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Folylpolyglutamate synthase (FPGS) catalyzes the polyglutamation of folic acid, methotrexate, and pemetrexed to produce highly active metabolites. To characterize genetic variation in the FPGS gene, FPGS, have resequenced the gene in four different ethnic populations. Thirty-four single nucleotide polymorphisms were identified including five nonsynonymous coding single nucleotide polymorphisms that altered the FPGS protein sequence: F13L and V22I polymorphisms in the mitochondrial isoform of FPGS, and R466/424C, A489/447V, and S499/457F polymorphisms, which exist in both the mitochondrial and cytosolic isoforms. When expressed in AuxB1 cells, the A447V cytosolic variant was functionally similar to the wild-type cytosolic (WT Cyt) allozyme, whereas the R424C and S457F cytosolic variants were reduced by ∼2-fold in protein expression compared with WT Cyt (P < 0.01). The intrinsic clearance of glutamate was reduced by 12.3-fold (R424C, P < 0.01) and 6.2-fold (S457F, P < 0.01), whereas the intrinsic clearance of methotrexate was reduced by 4.2-fold (R424C, P < 0.05) and 5.4-fold (S457F, P < 0.05) in these two cytosolic variants when compared with the WT Cyt isoform. Additionally, the in vitro enzyme velocity at saturating pemetrexed concentrations was reduced by 1.6-fold (R424C, P < 0.05) and 2.6-fold (S457F, P < 0.01) compared with WT Cyt. AuxB1 cells harboring these same cytosolic variant allozymes displayed significant increases in the EC50 for folic acid and in the IC50 values for both methotrexate and pemetrexed relative to the WT Cyt form of FPGS. These observations suggest that genetic variations in FPGS may alter the efficacy of antifolate therapy in cancer patients. [Cancer Res 2007;67(18):8772–82]

Supplementary Legends 1-2 from Identification and Characterization of Genetic Variation in the Folylpolyglutamate Synthase Gene

Supplementary Figure 1 from Identification and Characterization of Genetic Variation in the Folylpolyglutamate Synthase Gene

Supplementary Materials from Human Aromatase: Gene Resequencing and Functional Genomics

Supplementary Figure 2 from Identification and Characterization of Genetic Variation in the Folylpolyglutamate Synthase Gene

Simple Summary Chemotherapy-induced peripheral neuropathy (CIPN) is a common debilitating complication of treatment with platinum-based compounds and taxanes. CIPN is predominantly a sensory symptom, causing numbness, tingling, and pain in the hands and/or feet. We performed a genome-wide association study on two independent study groups (N08Cx comprised of NCCTG clinical trial participants in the N08C1, N08CA, and N08CB studies; and Mayo Clinic Breast Disease Registry (MCBDR)) to find genetic variants that are associated with sensory symptoms during or after paclitaxel, paclitaxel and carboplatin, or oxaliplatin receipt. A genetic variant (single nucleotide polymorphism, SNP) rs56360211 near PDE6C had a very strong association with CIPN in N08Cx but not in the MCBDR, while the variant rs113807868 near TMEM150C was significantly associated with CIPN in the MCBDR but not in N08Cx. This lack of replication suggests that neither is actually strongly associated with CIPN. Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially permanent adverse effect of chemotherapeutic agents including taxanes such as paclitaxel and platinum-based compounds such as oxaliplatin and carboplatin. Previous studies have suggested that genetics may impact the risk of CIPN. We conducted genome-wide association studies (GWASs) for CIPN in two independent populations who had completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-CIPN20 assessments (a CIPN-specific 20-item questionnaire which includes three scales that evaluate sensory, autonomic, and motor symptoms). The study population N08Cx included 692 participants from three clinical trials (North Central Cancer Treatment Group (NCCTG) N08C1, N08CA, and N08CB) who had been treated with paclitaxel, paclitaxel plus carboplatin, or oxaliplatin. The primary endpoint for the GWAS was the change from pre-chemotherapy CIPN20 sensory score to the worse score over the following 18 weeks. Study population The Mayo Clinic Breast Disease Registry (MCBDR) consisted of 381 Mayo Clinic Breast Disease Registry enrollees who had been treated with taxane or platinum-based chemotherapy. The primary endpoint for the GWAS assessed was the earliest CIPN20 sensory score available after the completion of chemotherapy. In multivariate model analyses, chemotherapy regimen (p = 3.0 × 10−8) and genetic ancestry (p = 0.007) were significantly associated with CIPN in the N08Cx population. Only age (p = 0.0004) was significantly associated with CIPN in the MCBDR population. The SNP most associated with CIPN was rs56360211 near PDE6C (p =7.92 × 10−8) in N08Cx and rs113807868 near TMEM150C in the MCBDR (p = 1.27 × 10−8). Due to a lack of replication, we cannot conclude that we identified any genetic predictors of CIPN.

Background Exploratory research showed that female oncologists are frequently under-represented in leadership roles. European Society for Medical Oncology (ESMO) Women for Oncology (W4O) therefore implemented gender equality programs in career development and established international studies on female representation at all stages of the oncology career pathway. Methods For 2017-2019, data were collected on (i) first and last authorship of publications in five major oncology journals and (ii) representation of women in leadership positions in oncology—as invited speakers at National/International congresses, board members or presidents of National/International societies and ESMO members. The 2015/2016 data from the first published W4O Study were incorporated for comparisons. Results Across 2017-2019, female oncologists were significantly more likely to be first than last authors (P < 0.001). The proportion of female first authors was similar across years: 38.0% in 2017, 37.1% in 2018, 41.0% in 2019 (P = 0.063). The proportion of female last authors decreased from 30.4% in 2017 to 24.2% in 2018 (P = 0.0018) and increased to 28.5% in 2019 (P = 0.018). Across 2015-2019, invited speakers at International/National oncology congresses were significantly less likely to be female than male (P < 0.001; 29.7% in 2015 to 36.8% in 2019). Across 2016-2019, board members of International/National oncology societies were significantly less likely to be female than male (P < 0.001; 26.8% in 2016 to 35.8% in 2019). There were statistically significant increasing trends in female speakers and board members across the study periods (P < 0.001 for both). Societies with a female president had a higher proportion of female board members across these periods (P = 0.026). Conclusions Reported progress towards gender equality in career development in oncology is real but slow. Women in leadership positions are essential for encouraging young women to aspire to and work towards similar or greater success. Therefore, continued monitoring is needed to inform ESMO W4O initiatives to promote gender balance at all stages of the career pathway., Highlights • Across 2017-2019, female oncologists were significantly more likely to be first than last authors (P < 0.001). • Across 2015-2019, invited speakers at International/National oncology congresses were significantly less likely to be female. • Across 2016-2019, board members of International/National oncology societies were significantly less likely to be female. • Societies with a female president had a higher proportion of female board members across these periods. • Reported progress towards gender equality in career development in oncology is real but slow.

