Pasi A Jänne

Harvard Medical School, Boston, Massachusetts, United States

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Publications (195)2211.36 Total impact

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    ABSTRACT: We identified new gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the high-affinity nerve growth factor receptor (TRKA protein). Both the MPRIP-NTRK1 and CD74-NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Tumor samples from 3 of 91 patients with lung cancer (3.3%) without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions.
    Nature medicine 10/2013; · 27.14 Impact Factor
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    ABSTRACT: The objective of this study was to define the volumetric tumor growth rate in patients who had advanced nonsmall cell lung cancer (NSCLC) with sensitizing epidermal growth factor receptor (EGFR) mutations and had initially received treatment with EGFR-tyrosine kinase inhibitor (TKI) therapy beyond progression. The study included 58 patients with advanced NSCLC who had sensitizing EGFR mutations treated with first-line gefitinib or erlotinib, had baseline computed tomography (CT) scans available that revealed a measurable lung lesion, had at least 2 follow-up CT scans during TKI therapy, and had experienced volumetric tumor growth. The tumor volume (in mm(3) ) of the dominant lung lesion was measured on baseline and follow-up CT scans during therapy. In total, 405 volume measurements were analyzed in a linear mixed-effects model, fitting time as a random effect, to define the growth rate of the logarithm of tumor volume (loge V). A linear mixed-effects model was fitted to predict the growth of loge V, adjusting for time in months from baseline. Loge V was estimated as a function of time in months among patients whose tumors started growing after the nadir: loge V = 0.12*time + 7.68. In this formula, the regression coefficient for time, 0.12/month, represents the growth rate of loge V (standard error, 0.015/month; P < .001). When adjusted for baseline volume, loge V0 , the growth rate was also 0.12/month (standard error, 0.015/month; P < .001; loge V = 0.12*months + 0.72 loge V0 + 0.61). Tumor volume models defined volumetric tumor growth after the nadir in patients with EGFR-mutant, advanced NSCLC who were receiving TKI, providing a reference value for the tumor growth rate in patients who progress after the nadir on TKI therapy. The results can be studied further in additional cohorts to develop practical criteria to help identify patients who are slowly progressing and can safely remain on EGFR-TKIs. Cancer 2013. © 2013 American Cancer Society.
    Cancer 08/2013; · 5.20 Impact Factor
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    ABSTRACT: ROS1 gene rearrangements are reported in 1% to 2% of lung adenocarcinomas (ACAs) and are associated with response to the multitargeted tyrosine kinase inhibitor crizotinib. ROS1 rearrangements can be detected using fluorescence in situ hybridization (FISH); however, immunohistochemistry (IHC) for ROS1 protein is a promising alternate screening modality. In this study, we examine the correlation between ROS1 IHC and FISH and describe the clinicopathologic characteristics of ROS1-rearranged lung tumors. ROS1 IHC was performed using clone D4D6 on whole-tissue sections. In a validation cohort, IHC was compared with ROS1 break-apart FISH in 53 cases of lung ACA enriched for an absence of known genetic alterations and never-smoking status. In a screening cohort, we performed ROS1 IHC on 167 consecutive cases of lung ACA from a routine molecular diagnostic practice and confirmed positive results by FISH. In the validation cohort, 6 cases (11%) were both FISH and IHC positive. One FISH-negative case was strongly ROS1 IHC positive. All IHC-negative cases were FISH negative. In the screening cohort, 2 of 167 (1.2%) had strong, diffuse ROS1 protein expression; a rearrangement was confirmed by FISH in both. ROS1-translocated tumors were wild type for EGFR, KRAS, and ALK and commonly had solid growth with mucinous/cribriform features and psammomatous calcification. ROS1 protein expression in tumor cells is 100% sensitive and 92% specific for ROS1 rearrangements by FISH. ROS1 IHC is an effective screening tool for this rare but clinically important subset of lung ACAs.
