Philip C Mack

University of California, Davis, Davis, California, United States

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Publications (109)494.91 Total impact

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    ABSTRACT: Extensive-stage small-cell lung cancer (SCLC) patients who progress after platinum-based chemotherapy are traditionally categorized as platinum sensitive (progression ≥ 90 days from last platinum dose) or refractory (progression < 90 days), a practice arising from seminal observations of worse survival in refractory patients. Subsequent trials accounted for platinum sensitivity, resulting in higher sample sizes and increased resource use. To assess whether platinum-sensitivity status remains associated with outcomes, patient-level data from recent Southwest Oncology Group trials in second- and/or third-line extensive-stage SCLC were pooled. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) accounting for platinum sensitivity were calculated using unadjusted and adjusted Cox Proportional Hazard models. Recursive partitioning was performed to define prognostic risk groups. Of 329 patients, 151 were platinum sensitive and 178 refractory. HRs from unadjusted Cox PFS and OS models for refractory versus sensitive disease were 1.0 (95% confidence interval, 0.81-1.25; p = 0.98) and 1.24 (0.99-1.57; p = 0.06), respectively. Adjusted Cox models showed that only elevated serum lactate dehydrogenase (HR, 2.04; p < 0.001), males (HR, 1.36; p = 0.04), performance status of 1 (HR, 1.25; p = 0.02), and weight loss greater than or equal to 5% (1.53, p = 0.01) were independently associated with OS. Platinum-sensitivity status was not associated with PFS (HR, 1.11; p = 0.49) or OS (HR, 1.25; p = 0.14), except in a model that excluded 36 patients who received more than one prior chemotherapy regimen (HR, 1.34; p = 0.049). Prognostic groups with differential OS outcomes (high, intermediate, and poor risk) were identified. Platinum-sensitivity status may no longer be strongly associated with PFS or OS in at least one multivariate model. Validation of prognostic risk groups identified here is warranted. These data have critical implications in the design of future SCLC trials.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2014; · 4.55 Impact Factor
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    ABSTRACT: Acquired resistance to erlotinib in patients with EGFR-mutant non-small cell lung cancer can result from aberrant activation of alternative receptor tyrosine kinases, such as the HGF-driven c-MET receptor. We sought to determine whether inhibition of AKT signaling could augment erlotinib activity and abrogate HGF-mediated resistance.
    Journal of Cancer Research and Clinical Oncology 10/2014; · 2.91 Impact Factor
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    ABSTRACT: Circulating tumor cells (CTC) are promising biomarkers in metastatic castration resistant prostate cancer (mCRPC), and telomerase activity (TA) is a recognized cancer marker. Therefore, we hypothesized that CTC TA may be prognostic of overall survival (OS) in mCRPC. To test this, we used a novel Parylene-C slot microfilter to measure live CTC TA in S0421, a phase 3 SWOG-led therapeutic trial. Blood samples underwent CTC capture and TA measurement by microfilter, as well as parallel enumeration by CellSearch (Janssen/J&J). Cox regression was used to assess baseline (pre-treatment) TA vs. OS, and recursive partitioning was used to explore potential prognostic subgroups and to generate Kaplan-Meier (KM) OS curves. Samples were obtained from 263 patients and generated 215 TA measures. In patients with baseline CTC count ≥5 (47% of patients), higher CTC TA was associated with hazard ratio 1.14 (p=0.001) for OS after adjusting for other clinical covariates including CTC counts and serum PSA at study entry. Recursive partitioning identified new candidate risk groups with KM OS curve separation based on CTC counts and TA. Notably, in men with an intermediate range baseline CTC count (6-54 CTCs/7.5ml), low vs. high CTC TA was associated with median survival of 19 vs. 12 months, respectively (p=0.009). Baseline telomerase activity from CTCs live-captured on a new slot microfilter is the first CTC-derived candidate biomarker prognostic of OS in a large patient subgroup in a prospective clinical trial. CTC telomerase activity thus merits further study and validation as a step towards molecular CTC-based precision cancer management. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 09/2014; · 6.20 Impact Factor
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    ABSTRACT: Erlotinib marginally improves survival when administered continuously with gemcitabine to patients with advanced pancreatic cancer; however, preclinical data suggest that there is antagonism between chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors when these are delivered concurrently. We tested a pharmacodynamic separation approach for erlotinib plus gemcitabine and interrogated EGFR signaling intermediates as potential surrogates for the efficacy of this strategy.