Background European Society for Medical Oncology Women for Oncology (ESMO W4O) research has previously shown under-representation of female oncologists in leadership roles. As early reports suggested disproportionate effects of the COVID-19 pandemic on women, the ESMO W4O Committee initiated a study on the impact of the pandemic on the lives of female and male oncologists. Methods A questionnaire was sent to ESMO members and put on the ESMO website between 8 June 2020 and 2 July 2020. Questions focused on the working (hospital tasks, laboratory tasks, science) and home (household management, childcare, parent care, personal care) lives of oncologists during and after COVID-19-related lockdowns. Results Of 649 respondents, 541 completed the questionnaire. Of these, 58% reported that COVID-19 had affected their professional career, 83% of whom said this was in a negative way (85% of women versus 76% of men). Approximately 86% reported that COVID-19 had changed their personal life and 82% their family life. Women were again significantly more affected than men: personal life (89% versus 78%; P = 0.001); family life (84% versus 77%; P = 0.037). During lockdowns, women reported increased time spent on hospital and laboratory tasks compared with men (53% versus 46% and 33% versus 26%, respectively) and a significantly higher proportion of women than men spent less time on science (39% versus 25%) and personal care (58% versus 39%). After confinement, this trend remained for science (42% versus 23%) and personal care (55% versus 36%). Conclusions The COVID-19 pandemic has adversely affected the professional and home lives of oncologists, especially women. Reduced research time for female oncologists may have long-lasting career consequences, especially for those at key stages in their career. The gender gap for promotion to leadership positions may widen further as a result of the pandemic., Highlights • Female oncologists were significantly more affected than men by COVID-19 in multiple aspects of their working and home life. • Reduced time available to female oncologists for research activities may have long-lasting career consequences. • The gender gap for promotion to leadership positions may widen further as a result of the pandemic. • Greater awareness is needed about gender inequalities in career development in oncology, especially after the pandemic. • Gender transformative policies and strategies are needed due to the impact of COVID-19 and other causes of inequalities.

Background: The importance of sex and gender as modulators of disease biology and treatment outcomes is well known in other disciplines of medicine, such as cardiology, but remains an undervalued issue in oncology. Considering the increasing evidence for their relevance, European Society for Medical Oncology decided to address this topic and organized a multidisciplinary workshop in Lausanne, Switzerland, on 30 November and 1 December 2018., Design: Twenty invited faculty members and 40 selected physicians/scientists participated. Relevant content was presented by faculty members on the basis of a literature review conducted by each speaker. Following a moderated consensus session, the final consensus statements are reported here., Results: Clinically relevant sex differences include tumour biology, immune system activity, body composition and drug disposition and effects. The main differences between male and female cells are sex chromosomes and the level of sexual hormones they are exposed to. They influence both local and systemic determinants of carcinogenesis. Their effect on carcinogenesis in non-reproductive organs is largely unknown. Recent evidence also suggests differences in tumour biology and molecular markers. Regarding body composition, the difference in metabolically active, fat-free body mass is one of the most prominent: in a man and a woman of equal weight and height, it accounts for 80% of the man's and 65% of the woman's body mass, and is not taken into account in body-surface area based dosing of chemotherapy., Conclusion: Sex differences in cancer biology and treatment deserve more attention and systematic investigation. Interventional clinical trials evaluating sex-specific dosing regimens are necessary to improve the balance between efficacy and toxicity for drugs with significant pharmacokinetic differences. Especially in diseases or disease subgroups with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration.

Health-related quality of life (HRQOL) is an important prognostic patient-reported outcome in oncology. Because prior studies suggest that HRQOL is, in part, heritable, we performed a GWAS to elucidate genetic factors associated with HRQOL in breast cancer survivors. Physical and mental HRQOL were measured via paper surveys that included the PROMIS-10 physical and mental health domain scales in 1442 breast cancer survivors participating in the Mayo Clinic Breast Disease Registry (MCBDR). In multivariable regression analyses, age and financial concerns were significantly associated with global physical health (age: p = 1.6 × 10−23, financial concerns: p = 4.8 × 10−40) and mental health (age: p = 3.5 × 10−7, financial concerns: p = 2.0 × 10−69). Chemotherapy was associated with worse global mental health (p = 0.01). In the GWAS, none of the SNPs reached the genome-wide association significance threshold of 5 × 10−8 for associations with either global physical or global mental health, however, a cluster of SNPs in SCN10A, particularly rs112718371, appeared to be linked to worse global physical health (p = 5.21 × 10−8). Additionally, SNPs in LMX1B, SGCD, PARP12 and SEMA5A were also moderately associated with worse physical and mental health (p &lt, 10−6). These biologically plausible candidate SNPs warrant further study as possible predictors of HRQOL.

Vascular endothelial growth factor (VEGF) stimulates angiogenesis. Human hepatocellular carcinoma (HCC) is a VEGF-driven tumor often associated with chronic hepatitis B or C virus infection. The woodchuck is a well-characterized model of hepatitis B virus related HCC and a valuable tool for translational studies of novel VEGF targeted agents. We cloned the cDNA encoding woodchuck VEGF (wVEGF), transiently expressed it in COS cells and functionally characterized the recombinant protein. The open reading frame of wVEGF contained 645 nucleotides encoding a protein of 214 amino acids. Two protein bands (17 and 25 kDa) were detected in conditioned media of wVEGF expressing COS-1 cells and a single band of 25 kDa was identified in cell lysates. Addition of recombinant wVEGF to COS cells enhanced cell proliferation and stimulated VEGFR2, Akt, ERK1/2, and FAK phosphorylation. Sunitinib, a tyrosine kinase inhibitor, inhibited wVEGF- induced VEGFR2 phosphorylation in a dose-dependent manner. Finally, development of HCC in woodchucks was accompanied by increased laminin and PECAM1 expressing vessels, VEGFR2 expression, increased ligation of VEGF to VEGFR2, and a decrease in collagen IV-positive blood vessels. Our results suggest that woodchuck model can be used further to study angiogenesis and the effect of VEGF directed therapies in human HCC.