    The American journal of surgical pathology 07/2013; · 4.06 Impact Factor
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    ABSTRACT: OBJECTIVE. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 has been rapidly accepted in clinical trials as a standard measure to assess tumor response to therapy and is expected to improve response assessment, especially in genomically defined patients. The impact of RECIST 1.1 was compared with RECIST 1.0 in non-small cell lung cancer (NSCLC) patients with sensitizing epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors. MATERIALS AND METHODS. Seventy patients with advanced NSCLC harboring sensitizing EGFR mutations treated with a first-line EGFR tyrosine kinase inhibitor were retrospectively studied. Tumor measurements and response assessment were performed using RECIST 1.0 and RECIST 1.1. The number of target lesions, the percentage change at the initial follow-up, best response, and time to progression were compared between RECIST 1.1 and RECIST 1.0. RESULTS. The number of target lesions identified using RECIST 1.1 was significantly lower compared with that using RECIST 1.0 (mean, 2.7 and 2.0, respectively; p < 0.0001; paired Student t test), with a decrease in 31 patients (44%). The initial proportional changes of the target lesion measurements had high correlation between the two criteria (R(2) = 0.8070), with concordant response assessment in 66 patients (94%). The best response showed almost perfect agreement (κw = 0.970). Time to progression (TTP) did not differ between the two criteria in 52 patients (74%), was longer by RECIST 1.1 in 15 patients (21%), and was shorter by RECIST 1.1 in three patients (4%). CONCLUSION. RECIST 1.1 provided highly concordant response assessment with a decreased number of target lesions compared with RECIST 1.0 in advanced NSCLC patients harboring sensitizing EGFR mutations treated with an EGFR tyrosine kinase inhibitor. RECIST 1.1 altered TTP in 25% of patients compared with RECIST 1.0.
    American Journal of Roentgenology 07/2013; 201(1):W64-71. · 2.90 Impact Factor
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    ABSTRACT: The study investigated whether tumor volume changes at 8 weeks of therapy is associated with outcomes in advanced non-small-cell lung cancer (NSCLC) patients harboring sensitizing epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs). In 56 advanced NSCLC patients with sensitizing EGFR mutations treated with first-line erlotinib or gefitinib, tumor volumes of dominant lung lesions were measured on baseline and follow-up computed tomography, and were analyzed for association with survival. Among 56 eligible patients, the median tumor volume was 17.8 cm (range, 1.3-172.7 cm) on the baseline scans. Forty-nine patients had follow-up computed tomography at approximately 8 weeks; the median tumor volume at 8 weeks was 7.1 cm (range, 0.4-62.3 cm), with the median proportional volume change of -59% (range, -90% to +91%) from baseline. The proportional volume change at 8 weeks was associated with survival (p = 0.02). Using the cutoff value of 38% volume decrease (75th percentile) at 8 weeks, patients with volume decrease more than 38% (n = 37) had a median overall survival of 43.5 months compared with 16.3 months among those with volume decrease of 38% or less (n = 12; p = 0.01). The median progression-free survival for patients with more than 38% volume decrease was 12.6 months, compared with 5.5 months for those with 38% or lesser volume decrease (p = 0.2). The proportional volume change at 8 weeks is associated with overall survival in EGFR-mutant advanced NSCLC patients treated with first-line EGFR-TKIs. The observation of the study, if confirmed in larger study cohorts, indicates that tumor volume analysis at 8 weeks may provide an early marker for survival, and contribute to therapeutic decision making by identifying patients who may benefit from additional anticancer therapy after 8 weeks of EGFR-TKI therapy.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2013; · 4.55 Impact Factor
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    ABSTRACT: Background In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. Methods We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. Results The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. Conclusions Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893 .).
    New England Journal of Medicine 06/2013; · 54.42 Impact Factor
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    ABSTRACT: PURPOSEWe undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non-small-cell lung cancer (NSCLC). METHODSKRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model. RESULTS: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02). CONCLUSIONKRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT.
    Journal of Clinical Oncology 04/2013; · 18.04 Impact Factor
  • Geoffrey R Oxnard, Pasi A Jänne
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    ABSTRACT: Widespread tumor genotyping has increased the complexity of lung cancer care, often identifying mutations of uncertain clinical significance. In the accompanying article, the authors perform a meta-analysis of the published literature on EGFR genotype and erlotinib/gefitinib sensitivity to develop a publically accessible database to inform patient care.