    International Journal of Clinical Oncology 08/2014; · 1.73 Impact Factor
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    ABSTRACT: Development of new therapies for previously treated small-cell lung cancer (SCLC) is a major unmet need. Here, we describe a randomized, phase II trial of weekly topotecan with or without ziv-aflibercept (VEGF-trap) in this clinical setting.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 07/2014;
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    ABSTRACT: Aurora kinases are key regulators of mitotic events. Dysfunction of these kinases can cause polyploidy and chromosomal instability, a contributor to tumorigenesis. MK-5108 is a potent inhibitor of Aurora A kinase that has shown preclinical potent activity in malignancies of breast, cervical, colon, ovarian, and pancreatic origin. We sought to assess the preclinical efficacy of MK-5108 in a panel of non-small-cell lung cancer cell lines as a single agent and in combination with cisplatin and docetaxel. Eleven lung cancer cell lines were studied. Growth inhibition by MK-5108 was assessed with short- and long-term MTT assays. Cell cycling was measured by flow cytometry. Immunoblotting was used to determine targeted activity of MK-5108 on Aurora A and downstream effects (TACC3 and Plk1). Efficacy of combination studies performed with cisplatin and docetaxel was evaluated by median effect analysis. All cell lines demonstrated sustained growth inhibition following MK-5108 at varying nanomolar concentrations. MK-5108 induced G2/M accumulation, polyploidy, and apoptosis (increased sub-G1/PARP cleavage). Levels of Aurora A, TACC3, and Plk1 diminished. Concurrent treatment of MK-5108 with cisplatin or docetaxel synergistically inhibited cell growth with the docetaxel combination performing better. When administered sequentially, treatment with docetaxel first followed by MK-5108 exhibited greater growth inhibition than the inverse; yet concurrent treatment remained superior. MK-5108 has potent anti-proliferative activity in lung cancer cell lines alone and in combination with chemotherapies. Determining how best to integrate Aurora inhibitors into current lung cancer treatment regimens would be beneficial.
    Journal of Cancer Research and Clinical Oncology 04/2014; · 2.91 Impact Factor
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    ABSTRACT: Papillary renal cell carcinoma (pRCC) represents the second most common histologic variant of kidney cancer. It exhibits a different molecular signature than clear-cell carcinoma and is typically not associated with mutations in the VHL (von Hippel-Lindau) tumor suppressor gene. pRCC is less responsive to modern drugs introduced in the management of kidney cancer in the past decade. In this article, the heredity and biology of 2 main variants of pRCC are outlined. New targets that are being explored in the treatment of this disease are discussed, with particular emphasis on inhibition of mesenchymal epithelial transition (MET) and epidermal growth factor receptor (EGFR) pathways. We discuss preclinical data providing rationale for the combination of MET and EGFR inhibitors and review recently completed and ongoing clinical trials that attempt to expand our therapeutic options for this important subset of kidney cancer.
    Clinical Genitourinary Cancer 04/2014; 12(2):74-79. · 1.43 Impact Factor
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    ABSTRACT: BACKGROUND This cooperative group adjuvant phase 2 trial in patients with completely resected stage I non-small cell lung cancer with tumor diameters measuring ≥ 2 cm was designed to assess the feasibility and preliminary efficacy of assigning patients to therapy or observation using a molecularly based decision algorithm.METHODS At least a lobectomy and sampling of recommended mediastinal lymph node stations, good Zubrod performance status, adequate organ function, and a formalin-fixed and paraffin-embedded tumor specimen were required. Excision repair cross-complementing group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) were analyzed using immunofluorescence-based in situ automated quantitative image analysis and categorized as high or low using prespecified cutoff values. Patients with high ERCC1 and RRM1 were assigned to observation and all others to 4 cycles of cisplatin and gemcitabine. Feasibility was defined as treatment assignment within 84 days from surgery in > 85% of patients. Secondary objectives were to estimate the 2-year survival.RESULTSTreatment assignment met the feasibility criteria in 88% of eligible patients (71 of 81 patients). The collective 2-year disease-free and overall survival rates were 80% and 96%, respectively. Protein levels for RRM1 fell within the previously established range, ERCC1 levels were slightly lower than expected, and they were significantly correlated (correlation coefficient, 0.4). The rates of assignment of patients to observation (22%) and chemotherapy (78%) were as expected.CONCLUSIONS Gene expression analysis for treatment assignment is feasible. Survival results are encouraging and require future validation. Real-time performance of quantitative in situ ERCC1 and RRM1 analysis requires further development. Cancer 2014. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