Background: ALK rearrangement is documented in 2%-7% of NSCLC, depending on the population studied and detection method used. Although the reverse transcriptasepolymerase chain reaction (RT-PCR) was the first used and published method, fluorescence in situ hybridization (FISH) has become the primary standard diagnostic method. Recently, immunohistochemistry (IHC) has also proven to be a reproducible, faster and sensitive technique. This is one of the first studies concurrently comparing all three techniques in resected lung adenocarcinomas from the large ETOP Lungscape cohort. Methods: 95 cases from the ETOP Lungscape iBiobank, selected based on any degree of IHC staining (clone 5A4 antibody, Novocastra, UK), were examined by ALK FISH (Abbott Molecular, Inc.; Blackhall, JCO 2014) and central RT-PCR. For the latter, formalin-fixed, paraffin-embedded (FFPE) unstained slides were collected from participating centers. Slides were de-paraffinized, Toluidine Blue stained, and tumors macro-dissected. Tissue digestion and RNA extraction were performed (Qiagen RNeasy FFPE Kit). Using primers described in the literature covering most of ALK known translocations, RT-PCR (Superscript One-Step RT-PCR with Platinum Taq - 40 loops) was performed, followed by capillary electrophoresis in two separate mixes. Co-amplification of B-actin was done to validate the procedure and RNA quality. All tests were duplicated. Results: 76 of 95 RT-PCR had adequate RNA quality (B-actin co-amplification present). Among these, 18 were FISH positive, 16 were RT-PCR positive, including EML4-ALK V3a/b in 7, V1 in 5, V2 in one, and undetermined variants in 3 cases. 53 of 54 FISH negative cases were also RT-PCR negative (98%). 15 of 18 FISH positives harbored a translocation by RT-PCR (83%). Among the 4 discrepant cases, 2 FISH+/ RT-PCR- cases had IHC H-scores of 180 and 260, and 98.3% and 95% of rearranged cells by FISH, probably corresponding to variants not covered by the RT-PCR. One had an IHC H-score of 5, and 16% cells rearranged on FISH, most probably corresponding to a FISH false positive case. The last had an IHC H-score of 200, 13% rearranged cells by FISH, and, thus is defined as a false negative FISH result. Provided IHC is defined as positive by an H-score above 120, all but one case (H-Score 20, FISH and RT-PCR positive) gave concordant results by a combination of FISH and RT-PCR. Overall, using as true negative or true positive the concordant result of two of the methods, the third method is characterized by high specificity and sensitivity with corresponding values of 100/98/100% and 94/94/89% for IHC/FISH/RT-PCR, respectively. Conclusion: RTPCR is a very good tool for sorting discordant IHC/FISH cases, however, we do not recommend using this technique as single method due to the lower sensitivity of RT-PCR, as not all variants are covered, and also due to the limitations with RNA preservation.

Background TP-0903 is a novel, oral small molecule AXL kinase inhibitor impacting oncogenesis and resistance. AXL is upregulated in many solid tumors and influences the mesenchymal phenotype, which drives resistance to targeted cancer therapeutics, traditional chemotherapies, and immuno-oncology agents. Methods A dose escalation study was performed to examine the safety and clinical activity of TP-0903 in patients with advanced solid tumors. Patients received oral TP-0903 once daily for 21 of 28-day cycles. Nine dose levels were explored using modified 3 + 3 dose escalation rules. The primary objective of the trial was to identify the maximum tolerated dose of TP-0903 prior to expanding into refractory colorectal, platinum refractory/resistant ovarian cancer and TP-0903 in combination with immunotherapy or EGFR tyrosine kinase inhibitor in immunotherapy-resistant tumors or non-small cell lung cancers. Potential biomarkers were evaluated using liquid biopsies and pre-and post-dose tumor biopsies will be reported. Results Thirty-six patients were enrolled between December 2016 and April 2019 receiving 1.5 to 37mg/m2 over 9 cohorts. The most frequently observed >Gr3 AEs were thrombocytopenia (3), anemia (2), nausea (2), syncope (2), and vomiting (2), all manageable with supportive care. Grade 4 thrombocytopenia was the dose limiting toxicity observed in one patient in cohort 8 (28 mg/m2), reoccurring as grade 3 thrombocytopenia in 2 patients in cohort 9 (37mg/m2) without meeting DLT criteria. Patients are currently still ongoing in cohort 9. Eleven patients, (11/36, 30.6%), had stable disease with a median duration of 3.7 months (range 1.6 to 7.4+ months). Baseline serum soluble AXL of all enrolled patients was determined by immunoassay and indicated higher levels in patients with documented stable disease vs. progressive disease (p = 0.0332). Conclusions The oral small molecule AXL kinase inhibitor TP-0903 is well tolerated with a manageable safety profile. Hematologic toxicity was observed as a DLT. Future studies will evaluate the role of TP0903 in selected disease cohorts as monotherapy and in combination. Serum soluble AXL will be evaluated as a potential predictive biomarker of response. Clinical trial identification NCT: 02729298. Legal entity responsible for the study Tolero Pharmaceuticals, Inc. Funding Tolero Pharmaceuticals, Inc. Disclosure J. Sarantopoulos: Research grant / Funding (institution): Tolero. G. Fotopoulos: Research grant / Funding (institution): Tolero Pharmaceuticals. F.Y. Tsai: Advisory / Consultancy: Tempus Lab; Officer / Board of Directors, Co-Founder: Caremission LLC; Shareholder / Stockholder / Stock options: Salarius Pharmaceuticals. M.S. Beg: Research grant / Funding (institution): Tolero Pharmaceuticals. A.A. Adjei: Research grant / Funding (institution): Tolero Pharmaceuticals. Y. Lou: Research grant / Funding (institution): Tolero Pharmaceuticals; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Stem Centrx; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Vaccinex; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MacroGenics. M. Seetharam: Research grant / Funding (institution): Tolero Pharmaceuticals. M.A. Villalona-Calero: Research grant / Funding (institution): Tolero Pharmaceuticals; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol Meyers; Research grant / Funding (institution): Novocure; Research grant / Funding (institution): Guardant. J. Melear: Research grant / Funding (institution): Tolero Pharmaceuticals. M. Janat-Amsbury: Full / Part-time employment: Tolero Pharmaceuticals. H. Beever: Full / Part-time employment: Tolero Pharmaceuticals. L. Mouritsen: Full / Part-time employment: Tolero Pharmaceuticals. M. Wade: Full / Part-time employment: Tolero Pharmaceuticals. B.V. Bryan: Full / Part-time employment: Tolero Pharmaceuticals. D.J. Bearss: Leadership role, Full / Part-time employment: Tolero Pharmaceuticals.

