. Partial responses were observed in one of 10 patients with non-small cell lung cancer and one of three patients with renal cell carcinoma. In conclusion, sorafenib 400 mg bid was well tolerated in Japanese patients with advanced refractory solid tumors. The recommended dose for future clinical trials is 400 mg bid. (Cancer Sci 2008; 99: 1492-1498)

Our findings suggest that pharmacogenetics can be used to predict the risk of morphine-induced adverse events.

A low NLR at baseline was significantly associated with improved PFS in patients treated with eribulin but not in those treated with nab-paclitaxel. Therefore, the baseline NLR might be clinically useful for selecting patients who would benefit from eribulin.

Pharmacogenetic testing for UDP-glucuronosyltransferase (UGT) 1A1*28, a promoter variant of the UGT1A1 gene, is now carried out clinically to estimate the risk of irinotecan-associated toxicity. We studied the clinical significance of UGT1A1*6 and UGT1A1*27, two variants in exon 1 of the UGT1A1 gene that are found mainly in Asians. The study group comprised 46 Japanese patients who received various regimens of chemotherapy including irinotecan at doses from 50 to 180 mg/m 2 . Pharmacogenetic relationships were explored between the UGT1A1 genotype and the ratio of the area under the plasma concentration-time curve (AUC) of the active metabolite of irinotecan (SN-38) to that of SN-38 glucuronide (SN-38G), used as a surrogate for UGT1A1 activity (AUC SN-38 /AUC SN-38G ). No patient was homozygous for UGT1A1*28, and none had UGT1A1*27. Two were heterozygous for UGT1A1*28. Two were homozygous and 15 heterozygous for UGT1A1*6, all of whom were wild type with respect to UGT1A1*28. Two patients were simultaneously heterozygous for UGT1A1*28 and UGT1A1*6, present on different chromosomes. The other 25 patients had none of the variants studied. The two patients simultaneously heterozygous for UGT1A1*28 and UGT1A1*6 and the two patients homozygous for UGT1A1*6 had significantly higher AUC SN-38 /AUC SN-38G ratios than the others (P = 0.0039). Concurrence of UGT1A1*28 and UGT1A1*6, even when heterozygous, altered the disposition of irinotecan remarkably, potentially increasing susceptibility to toxicity. Patients homozygous for UGT1A1*6 should also be carefully monitored. UGT1A1 polymorphisms in the coding region of the UGT1A1 gene should be genotyped in addition to testing for UGT1A1*28 to more accurately predict irinotecan-related toxicity, at least in Asian patients. (Cancer Sci 2006; 97: 1255-1259)

S-1 is an oral anticancer agent composed of tegafur (FT),S -1 (Taiho Pharmaceutical, Tokyo, Japan) is an oral anticancer agent. This anticancer drug is currently one of the most widely prescribed agents for treatment of gastric cancer in Japan, as a standard option for chemotherapy.(1-3) S-1 is a formulation of FT, CDHP, and Oxo in a molar ratio of 1:0.4:1. (4) FT is a pro-drug for cytotoxic 5-FU. The biotransformation of FT to 5-FU is demonstrated to be catalyzed by the liver drug-metabolizing enzyme CYP2A6.(5,6) The addition of CDHP increases the plasma level of 5-FU, as CDHP prevents degradation of 5-FU by competitively inhibiting DPD, (7) which is a rate-limiting enzyme responsible for 5-FU detoxification.(8) Oxo reduces the gastrointestinal toxicity caused by the active 5-FU by blocking the orotate phosphoribosyltransferase pathway, which relates to further activation of 5-FU. (9,10) CYP2A6 is a polymorphic enzyme that shows considerable interindividual variability in its activity.(11-18) CYP2A6*1 is defined as the wild-type allele. CYP2A6*4 is a complete deletion of the CYP2A6 gene.(11-13) Among the CYP2A6*4 variants, CYP2A6*4A is a major variant seen in the Japanese population.(12,13) CYP2A6*7 is a single nucleotide polymorphism (1412T>C) causing an amino acid change (I471T) that decreases enzymatic activity.(14) CYP2A6*9 has a -48T>G nucleotide substitution in the TATA box of the 5′ flanking region of the CYP2A6 gene, which reduces the expression levels of CYP2A6 mRNA and protein in human livers.(15,16) These CYP2A6 polymorphisms are seen frequently in Japanese people with allele frequencies of approximately 20% for CYP2A6*4A, 6% for CYP2A6*7, and 20% for CYP2A6*9. (13,17,18) Thus, it was postulated that these CYP2A6 genetic polymorphisms in Japanese people influenced the PK variability of FT and 5-FU and susceptibility to adverse effects as well as S-1 anticancer activity. The results obtained by Daigo et al. partly support this hypothesis. (19) They found that the four-fold higher AUC of FT seen in one patient compared with four other patients was attributed to the simultaneous presence of CYP2A6*4A and CYP2A6*11 (S224P), causing reduced catalytic activity in the patient. This implies that CYP2A6 genetic polymorphisms alter the PK of FT.Because CDHP has been reported to be predominantly excreted in the urine, (20) interindividual variability of the plasma level of CDHP caused by renal function was expected to occur. The variability in the plasma concentration of CDHP that thus occurred was assumed to affect the PK of 5-FU. Ikeda et al. have suggested this point with data obtained from four patients. (21) Taking these considerations into account, the PK of 5-FU were expected to be influenced by polymorphisms in the CYP2A6 gene, (11)(12)(13)(14)(15)(16)(17)(18) and the PK of CDHP. Therefore, in the present study, the effects of CYP2A6 genotype and plasma

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