    Cancer 04/2014; · 5.20 Impact Factor
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    ABSTRACT: Molecular testing of patients with advanced non-small cell lung cancer for personalized therapy often is limited by insufficient specimen from nonsurgical biopsies. We measured the feasibility, patient safety, and clinical impact of thoracic surgical tumor biopsy in patients with stage IV non-small cell lung cancer. This is a single institution retrospective analysis. Patients with stage IV non-small cell lung cancer undergoing elective surgical tissue biopsy for molecular analysis were evaluated from March 2011 to November 2012. Perioperative specific variables were measured. Twenty-five patients with known or suspected stage IV non-small cell lung cancer undergoing surgical biopsy were identified. All cases were discussed at a multidisciplinary thoracic oncology conference or a multidisciplinary thoracic oncology clinic. Preoperative histologies included adenocarcinoma in 20 patients (80.0%) and squamous cell carcinoma in 2 patients (8.0%). Surgical procedures consisted of video-assisted thoracic surgery wedge biopsy (16, 64%), video-assisted thoracic surgery pleural biopsy (4, 16.0%), mediastinoscopy (2, 8.0%), supraclavicular/cervical lymph node excisional biopsy (3, 12.0%), and rib/chest wall resection (2, 8.0%). There were no deaths and 5 postoperative complications (20.0%). Surgery identified potentially targetable molecular information in 19 of the total patients undergoing operation (76.0%) and changed the treatment strategy in 14 patients (56.0%); 10 of the total cohort (40.0%) were enrolled into therapeutic targeted clinical trials. These data suggest that thoracic surgical biopsy can be safely performed in appropriately selected patients with stage IV non-small cell lung cancer and direct personalized therapy and enrollment into relevant clinical trials. Patients with advanced-stage non-small cell lung cancer should be discussed in a multidisciplinary setting to determine the need and strategy for thoracic surgical biopsy for molecular analysis.
    The Journal of thoracic and cardiovascular surgery 03/2014; · 3.41 Impact Factor
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    ABSTRACT: Circulating tumor cell (CTC) enumeration has not been prospectively validated in standard first-line docetaxel treatment for metastatic castration-resistant prostate cancer. We assessed the prognostic value of CTCs for overall survival (OS) and disease response in S0421, a phase III trial of docetaxel plus prednisone with or without atrasentan. CTCs were enumerated at baseline (day 0) and before cycle two (day 21) using CellSearch. Baseline counts and changes in counts from day 0 to 21 were evaluated for association with OS, prostate-specific antigen (PSA), and RECIST response using Cox regression as well as receiver operator characteristic (ROC) curves, integrated discrimination improvement (IDI) analysis, and regression trees. Median day-0 CTC count was five cells per 7.5 mL, and CTCs < versus ≥ five per 7.5 mL were significantly associated with baseline PSA, bone pain, liver disease, hemoglobin, alkaline phosphatase, and subsequent PSA and RECIST response. Median OS was 26 months for < five versus 13 months for ≥ five CTCs per 7.5 mL at day 0 (hazard ratio [HR], 2.74 [adjusting for covariates]). ROC curves had higher areas under the curve for day-0 CTCs than for PSA, and IDI analysis showed that adding day-0 CTCs to baseline PSA and other covariates increased predictive accuracy for survival by 8% to 10%. Regression trees yielded new prognostic subgroups, and rising CTC count from day 0 to 21 was associated with shorter OS (HR, 2.55). These data validate the prognostic utility of CTC enumeration in a large docetaxel-based prospective cohort. Baseline CTC counts were prognostic, and rising CTCs at 3 weeks heralded significantly worse OS, potentially serving as an early metric to help redirect and optimize therapy in this clinical setting.