This abstract was withdrawn by the authors. Citation Format: Das GM, Kulkarni S, Oturkar C, Edge SB, Wilton JH, Wang J, Swetzig WM, Adjei AA, Bies R, Hutson AD, Morrison CD, Kaipparettu BA, Groman A, Kumar S, Capuccino H. Withdrawn [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-04.

Thiopurine S-methyltransferase (TPMT) modulates the cytotoxic effects of thiopurine prodrugs such as 6-mercaptopurine by methylating them in a reaction using S-adenosyl- l-methionine as the donor. Patients with TPMT variant allozymes exhibit diminished levels of protein and/or enzyme activity and are at risk for thiopurine drug-induced toxicity. We have determined two crystal structures of murine TPMT, as a binary complex with the product S-adenosyl- l-homocysteine and as a ternary complex with S-adenosyl- l-homocysteine and the substrate 6-mercaptopurine, to 1.8 and 2.0 A resolution, respectively. Comparison of the structures reveals that an active site loop becomes ordered upon 6-mercaptopurine binding. The positions of the two ligands are consistent with the expected S N2 reaction mechanism. Arg147 and Arg221, the only polar amino acids near 6-mercaptopurine, are highlighted as possible participants in substrate deprotonation. To probe whether these residues are important for catalysis, point mutants were prepared in the human enzyme. Substitution of Arg152 (Arg147 in murine TPMT) with glutamic acid decreases V max and increases K m for 6-mercaptopurine but not K m for S-adenosyl- l-methionine. Substitution at this position with alanine or histidine and similar substitutions of Arg226 (Arg221 in murine TPMT) result in no effect on enzyme activity. The double mutant Arg152Ala/Arg226Ala exhibits a decreased V max and increased K m for 6-mercaptopurine. These observations suggest that either Arg152 or Arg226 may participate in some fashion in the TPMT reaction, with one residue compensating when the other is altered, and that Arg152 may interact with substrate more directly than Arg226, consistent with observations in the murine TPMT crystal structure.

Phenylethanolamine N-methyltransferase (PNMT, EC2.1.1.28) catalyzes the N-methylation of norepinephrine to form epinephrine. As a step toward understanding the possible contribution of inheritance to individual variation in PNMT-catalyzed epinephrine formation, we 're-sequenced' the entire human PNMT gene, including the three exons, the introns and approximately 1 kb of the 5'-flanking region (5'-FR), using DNA samples from 60 African-American (AA) and 60 Caucasian-American (CA) subjects. Within the 3.5 kb re-sequenced, 18 single nucleotide polymorphisms (SNPs) were observed, including four non-synonymous coding SNPs (cSNPs) that resulted in the following alterations in encoded amino acid sequence: Asn9Ser, Thr98Ala, Arg112Cys and Ala175Thr. When constructs for the non-synonymous cSNPs were transiently expressed in COS-1 cells, the Ala98 allozyme displayed significantly lower levels of both activity and immunoreactive protein (p < 0.002) than did the wild-type (WT) enzyme due, at least in part, to accelerated protein degradation by a proteasome-mediated process. Luciferase reporter gene constructs were also created for the six common PNMT 5'-FR haplotypes observed. Significant differences were observed among haplotypes in their ability to drive transcription. These observations raise the possibility of inherited variation in the ability to form epinephrine from norepinephrine as a result of variant PNMT polymorphisms and haplotypes.

Estrogens are used as drugs and estrogen exposure is a risk factor for hormone-dependent diseases such as breast cancer. Sulfate conjugation is an important pathway for estrogen metabolism. The sulfotransferase (SULT) enzyme SULT1E1 has the lowest Km values for estrogens and catecholestrogens of the 10 known human SULT isoforms. We previously cloned and characterized the human SULT1E1 cDNA and gene as steps toward pharmacogenetic studies. In the present experiments, we set out to determine whether common, functionally significant genetic polymorphisms might exist for SULT1E1. As a first step, we ‘resequenced’ the eight SULT1E1 exons and exon–intron splice junctions as well as portions of the 5′-flanking region using DNA from 60 African-American and 60 Caucasian-American subjects. In all, 23 polymorphisms, 22 single nucleotide polymorphisms (SNPs) and one insertion deletion were observed. There were three nonsynonymous coding SNPs (cSNPs) that altered the following encoded amino acids: Asp22Tyr, Ala32Val and Pro253His. Among these, 12 pairs of SNPs were tightly linked. In addition, 12 unambiguous SULT1E1 haplotypes were identified, including six that were common to both populations studied. Transient expression in COS-1 cells of constructs containing the three nonsynonymous cSNPs showed significant decreases in SULT1E1 activity for the Tyr22 and Val32 allozymes, with corresponding decreases in levels of immunoreactive protein. There were no changes in levels of either activity or immunoreactive protein for the His253 allozyme. Apparent Km values of the Val32 allozyme for the two cosubstrates for the reaction, 17β-estradiol and 3′-phosphoadenosine 5′-phosphosulfate, were not significantly different from those of the wild-type enzyme, but there was a two- to three-fold increase in Km values for the His253 allozyme and a greater than five-fold increase for the Tyr22 allozyme. These observations raise the possibility that genetically determined variation in SULT1E1-catalyzed estrogen sulfation might contribute to the pathophysiology of estrogen-dependent diseases as well as variation in the biotransformation of exogenously administered estrogens. British Journal of Pharmacology (2003) 139, 1373–1382. doi:10.1038/sj.bjp.0705369