    Clinical Cancer Research 02/2013; · 7.84 Impact Factor
  • Geoffrey R Oxnard, Adam Binder, Pasi A Jänne
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    ABSTRACT: The identification of oncogenic driver mutations underlying sensitivity to epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors has led to a surge of interest in identifying additional targetable oncogenes in non-small-cell lung cancer. A number of new potentially oncogenic gene alterations have been characterized in recent years, including BRAF mutations, HER2 insertions, PIK3CA mutations, FGFR1 amplifications, DDR2 mutations, ROS1 rearrangements, and RET rearrangements. In this review, we will discuss the techniques used to discover each of these candidate oncogenes, the prevalence of each in non-small-cell lung cancer, the preclinical data supporting their role in lung cancer, and data on small molecular inhibitors in development.
    Journal of Clinical Oncology 02/2013; · 18.04 Impact Factor
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    ABSTRACT: Lung cancer is the most common cause of cancer deaths. Most patients present with advanced-stage disease, and the prognosis is generally poor. However, with the understanding of lung cancer biol-ogy, and development of molecular targeted agents, there have been improvements in treatment outcomes for selected subsets of patients with non–small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significantly improved tumor responses and progression-free survival in subsets of patients with advanced NSCLC, particularly those with tumors harboring activating EGFR mutations. Testing for EGFR
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    ABSTRACT: INTRODUCTION:: Exon 20 insertions are the third most common family of epidermal growth factor receptor (EGFR) mutations found in non-small-cell lung cancer (NSCLC). Little is known about cancers harboring these mutations aside from their lack of response to EGFR tyrosine kinase inhibitors, impairing the development of effective targeted therapies. METHODS:: NSCLC patients with EGFR genotyping were studied using a mechanism approved by the Institutional Review Board. Cancers with exon 20 insertions were indentified, sequences were characterized, and effectiveness of different treatment regimens was reviewed retrospectively. Clinical characteristics and survival were compared with cancers harboring common EGFR mutations and cancers with wild-type EGFR. RESULTS:: One thousand eighty-six patients underwent EGFR genotyping from 2004 to 2012. Twenty seven (2.5%) harbored exon 20 insertions, making up 9.2% of all cancers with documented EGFR mutations. Compared with wild-type cancers, those with exon 20 insertions were more commonly found in never-smokers and Asian patients. Insertion sequences were highly variable, with the most common variant (V769_D770insASV) making up only 22% of cases. Median survival of patients with exon 20 insertions was 16 months, similar to the survival of wild-type cancers and shorter than the survival of cancers with common EGFR mutations. CONCLUSIONS:: Patients with EGFR exon 20 insertions have similar clinical characteristics to those with common EGFR mutations but a poorer prognosis. The prevalence of this subset of NSCLC is similar to that of other genotype-defined subsets of lung adenocarcinoma (e.g. those with BRAF mutations, HER2 insertions, ROS1 rearrangements) and is a population of interest for trials of new targeted therapies.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2013; 8(2):179-184. · 4.55 Impact Factor
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    ABSTRACT: Lung cancer is the most common cause of cancer deaths. Most patients present with advanced-stage disease, and the prognosis is generally poor. However, with the understanding of lung cancer biol-ogy, and development of molecular targeted agents, there have been improvements in treatment outcomes for selected subsets of patients with non–small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significantly improved tumor responses and progression-free survival in subsets of patients with advanced NSCLC, particularly those with tumors harboring activating EGFR mutations. Testing for EGFR