    Journal of Clinical Oncology 03/2014; · 18.04 Impact Factor
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    ABSTRACT: Prior studies suggest that elevated markers of bone turnover are prognostic for poor survival in castration-resistant prostate cancer (CRPC). The predictive role of these markers relative to bone-targeted therapy is unknown. We prospectively evaluated the prognostic and predictive value of bone biomarkers in sera from CRPC patients treated on a placebo-controlled phase III trial of docetaxel with or without the bone targeted endothelin-A receptor antagonist atrasentan (SWOG S0421). Markers for bone resorption (N-telopeptide and pyridinoline) and formation (C-terminal collagen propeptide and bone alkaline phosphatase) were assayed in pretreatment and serial sera. Cox proportional hazards regression models were fit for overall survival. Models were fit with main effects for marker levels and with/without terms for marker-treatment interaction, adjusted for clinical variables, to assess the prognostic and predictive value of atrasentan. Analysis was adjusted for multiple comparisons. Two-sided P values were calculated using the Wald test. Sera from 778 patients were analyzed. Elevated baseline levels of each of the markers were associated with worse survival (P < .001). Increasing marker levels by week nine of therapy were also associated with subsequent poor survival (P < .001). Patients with the highest marker levels (upper 25th percentile for all markers) not only had a poor prognosis (hazard ratio [HR] = 4.3; 95% confidence interval [CI] = 2.41 to 7.65; P < .001) but also had a survival benefit from atrasentan (HR = 0.33; 95% CI = 0.15 to 0.71; median survival = 13 [atrasentan] vs 5 months [placebo]; P interaction = .005). Serum bone metabolism markers have statistically significant independent prognostic value in CRPC. Importantly, a small group of patients (6%) with highly elevated markers of bone turnover appear to preferentially benefit from atrasentan therapy.
    CancerSpectrum Knowledge Environment 02/2014; · 14.07 Impact Factor
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    ABSTRACT: Cetuximab and bevacizumab have each been demonstrated to prolong survival when added to chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). However, the potential benefit of combining cetuximab and bevacizumab together with a platinum-based doublet had not been explored. We designed this phase II trial to evaluate the safety, tolerability, and efficacy of the combination of carboplatin, paclitaxel, cetuximab, and bevacizumab in chemotherapy-naive patients with advanced, nonsquamous NSCLC. Patients received with up to six cycles of carboplatin (area under curve 6), paclitaxel (200 mg/m), cetuximab (400 mg/m day 1 then 250 mg/m weekly), and bevacizumab (15 mg/kg) every 21 days. Patients with an objective response or stable disease received maintenance cetuximab (250 mg/m weekly) and bevacizumab (15 mg/kg every 21 days) until disease progression. The primary endpoint was safety as defined by the frequency and severity of hemorrhagic toxicities. Secondary endpoints included response rate, progression-free survival, overall survival, and toxicity. Molecular biomarkers were assessed in an exploratory manner. The primary endpoint of grade 4 or higher hemorrhage of 2% (95% confidence interval: 0%-7%) met prespecified criteria for safety. One hundred ten patients were enrolled. There were four treatment-related deaths including lung hemorrhage (2), infection (1), and unknown (1). Median progression-free survival was 7 months and median overall survival was 15 months. The response rate was 56% with an overall disease control rate of 77%. This regimen was safe, feasible, and effective as a frontline treatment of advanced NSCLC, providing the basis for the ongoing phase III trial S0819.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 11/2013; · 4.55 Impact Factor
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    ABSTRACT: In the emerging era of targeted therapy for advanced-stage non-small-cell lung cancer, it is becoming increasingly important to anticipate underlying driver oncogene alterations at the time of initial diagnosis and tumor-tissue acquisition, so that patients can be selected in a timely fashion for first-line tyrosine kinase inhibitor (TKI) therapy if their cancers are found to harbor tyrosine-kinase-activating mutations in the epidermal growth factor receptor gene or gain-of-function rearrangements in the anaplastic lymphoma kinase gene. However, despite the clear benefits of TKI therapy over chemotherapy in these settings, the eventual emergence of acquired resistance and progressive disease (PD) is universal. How to best approach oncogene-driven non-small-cell lung cancer at the time of acquired resistance to initial TKI therapy is an increasingly complex question because of variability in mechanisms of resistance, extent of PD, and inter- and intrapatient tumor heterogeneity. Here we propose an approach to subtyping PD in the setting of acquired resistance as well as subsequent clinical implications.