Background Irinotecan (CPT-11) and 5-fluorouracil (5-FU)/leucovorin are active agents in colorectal cancer. A sequence-dependent synergism of SN-38 followed by 5-FU/leucovorin in vitro led us to conduct a phase I trial of CPT-11 followed by 5-FU/leucovorin to determine the maximum tolerated dose (MTD) and toxicities of this regimen and to obtain preliminary indications of its activity in patients with advanced solid tumors. Patients and methods Fifty-six patients were enrolled in sequential cohorts to receive escalating doses of CPT-11 (90 min infusion) on day 1, followed by leucovorin 20 mg/m2 (intravenous push) and 5-FU (90 min infusion) on days 2–5 of each 21-day cycle. Results A total of 347 treatment cycles (median 4, range 1–25) were administered. Dose-limiting toxicities were diarrhea, neutropenia and fatigue. Nine patients with colorectal cancer and one with gastric cancer had partial or minor responses. Eight of the 10 had prior chemotherapy. Conclusions CPT-11 and 5-FU/leucovorin, as constituents of this novel mechanism-based schedule, have promising activity in patients who have received prior chemotherapy. The recommended phase II/III starting doses are CPT-11 275 mg/m2 over 90 min on day 1, and 5-FU 400 mg/m2 plus leucovorin 20 mg/m2 on days 2–5 every 21 days. This combination can be administered safely to this schedule if there is strict adherence to the 90 min infusion time for both CPT-11 and 5-FU.

A growing body of evidence supports the hypothesis that estrogens can be carcinogens as a result of their conversion to genotoxins after biotransformation to form the catecholestrogens (CEs) 2-hydroxyestrone (2-OHE1), 2-hydroxyestradiol (2-OHE2), 4-hydroxyestrone (4-OHE1) and 4-hydroxyestradiol (4-OHE2). CEs can then undergo further metabolism to form quinones that interact with DNA to form either stable or depurinating adducts. These events could potentially be interrupted by the sulfate conjugation of both the parent estrogens and/or the CEs. We set out to determine whether CEs can serve as substrates for sulfate conjugation, and-if so-which of the growing family of human sulfotransferase (SULT) isoforms are capable of catalyzing those reactions. We determined apparent K(m) values for 10 recombinant human SULT isoforms, as well as the three most common allozymes for SULT1A1 and SULT1A2, with 2-OHE1, 2-OHE2, 4-OHE1, and 4-OHE2, and with the endogenous estrogens, estrone (E1) and 17beta-estradiol (E2), as substrates. With the exception of SULT1B1, SULT1C1, and SULT4A1, all of the human SULTs studied catalyzed the sulfate conjugation of CEs. SULT1E1 had the lowest apparent K(m) values, 0.31, 0.18, 0.27, and 0.22 microM for 4-OHE1, 4-OHE2, 2-OHE1, and 2-OHE2, respectively. These results demonstrate that SULTs can catalyze the sulfate conjugation of CEs, and they raise the possibility that individual variation in this pathway for estrogen and CE metabolism as a result of common genetic polymorphisms could represent a risk factor for estrogen-dependent carcinogenesis.

Background: This pooled analysis evaluated the outcomes of prophylactic cranial irradiation (PCI) in 739 small-cell lung cancer (SCLC patients with stable disease (SD) or better following chemotherapy ± thoracic radiation therapy (TRT) to examine the potential advantage of PCI in a wider spectrum of patients than generally participate in PCI trials. Patients and methods: Three hundred eighteen patients with extensive SCLC (ESCLC) and 421 patients with limited SCLC (LSCLC) participated in four phase II or III trials. Four hundred fifty-nine patients received PCI (30 Gy/15 or 25 Gy/10) and 280 did not. Survival and adverse events (AEs) were compared. Results: PCI patients survived significantly longer than non-PCI patients {hazard ratio [HR] = 0.61 [95% confidence interval (CI): 0.52–0.72]; P< 0.0001}. The 1- and 3-year survival rates were 56% and 18% for PCI patients versus 32% and 5% for non-PCI patients. PCI was still significant after adjusting for age, performance status, gender, stage, complete response, and number of metastatic sites (HR = 0.82, P = 0.04). PCI patients had significantly more grade 3+ AEs (64%) compared with non-PCI patients (50%) (P= 0.0004). AEs associated with PCI included alopecia and lethargy. Dose fractionation could be compared only for LSCLC patients and 25 Gy/10 was associated with significantly better survival compared with 30 Gy/15 (HR = 0.67, P = 0.018). Conclusions: PCI was associated with a significant survival benefit for both ESCLC and LSCLC patients who had SD or a better response to chemotherapy ± TRT. Dose fractionation appears important. PCI was associated with an increase in overall and specific grade 3+ AE rates.

BACKGROUND: Acetaminophen (APAP) use in early pregnancy has been associated with the risk of gastroschisis, a rare but serious congenital defect of the abdominal wall. The purpose of this study was to characterize the variability of APAP sulfation in a panel of human fetal livers and to identify the sulfotransferases (SULT) isoform(s) responsible for catalyzing that activity. METHODS: APAP sulfation was determined in a panel of human fetal (n = 73) and postnatal (n = 18) liver cytosol preparations and correlated with the catalytic activity of various SULT isoforms as determined using prototypic substrates and specific antibodies. RESULTS: Of 10 heterologously expressed SULT isoforms examined, SULT1A1, SULT1A3/4, SULT1E1, and SULT2A1 all catalyzed the formation of APAP sulfate with Km values of 2.4, 1.5, 1.9, and 3.7 mM, respectively. Catalytic activities for these four isoforms were expressed at varying levels in human fetal liver, and APAP sulfation was positively correlated with each of the four prototypic activities. Several regression and clustering approaches revealed that SULT1A3/4 was the primary determinant of prenatal APAP sulfation but that SULT1A1 or SULT1E1 were also major contributors in subsets of samples. CONCLUSIONS: The results of this study lead to the hypothesis that genetic variation in SULT1A3/4 represents a risk factor for the development of gastroschisis in the offspring of mothers exposed to APAP early in pregnancy. Interpretation of genetic association studies conducted to test this hypothesis will be complicated by the variable contributions of other SULTs toward APAP-sulfate formation in individual subjects. Birth Defects Research (Part A), 2007. © 2007 Wiley-Liss, Inc.

