Treating non-small cell lung cancer with selumetinib: an up-to-date drug evaluation.

INTRODUCTION: RAS-RAF-MEK-ERK signaling is implicated in tumor development by promoting cell proliferation and other cancer hallmarks. MEK1/2 kinases are up-regulated in the majority of human cancers due to activation of tyrosine kinase receptors, RAS proteins, BRAF kinase, or some other members of the MAPK pathway. Targeting of MEK1/2 kinases may counterbalance cancer progression. AREAS COVERED: The authors analyze the scientific publications relevant to selumetinib (AZD6244, ARRY-142886) systematically and provide their expert opinion. EXPERT OPINION: Selumetinib is an oral selective allosteric inhibitor of MEK1 and MEK2 kinases. Single-agent selumetinib is usually administered in hydrogen sulfate capsules 75 mg twice a day; combination with other therapeutic compounds may or may not require reduced dosing of this drug. The established dose for pediatric patients is 25 mg per square meter twice a day. Selumetinib was extensively evaluated in non-small cell lung cancer (NSCLC) patients. Studies utilizing this drug as a monotherapy did not confirm its efficacy toward NSCLC. A phase II trial showed that the addition of selumetinib to docetaxel improved response rates and progression-free survival (PFS) in chemotherapy-pretreated KRAS-mutated NSCLC patients; however, a subsequent phase III study did not confirm these findings. There are several highly successful non-NSCLC selumetinib trials involving, e.g., patients with neurofibromatosis type 1 related tumors and children with low-grade BRAF-driven gliomas.

Rapid selection of BRCA1-proficient tumor cells during neoadjuvant therapy for ovarian cancer in BRCA1 mutation carriers.

Ovarian carcinomas (OC) often demonstrate rapid tumor shrinkage upon neoadjuvant chemotherapy (NACT). However, complete pathologic responses are very rare and the mechanisms underlying the emergence of residual tumor disease remain elusive. We hypothesized that the change of somatic BRCA1 status may contribute to this process. The loss-of-heterozygosity (LOH) at the BRCA1 locus was determined for 23 paired tumor samples obtained from BRCA1 germ-line mutation carriers before and after NACT. We observed a somatic loss of the wild-type BRCA1 allele in 74% (17/23) of OCs before NACT. However, a retention of the wild-type BRCA1 copy resulting in a reversion of LOH status was detected in 65% (11/17) of those patients after NACT. Furthermore, we tested 3 of these reversion samples for LOH at intragenic BRCA1 single nucleotide polymorphisms (SNPs) and confirmed a complete restoration of the SNP heterozygosity in all instances. The neoadjuvant chemotherapy for BRCA1-associated OC is accompanied by a rapid expansion of pre-existing BRCA1-proficient tumor clones suggesting that continuation of the same therapy after NACT and surgery may not be justified even in patients initially experiencing a rapid tumor regression.

Double heterozygotes among breast cancer patients analyzed for BRCA1, CHEK2, ATM, NBN/NBS1, and BLM germ-line mutations.

17 double heterozygous (DH) breast cancer (BC) patients were identified upon the analysis of 5,391 affected women for recurrent Slavic mutations in BRCA1, CHEK2, NBN/NBS1, ATM, and BLM genes. Double heterozygosity was found for BRCA1 and BLM (4 patients), BRCA1 and CHEK2 (4 patients), CHEK2 and NBS1 (3 patients), BRCA1 and ATM (2 patients), CHEK2 and BLM (2 patients), CHEK2 and ATM (1 patient), and NBS1 and BLM (1 patient). DH BC patients were on average not younger than single mutation carriers and did not have an excess of bilateral BC; an additional non-breast tumor was documented in two BRCA1/BLM DH patients (ovarian cancer and lymphoplasmacytic lymphoma). Loss-of-heterozygosity (LOH) analysis of involved genes was performed in 5 tumors, and revealed a single instance of somatic loss of the wild-type allele (LOH at CHEK2 locus in BRCA1/CHEK2 double heterozygote). Distribution of mutations in patients and controls favors the hypothesis on multiplicative interaction between at least some of the analyzed genes. Other studies on double heterozygosity for BC-predisposing germ-line mutations are reviewed.

Distribution of coding apoptotic gene polymorphisms in women with extreme phenotypes of breast cancer predisposition and tolerance.

AIMS AND BACKGROUND: Comparison of subjects with extreme phenotypes of cancer susceptibility and tolerance allows to detect low-penetrance gene-disease interactions with a relatively small study size. METHODS AND STUDY DESIGN: We analyzed the distribution of 19 coding apoptotic gene polymorphisms (Bid Gly10Ser; Casp2 Leu141Val; Casp5 Ala90Thr and Val318Leu; Casp7 Glu255Asp; Casp8 His302Asp; Casp9 Val28Ala, His173Arg and Arg221Gln; Casp10 Ile479Leu; Faim Thr117Ala and Ser127Leu; DR4 Arg141His, Thr209Arg, Ala228Glu and Lys441Arg; Survivin Lys129Glu; TNFR1 Gln121Arg; XIAP Pro423Gln) in 121 breast cancer patients with clinical features of a hereditary predisposition (family history and/or early onset and/or bilaterality) and 142 elderly tumor-free women. RESULTS: None of the individual single nucleotide polymorphisms (SNPs) demonstrated an association with breast cancer risk. The analysis of gene interactions revealed that the combination of XIAP Pro423Gln (rs5956583) AA genotype with Casp7 Glu255Asp (rs2227310) CG genotype appeared to prevail in "supercases" relative to "supercontrols" (25/121 [21%] vs 11/142 [8%], P = 0.002). We attempted to validate this association in the second round of case-control analysis, which involved 519 randomly selected breast cancer patients and 509 age-matched healthy women, but no difference was detected upon this comparison. CONCLUSIONS: Coding apoptotic gene polymorphisms do not play a major role in BC predisposition. The results of this investigation may be considered while designing future studies on breast cancer-associated candidate SNPs.