    Clinical Lung Cancer 10/2013; · 2.04 Impact Factor
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    ABSTRACT: Background Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in non-small cell lung cancer (NSCLC). Based on preclinical demonstration of additive cytotoxicity, we evaluated the safety and efficacy of combining pemetrexed and nanoparticle albumin bound (nab) paclitaxel with a focus on NSCLC for phase II expansion. Methods A 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: pemetrexed 500 mg/m(2) day 1 and nab-paclitaxel day 1 at 180, 220, & 260 mg/m(2) every 21 days. Phase II eligibility included advanced NSCLC, ≤2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25 %. Results Planned dose escalation was completed without reaching the MTD. The RP2D was pemetrexed 500 mg/m(2) and nab-paclitaxel 260 mg/m(2). The phase II portion accrued 37 pts before early closure due to increasing first-line pemetrexed/platinum doublet use in non-squamous NSCLC. In 31 assessable phase II patients there were 5 partial responses, 12 stable disease, 14 progressive disease. The median overall survival was 8.8 months; progressive disease 4.4 months and disease control 15.6 months. Conclusions Pemetrexed 500 mg/m(2) day 1 with nab-paclitaxel 260 mg/m(2) was feasible and well tolerated. The phase II component demonstrated activity in second/third-line therapy of advanced NSCLC; response rate 14 % and disease control rate 46 %. Treatment practice patterns of advanced NSCLC have evolved; further trials of this regimen are not planned.
    Investigational New Drugs 09/2013; · 3.50 Impact Factor
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    ABSTRACT: Histologic subtyping has been advocated to select chemotherapy for patients with advanced-stage non-small-cell lung cancer (NSCLC). To determine whether histologic subtype was associated with efficacy for the commonly used antimicrotubule (AMT) agents, paclitaxel, docetaxel, and vinorelbine plus a platinum compound, we examined the Southwest Oncology Group (SWOG) lung cancer database. Data from 4 randomized trials (S9308, S9509, S9806, and S0003) administering an AMT agent plus platinum in patients receiving first-line treatment for advanced-stage NSCLC were analyzed. Overall survival (OS) and progression-free survival (PFS) comparisons were performed using Cox proportional hazard regression, adjusting for sex. Median survival times were estimated by Kaplan-Meier. Of 1146 patients included in this analysis, 640 had adenocarcinoma (56%), 220 had squamous cell carcinoma (19%), 121 had large cell carcinoma (11%), and 165 had NSCLC not otherwise specified (NOS) (14%). Median OS times by histologic subtypes were 8.5, 8.4, 8.2, and 9.6 months, respectively, and median PFS times were 4.2, 4.3, 4.3, and 4.6 months, respectively. No difference in OS or PFS was observed by histologic subtype and, specifically, between nonsquamous and squamous histologies. This pooled analysis from 4 SWOG trials using an AMT-platinum regimen did not show a difference in survival outcomes by histologic subtype. Because the majority of patients with advanced NSCLC continue to receive chemotherapy, defining molecular-based predictive markers of responsiveness is warranted.
    Clinical Lung Cancer 07/2013; · 2.04 Impact Factor
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    ABSTRACT: The endothelin pathway has a role in bone metastases, which are characteristic of advanced prostate cancer. Atrasentan, an endothelin receptor antagonist, has shown activity in prostate cancer. We therefore assessed its effect on survival in patients with castration-resistant prostate cancer with bone metastases. In a double-blind phase 3 trial, men with metastatic castration-resistant prostate cancer, stratified for progression type (prostate-specific antigen or radiological), baseline pain, extraskeletal metastases, and bisphosphonate use, were randomly assigned in a 1:1 ratio to docetaxel (75 mg/m(2) every 21 days, intravenously) with atrasentan (10 mg/day, orally) or placebo for up to 12 cycles and treated until disease progression or unacceptable toxicity. Patients who did not progress on treatment were permitted to continue atrasentan or placebo for up to 52 weeks. Coprimary endpoints were progression-free survival (PFS) and overall survival. Analysis was by intention to treat. This trial is registered with, number NCT00134056. 498 patients were randomly assigned to the atrasentan group and 496 to the placebo group. The trial was halted early for futility in April, 2011, after a planned interim analysis. Median PFS was 9·2 months (95% CI 8·5-9·9) in the atrasentan group and 9·1 months (8·4-10·2) in the placebo group (hazard ratio 1·02, 0·89-1·16; p=0·81). Median overall survival was 17·8 months (16·4-19·8) in the atrasentan group versus 17·6 months (16·4-20·1) in the placebo group (1·04, 0·90-1·19; p=0·64). 278 (57%) of 492 patients in the atrasentan group had grade 3 and greater toxicity compared with 294 (60%) of 486 in the placebo group (p=0·22). Three deaths in the atrasentan group and seven in the placebo group were judged to be possibly or probably due to protocol treatment. Atrasentan, when added to docetaxel, does not improve overall survival or PFS in men with castration-resistant prostate cancer and bone metastases; therefore, single-agent docetaxel should remain as one of the standard treatments. National Cancer Institute, Sanofi-Aventis, and Abbott Laboratories.