The purpose of this study was to investigate the sulfation of resveratrol (3,5,4'-trihydroxystilbene) and its potential to exhibit drug-drug interactions via sulfation. The possible interaction of resveratrol with 17beta-estradiol (E2), a major estrogen hormone and prototypic substrate for sulfate conjugation, was studied. Resveratrol and E2 are both known to undergo sulfate conjugation catalyzed by human sulfotransferases (SULTs). Resveratrol is a phytoestrogen with mixed estrogen agonist/antagonist properties that is being developed as a chemopreventive agent. The sulfate conjugation of E2 and resveratrol were studied individually using S9 fractions from human liver and jejunum as well as recombinant human SULT isoforms. The sulfation of E2 (3-20 nM) was then investigated in the presence of various concentrations (0, 0.5, 1, and 2 microM) of resveratrol using the two S9 preparations as well as recombinant SULT1E1, the major isoform responsible for E2 sulfation. Resveratrol inhibited E2 sulfation with estimated K(i) values of 1.1 microM (liver), 0.6 microM (jejunum), and 2.3 microM (SULT1E1), concentrations that could be pharmacologically relevant. The results suggest that these phytoestrogens can potentially alter the homeostasis of estrogen levels. These findings also imply that resveratrol may inhibit the metabolism of other estrogen analogs or therapeutic agents such as ethinylestradiol or dietary components that are also substrates for SULT1E1.

152 Background: Advanced EGC is an aggressive cancer with limited treatment (Rx) options. In preclinical studies P has demonstrated increased cellular uptake and polyglutamylation relative to other anti-folates plus is synergistic with platinum. We evaluated combination P plus O in aEGC and examined pharmacogenomics and tumor microRNA profiling to identify predictive signatures for response and toxicity. Here we report on clinical outcome data for the entire cohort. Methods: Objective response (OR) following P+O was assessed in an exact 2-stage design, including early stopping for futility and a safety lead-in cohort of 6 patients (pts) with provisions for dose de-escalation for dose limiting toxicity (DLT). Eligibility included metastatic/unresectable, therapy-naïve EGC pts with adequate organ and functional status and < G2 neuropathy. Rx consisted of biweekly O (85mg/m2) plus P (Dose level [D] 1, 120mg/m2; dose level -1 [D-1] 100 mg/m2). O was stopped after 12 cycles. Secondary endpoints were toxicity, survival and molecular correlates. Results: The study met its interim efficacy threshold and proceeded to full accrual. 35 pts, median age 67 yrs (39-83), 32 males, mostly adenocarcinoma (29) were accrued. 2/4 pts at D1 developed DLTs (1 G3 diarrhea, 1 G3 mucositis). All remaining pts were treated at D-1, which had no DLTs in the safety cohort. G4 toxicity included neutropenia (2) and myocardial infarction (1). The most common G3 events were mucositis (5), dehydration and neutropenia (4 each), anorexia, neuropathy, fatigue and nausea/vomiting (all 3 each). Including G1 and 2 events, myelosuppression, mucositis and neuropathy were the most common toxicities. Median # of P cycles administered at D-1 was 8 (1, 17). In an intent to treat analysis, confirmed OR was 23% (8/35) and 16 pts (46%) had stable disease. 3 pts were non-evaluable for response. Conclusions: Combination O and P administered biweekly at 85mg/m2 and 100 mg/m2 respectively is safe, well-tolerated and has modest efficacy in aEGC. Survival analysis results will be available for the meeting. This study was approved and funded by the NCCN from general research support provided by Allos Therapeutics, a subsidiary of Spectrum Pharmaceuticals, Inc. Clinical trial information: NCT01178944.

SULT1A1, which catalyzes the sulfate conjugation of a wide variety of natural and synthetic compounds, is genetically polymorphic. Biochemical and pharmacogenetic studies have demonstrated that individual variation in the level of enzyme activity is inherited. Common single-nucleotide polymorphisms (SNPs) located in the open reading frame and in the 5'-flanking region (5'-FR) may account for a portion of this individual variation. In this study, we demonstrate the presence of SULT1A1 gene deletions and duplications, representing an additional source of variability in the metabolic activity of this enzyme. A quantitative multiplex PCR assay was used to measure the extent of copy number differences and the frequency of these events in different populations. An analysis of DNA from 362 Caucasian-American and 99 African-American showed the presence of 1 to approximately 5 copies of SULT1A1 in individual samples: 5% of Caucasian subjects contained a single copy of the gene and 26% had three or more copies, while 63% of African-American subjects had three or more copies. Analysis of the genomic region surrounding the SULT1A1 gene in three separate cases with a deletion demonstrated that the entire SULT1A1 gene was affected. Reporter assays, constructed for each of the various 5'-FR SNP haplotypes, suggest that these may also play a role in SULT1A1 activity. However, the variability in the level of enzyme activity among 23 human platelet and 267 human liver samples was best explained by gene copy number differences when all sources of genetic variability were considered (P < 0.0001). Overall, these observations have obvious implications for the effectiveness of SULT1A1 as a drug and hormone metabolizing enzyme and its potential role as a risk factor for disease.

Aromatase [cytochrome P450 19 (CYP19)] is a critical enzyme for estrogen biosynthesis, and aromatase inhibitors are of increasing importance in the treatment of breast cancer. We set out to identify and characterize genetic polymorphisms in the aromatase gene, CYP19, as a step toward pharmacogenomic studies of aromatase inhibitors. Specifically, we “resequenced” all coding exons, all upstream untranslated exons plus their presumed core promoter regions, all exon-intron splice junctions, and a portion of the 3′-untranslated region of CYP19 using 240 DNA samples from four ethnic groups. Eighty-eight polymorphisms were identified, resulting in 44 haplotypes. Functional genomic studies were done with the four nonsynonymous coding single nucleotide polymorphisms (cSNP) that we observed, two of which were novel. Those cSNPs altered the following amino acids: Trp39Arg, Thr201Met, Arg264Cys, and Met364Thr. The Cys264, Thr364, and double variant Arg39Cys264 allozymes showed significant decreases in levels of activity and immunoreactive protein when compared with the wild-type (WT) enzyme after transient expression in COS-1 cells. A slight decrease in protein level was also observed for the Arg39 allozyme, whereas Met201 displayed no significant changes in either activity or protein level when compared with the WT enzyme. There was also a 4-fold increase in apparent Km value for Thr364 with androstenedione as substrate. Of the recombinant allozymes, only the double mutant (Arg39Cys264) displayed a significant change from the WT enzyme in inhibitor constant for the aromatase inhibitors exemestane and letrozole. These observations indicate that genetic variation in CYP19 might contribute to variation in the pathophysiology of estrogen-dependent disease.

Purpose We determined the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLT) of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when infused on days 1, 8, and 15 of a 28-day cycle in advanced solid tumor patients. We also characterized the pharmacokinetics of 17-AAG, its effect on chaperone and client proteins, and whether cytochrome P450 (CYP) 3A5 and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphisms affected 17-AAG disposition or toxicity. Patients and Methods An accelerated titration design was used. Biomarkers were measured in peripheral-blood mononuclear cells (PBMCs) at baseline and on days 1 and 15, and pharmacokinetic analysis was performed on day 1 of cycle 1. CYP3A5*3 and NQO1*2 genotypes were determined and correlated with pharmacokinetics and toxicity. Results Twenty-one patients received 52 courses at 11 dose levels. DLTs at 431 mg/m2 were grade 3 bilirubin (n = 1), AST (n = 1), anemia (n = 1), nausea (n = 1), vomiting (n = 1), and myalgias (n = 1). No tumor responses were seen. 17-AAG consistently increased heat shock protein (Hsp) 70 levels in PBMCs. At the MTD, the clearance and half-life (t1/2) of 17-AAG were 11.6 L/h/m2 and 4.15 hours, respectively; whereas the active metabolite 17-aminogeldanamycin had a t1/2 of 7.63 hours. The CYP3A5*3 and NQO1*2 polymorphisms were not associated with 17-AAG toxicity. The CYP3A5*3 polymorphism was associated with higher 17-AAG clearance. Conclusion The MTD of weekly 17-AAG is 308 mg/m2. 17-AAG induced Hsp70 in PBMCs, indicating that Hsp90 has been affected. Further evaluation of 17-AAG is ongoing using a twice-weekly regimen, and this schedule of 17-AAG is being tested in combination with chemotherapy.

1. Estrogens are used as drugs and estrogen exposure is a risk factor for hormone-dependent diseases such as breast cancer. Sulfate conjugation is an important pathway for estrogen metabolism. The sulfotransferase (SULT) enzyme SULT1E1 has the lowest K(m) values for estrogens and catecholestrogens of the 10 known human SULT isoforms. 2. We previously cloned and characterized the human SULT1E1 cDNA and gene as steps toward pharmacogenetic studies. In the present experiments, we set out to determine whether common, functionally significant genetic polymorphisms might exist for SULT1E1. As a first step, we 'resequenced' the eight SULT1E1 exons and exon-intron splice junctions as well as portions of the 5'-flanking region using DNA from 60 African-American and 60 Caucasian-American subjects. 3. In all, 23 polymorphisms, 22 single nucleotide polymorphisms (SNPs) and one insertion deletion were observed. There were three nonsynonymous coding SNPs (cSNPs) that altered the following encoded amino acids: Asp22Tyr, Ala32Val and Pro253His. Among these, 12 pairs of SNPs were tightly linked. In addition, 12 unambiguous SULT1E1 haplotypes were identified, including six that were common to both populations studied. 4. Transient expression in COS-1 cells of constructs containing the three nonsynonymous cSNPs showed significant decreases in SULT1E1 activity for the Tyr22 and Val32 allozymes, with corresponding decreases in levels of immunoreactive protein. There were no changes in levels of either activity or immunoreactive protein for the His253 allozyme. Apparent K(m) values of the Val32 allozyme for the two cosubstrates for the reaction, 17beta-estradiol and 3'-phosphoadenosine 5'-phosphosulfate, were not significantly different from those of the wild-type enzyme, but there was a two- to three-fold increase in K(m) values for the His253 allozyme and a greater than five-fold increase for the Tyr22 allozyme. 5. These observations raise the possibility that genetically determined variation in SULT1E1-catalyzed estrogen sulfation might contribute to the pathophysiology of estrogen-dependent diseases as well as variation in the biotransformation of exogenously administered estrogens.

Docetaxel has yielded promising response rates as a component of doxorubicin-based combination schedules in patients with metastatic breast cancer, including docetaxel/doxorubicin and docetaxel/doxorubicin/cyclophosphamide (AC). This randomized two-stage phase II study was conducted to evaluate sequential treatment with docetaxel and AC as first-line treatment in patients with recurrent or metastatic breast cancer previously untreated with chemotherapy for metastatic disease.Thirty-three patients were randomized to either docetaxel (100 mg/m(2)) on day 1 of a 21-day cycle for three cycles followed by AC (60/600 mg/m(2)) on day 1 of a 21-day cycle for three cycles (n = 17) or vice-versa (n = 16), without prophylactic granulocyte colony-stimulating factor support. In addition, we compared pre-treatment serum sErbB1 and sErbB2 protein concentrations with that of an age- and menopausal status-matched group of healthy women, and examined changes in serum sErbB1 and sErbB2 protein concentrations in these two treatment schedules. Data from each one of the two arms of the trial (docetaxel then AC, or AC and then docetaxel) were analyzed separately.Enrollment was suspended after the first-stage of accrual, based on statistical design. Confirmed objective response rates after six cycles of treatment were 35% [95% confidence interval (CI) 14% to 62%] with docetaxel then AC and 38% (95% CI 15% to 65%) with AC then docetaxel. Dose reductions were frequent and mostly due to grade 4 neutropenia. Median survival time was 2.5 years in the docetaxel then AC group, and 1.1 years in the AC then docetaxel group. Serum sErbB1 concentrations were not significantly different between the study patients and healthy women, and did not change significantly after three and six cycles of treatment. In contrast, serum sErbB2 concentrations were significantly higher in the study patients compared with healthy women and tended to decrease after three and six cycles of treatment.Response rates at the end of six cycles of treatment, which led to termination of accrual after the first stage using either the sequence of docetaxel first or docetaxel after AC chemotherapy, were lower than anticipated. However, median survival times and median progression-free survival times are similar to those reported in other studies. These data further suggest that additional studies to assess whether serum sErbB2 concentrations are useful predictors of responsiveness to chemotherapy are warranted.