    The Lancet Oncology 07/2013; · 25.12 Impact Factor
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    ABSTRACT: INTRODUCTION:: On the basis of the results of recent clinical trials, histology-based decision-making for therapy of non-small-cell lung cancer has been advocated. We hypothesized associations of the biomarkers excision repair cross-complementing 1 (ERCC1), ribonucleotide reductase M1 (RRM1), and thymidylate synthase (TS) with histology as a contributing factor to reported differences in chemotherapy outcomes between squamous cell carcinoma (SCCA) and adenocarcinoma (AC) subtypes. Here, we report analysis of the Response Genetics Inc., database and implications for histology-based therapy. METHODS:: RNA from microdissected formalin-fixed paraffin-embedded tumors was extracted and analyzed as previously described. Specimens from 2540 individual non-small-cell lung cancer patients were analyzed for one or more biomarkers, of which 1457 were categorized as AC or SCCA. RESULTS:: For each biomarker, gene expression was lower in AC compared with SCCA (<0.001), although there was a wide range between individual patients. Gene expression was higher in men versus women: ERCC1: 2.51 versus 2.22 (p = 0.005); RRM1: 1.41 versus 1.24 (p = 0.004); TS: 3.23 versus 2.83 (p < 0.001). However, SCCA was more frequent in men versus women (30%/19%; p < 0.001). When AC and SCCA were assessed separately, the statistical significance between gene expression and sex was lost (in SCCA: ERCC1, p = 0.14; RRM1, p = 0.26; TS, p = 0.11). CONCLUSIONS:: This analysis represents the largest data set for gene expression of these biomarkers reported so far. Significant histology-related associations for ERCC1, RRM1, and TS are seen. However, marked heterogeneity exists in individual patient tumor expression levels. Randomized phase III trials assessing the predictive value of these chemotherapy-related biomarkers are warranted.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2013; · 4.55 Impact Factor
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    ABSTRACT: Substantial advances have been made in understanding critical molecular and cellular mechanisms driving tumor initiation, maintenance, and progression in non-small-cell lung cancer (NSCLC). Over the last decade, these findings have led to the discovery of a variety of novel drug targets and the development of new treatment strategies. Already, the standard of care for patients with advanced-stage NSCLC is shifting from selecting therapy empirically based on a patient's clinicopathologic features to using biomarker-driven treatment algorithms based on the molecular profile of a patient's tumor. This approach is currently best exemplified by treating patients with NSCLC with first-line tyrosine kinase inhibitors when their cancers harbor gain-of-function hotspot mutations in the epidermal growth factor receptor (EGFR) gene or anaplastic lymphoma kinase (ALK) gene rearrangements. These genotype-based targeted therapies represent the first step toward personalizing NSCLC therapy. Recent technology advances in multiplex genotyping and high-throughput genomic profiling by next-generation sequencing technologies now offer the possibility of rapidly and comprehensively interrogating the cancer genome of individual patients from small tumor biopsies. This advance provides the basis for categorizing molecular-defined subsets of patients with NSCLC in whom a growing list of novel molecularly targeted therapeutics are clinically evaluable and additional novel drug targets can be discovered. Increasingly, practicing oncologists are facing the challenge of determining how to select, interpret, and apply these new genetic and genomic assays. This review summarizes the evolution, early success, current status, challenges, and opportunities for clinical application of genotyping and genomic tests in therapeutic decision making for NSCLC.
    Journal of Clinical Oncology 02/2013; · 18.04 Impact Factor
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    ABSTRACT: Background KRAS mutations are associated with diverse biologic functions as well as prognostic and predictive impact in non-small cell-lung cancer (NSCLC) and colorectal cancer (CRC). In CRC, benefit from monoclonal antibody therapies targeting EGFR is generally limited to patients whose tumors have wild-type (WT) KRAS, whereas data suggest that this association is not present for NSCLC. We hypothesized that the unique tobacco-related carcinogenesis of NSCLC results in a divergence of KRAS MT genotype compared with CRC, contributing to differences in outcomes from EGFR-targeted therapies. Material and Methods Tumor from 2603 patients (838 CRC and 1765 NSCLC) was analyzed for KRAS mutations. DNA was extracted from microdissected formalin-fixed-paraffin-embedded specimens (FFPE) and 7 different base substitutions in codons 12 and 13 of KRAS were determined.≤ABS-P ≥ Results KRAS mutation genotype differed significantly between NSCLC and CRC in frequency (25% vs. 39%; p < 0.001), smoking-associated G > T transversions (73% versus 27%; p < 0.001), and ratio of transversions to transitions (3.5 vs. 0.79; p < 0.001). In NSCLC GLY12Cys mutations, resulting from a codon 12 GGT > TGT substitution, were observed in 44% compared to 10% for CRC. In contrast, codon 12 or 13 GLY > ASP substitutions (resulting in a G > A transition) were more frequent in CRC (42%) compared with NSCLC (21%). Conclusion In this large dataset, KRAS mutation patterns are quantitatively and qualitatively distinct between NSCLC and CRC, reflecting in part differences in tobacco-related carcinogenesis. In light of differences in predictive value for EGFR-directed monoclonal antibody therapy and prognosis for specific KRAS mutations between NSCLC and CRC, these data provide an underlying biologic rationale.
    Lung cancer (Amsterdam, Netherlands) 01/2013; · 3.14 Impact Factor
  • Philip C Mack, David R Gandara, Primo N Lara
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    ABSTRACT: Historically, notable variability has been observed in clinical trial outcomes between different regions and populations worldwide, even when employing the same cytotoxic regimen in lung cancer. These divergent results underscore the inherent challenges in interpreting trials conducted abroad and raise questions regarding the general applicability of transnational clinical trials. Various reasons have been postulated to account for these differences in efficacy and toxicity, including trial design, eligibility criteria, patient demographics and, perhaps most intriguingly, population-related pharmacogenomics. However, without methodology to control for such variables, these hypotheses remain largely untested. The authors previously developed the 'common arm' approach in order to directly compare efficacy and toxicity results of trials simultaneously performed in different countries. By standardizing clinical trial-associated variables such as treatment regimens (dose, schedule, and so on), eligibility, staging, response and toxicity criteria, this approach has the potential to determine the underlying reasons for divergences in trial outcomes across countries, and whether population-associated polymorphisms contribute to these differences. In the past decade, Japanese and US investigators have applied the common arm analytic method to trials in both extensive-stage small-cell lung cancer (SCLC) and advanced nonSCLC. In the SCLC analysis, a comparison of the cisplatin/irinotecan arms from both trials revealed significant differences in response rates and overall survival. Significant differences were also observed in the distribution of gender and performance status. The common arm analysis in nonSCLC included two trials from Japan and one from the USA, each containing a 'common' carboplatin/paclitaxel arm. Clinical results were similar in the two Japanese trials, but were significantly different from the US trial with regard to survival, neutropenia, febrile neutropenia and anemia. The underlying basis for these divergent outcomes is discussed. The common arm methodology provides a template for identifying and interpreting patient outcome differences across populations, and is an instructive lesson in the burgeoning era of clinical trials globalization.
    Expert Review of Anti-infective Therapy 12/2012; 12(12):1591-6. · 3.06 Impact Factor

Publication Stats

2k Citations
494.91 Total Impact Points


  • 1997–2014
    • University of California, Davis
      • • School of Medicine
      • • Department of Internal Medicine
      Davis, California, United States
  • 2013
    • BC Cancer Agency
      Vancouver, British Columbia, Canada
    • University of Southern California
      Los Angeles, California, United States
  • 2011
    • University of Alberta
      Edmonton, Alberta, Canada
    • Inselspital, Universitätsspital Bern
      • Department of Medical Oncology
      Berna, Bern, Switzerland
  • 1998–2011
    • California State University, Sacramento
      Sacramento, California, United States
  • 2010
    • University of Texas MD Anderson Cancer Center
      • Department of Thoracic Head Neck Medical Oncology
      Houston, TX, United States
    • Emory University
      • Department of Hematology and Medical Oncology
      Atlanta, GA, United States
  • 2009
    • University of Pittsburgh
      Pittsburgh, Pennsylvania, United States
  • 2008
    • St. Elizabeth's Medical Center
      Boston, Massachusetts, United States