Our previous studies have shown that the in vitro cytotoxicity of gemcitabine and SN-38, the active metabolite of irinotecan (CPT-11), is synergistic in human tumor cell lines.Twenty-four patients with solid tumors, refractory to standard chemotherapy or for whom no effective therapy existed (age range 31-74; 7 female, 17 male; ECOG PS 0 = 12, 1 = 11, 2 = 1), received gemcitabine and CPT-11 weekly for four weeks out of every six weeks. Fifty courses of treatment (median 2, range 1-8) were given through five dose levels of gemcitabine/CPT-11 (600/75, 800/75, 800/100, 1000/100, 1000/125 mg/m2).Grade 3 and 4 neutropenia occurred in eight and two patients, respectively. Grade 3 and 4 thrombocytopenia occurred in one and three patients, respectively. Hematologic toxicity resulted inor = 2 missed doses of treatment in two out of six patients and was therefore dose limiting at gemcitabine 1000 mg/m2 and CPT-11 125 mg/m2. Grade 3 and 4 diarrhea occurred in two and one patients, respectively. Other moderate non-hematologic toxicities included alopecia, anorexia, fatigue, nausea, vomiting, and weight loss.The maximum tolerated dose for this study recommended for phase II testing is gemcitabine 1000 mg/m2 and CPT-11 100 mg/m2. A partial response was seen in transitional cell carcinoma.

Raltitrexed (Tomudex) is a specific inhibitor of thymidylate synthase with clinical activity in colorectal cancer. The combination of raltitrexed and 5-iodo-2'-deoxyuridine (IdUrd, a cytotoxic pyrimidine analog) resulted in increased IdUrd incorporation into DNA and exhibited in vitro synergism against colon and bladder human carcinoma cell lines. We designed a phase I trial to determine the MTD, pharmacokinetics, and biologic effects of escalating doses of the combination of IdUrd given as a 24-hour infusion after a raltitrexed 15-minute infusion every three weeks. Thirty-four patients received 95 courses of raltitrexed and IdUrd at doses ranging from raltitrexed 1 mg/m2 and IdUrd 750 mg/m2 to raltitrexed 2.5 mg/m2 and IdUrd 10,400 mg/m2. The median number of cycles administered was 2 (range 1-10). Dose limiting hematologic toxicity occurred at doses of raltitrexed 2.5 mg/m2 and IdUrd 10,400 mg/m2. In addition, we determined the mean plasma concentrations C(SS) of IdUrd, the iodouracil level at 22 hours and the IdUrd clearance. Raltitrexed did not appear to affect the pharmacokinetics of IdUrd in the dose range tested. The recommended phase II dose is raltitrexed 2 mg/m2 and IdUrd 10,400 mg/m2 repeated every three weeks. Evidence of potential antitumor activity was observed: 1 patient (with colon cancer) had a partial response while 15 others had stable disease.

Pemetrexed disodium (ALIMTA, LY231514 (MTA)) is a novel multitargeted antifolate, that inhibits at least three enzymes involved in folate metabolism and DNA synthesis. These enzymes are thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. This agent has shown broad antitumor activity in phase II trials in a wide variety of solid tumors, including non-small cell lung cancer, breast, colon, pancreas, bladder, head and neck, and cervical carcinomas, and is undergoing randomized phase III studies. MTA has also shown promising activity in a broad range of tumors in combination with other active agents such as gemcitabine and cisplatin. The clinical pharmacology, toxicity and clinical activity of MTA are reviewed in this report.

Background Metaplastic breast cancer is a rare disease with little information available to guide therapy. The goals of this study were to describe the patient characteristics, systemic therapies and clinical outcomes of all patients with primary metaplastic breast cancer treated at Mayo Clinic between 1976 and 1997. Patients and methods Patients were identified through the medical index of Mayo Clinic. Clinical information was abstracted from the medical record of each patient. A literature search using MEDLINE and CANCERLIT for the years 1966-1997 was performed to identify all previously reported case series in the English language containing 10 or more patients. Results Twenty-seven patients were identified with a median age at diagnosis of 59 years (range 39-90 years). The median tumor size was 3.4 cm (range 0.5-7.0 cm). One patient had metastatic disease at presentation. Twenty-three patients had information available on nodal status, estrogen receptor (ER) and progesterone receptor (PR) status. Twenty patients (87%) were node-negative and three patients (13%) were both ER and PR positive. Disease-free survival (DFS) and overall survival (OS) were assessed for those who presented with local-regional disease. The three-year DFS was 40% (95% CI: 23%-73%) and the three-year OS was 71% (95% CI: 51%-97%). In univariate analysis, those patients 60 years of age or older at diagnosis were found to have an increased DFS (P = 0.011). Among those with prior estrogen use, both DFS (P = 0.022) and OS (P = 0.003) were decreased. Thirteen patients (50%) developed metastases with a median DFS time of 2.4 years. Ten different chemotherapy regimens were utilized for metastatic disease and one partial response was observed. There were no responses to tamoxifen in four patients with metastatic disease. Median survival after the development of metastases was eight months. Conclusions Despite presenting more commonly as node-negative disease, DFS and OS in metaplastic breast cancer is decreased compared to typical adenocarcinomas. Systemic therapy also appears to be less effective. Patients with metaplastic breast cancer, particularly those with metastatic disease could be appropriate candidates for innovative therapeutic regimens.

7074 Background: This pooled analysis was performed to evaluate the results of PCI in SCLC patients (pts). 739 pts with stable disease or better following chemotherapy+/-thoracic RT (TRT) were included to examine the potential advantage of PCI in a wider spectrum of pts than generally participate in PCI trials. Methods: 318 pts with extensive SCLC (ESCLC) and 421 pts with limited SCLC (LSCLC) participated in 4 NCCTG phase II trials. 459 pts received PCI (30Gy/15 or 25Gy/10) and 280 did not. Survival and acute events (AEs) were compared using a landmark analysis. Results: PCI pts had significantly improved survival as compared to pts who didn’t receive PCI (HR=0.61 [95% CI: 0.52, 0.72]; p

7013 Background: Adj chemo has been shown to improve absolute survival after resection of early stage NSCLC by 5-15%. Encouraging results with B on E4599 in advanced stage NSCLC led to trial develo...