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lung cancer is the most common cause of cancer deaths. Most patients present with advanced-stage disease, and the prognosis is generally poor. However, with the understanding of lung cancer biology, and development of molecular targeted agents, there have been improvements in treatment outcomes for selected subsets of patients with non-small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significantly improved tumor responses and progression-free survival in subsets of patients with advanced NSCLC, particularly those with tumors harboring activating EGFR mutations. Testing for EGFR mutations is a standard procedure for identification of patients who will benefit from first-line EGFR TKIs. For patients with advanced NSCLC and no activating EGFR mutations (EGFR wild-type) or no other driving oncogenes such as ALK-gene rearrangement, chemotherapy is still the standard of care. A new generation of EGFR TKIs, targeting multiple receptors and with irreversible bindings to the receptors, are in clinical trials and have shown encouraging effects. Research on primary and acquired resistant mechanisms to EGFR TKIs are ongoing. Monoclonal antibodies (e.g. cetuximab), in combination with chemotherapy, have demonstrated improved outcomes, particularly for subsets of NSCLC patients, but further validations are needed. Novel monoclonal antibodies are combined with chemotherapy, and randomized comparative studies are ongoing. This review summarizes the current status of EGFR inhibitors in NSCLC in 2012 and some of the major challenges we are facing.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 01/2013; · 4.55 Impact Factor
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    ABSTRACT: PURPOSE: Advanced NSCLC harboring epidermal growth factor receptor (EGFR) mutations treated with EGFR tyrosine kinase inhibitors (TKIs) typically progresses after initial response due to acquired resistance. TKIs are often continued beyond progressive disease by RECIST. We investigated the practice of continuing EGFR-TKIs after RECIST-PD via CT findings. METHODS: Among 101 advanced NSCLC patients with sensitizing EGFR mutations treated with first-line EGFR-TKIs, 70 patients had baseline and at least one follow-up CT for retrospective radiographic assessments using RECIST1.1; 56 patients had experienced PD by the data closure date of June 2011. RESULTS: Among 56 patients experiencing PD, 82% were female, median age was 63 years, 50% were never-smokers, 57% had distant metastasis, 57% had exon 19 deletion, and 89% were treated with erlotinib. 49 patients (88%) continued TKI therapy beyond retrospectively assessed PD. 31/32 (97%) patients who progressed by an increase in their target lesions continued TKI. 13/16 (81%) patients who progressed by appearance of a new lesion remained on TKI. 5/6 (83%) patients with both increase of target lesions and new lesion at PD continued TKI. Two patients with PD in non-target lesions discontinued therapy at PD. In 49 continuing patients, the median time from retrospectively assessed RECIST-PD to termination of TKI was 10.1 months. CONCLUSIONS: 88% of EFGR-mutant NSCLC patients who progressed on first-line TKI continued therapy beyond RECIST-PD, which is not the single determining factor for terminating TKI in EGFR-mutant NSCLC patients. Additional radiographically defined progression criteria are needed for this population.
    Lung cancer (Amsterdam, Netherlands) 12/2012; · 3.14 Impact Factor
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    ABSTRACT: BACKGROUND:: Genomic testing to identify driver mutations that enable targeted therapy is emerging for patients with non-small-cell lung cancer (NSCLC). We report the implementation of systematic prospective genotyping for somatic alterations in BRAF, PIK3CA, HER2, and ALK, in addition to EGFR and KRAS, in NSCLC patients at the Dana-Farber Cancer Institute. METHODS:: Patients with NSCLC were prospectively referred by their providers for clinical genotyping. Formalin-fixed, paraffin embedded tumor samples were analyzed by Sanger sequencing for mutations in selected exons of EGFR, KRAS, BRAF, PIK3CA, and HER2. ALK rearrangements were detected by fluorescence in situ hybridization or immunohistochemistry. RESULTS:: Between July 1, 2009 and August 1, 2010, 427 specimens from 419 patients were referred for genomic characterization; 344 (81%) specimens were successfully genotyped with a median turnaround time of 31 days (range, 9-155). Of the 344 specimens, 185 (54%) had at least one identifiable somatic alteration (KRAS: 24%, EGFR: 17%, ALK: 5%, BRAF: 5%, HER2: 4%, PIK3CA: 2%). As of August 1, 2011, 63 of 288 advanced NSCLC patients (22%) had received molecularly targeted therapy based on their genotypic results, including 34 of 42 patients (81%) with EGFR mutations, 12 of 15 (80%) with ALK rearrangements, and 17 of 95 (18%) with KRAS, BRAF, or HER2 mutations. CONCLUSIONS:: Large-scale testing for somatic alterations in EGFR, KRAS, BRAF, PIK3CA, HER2, and ALK is feasible and impacts therapeutic decisions. As the repertoire for personalized therapies expands in lung cancer and other malignancies, there is a need to develop new genomics technologies that can generate a comprehensive genetic profile of tumor specimens in a time- and cost-effective manner.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2012; 7(12):1767-1774. · 4.55 Impact Factor
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    ABSTRACT: BACKGROUND: No targeted therapies are available for KRAS-mutant non-small-cell lung cancer (NSCLC). Selumetinib is an inhibitor of MEK1/MEK2, downstream of KRAS, with preclinical evidence of synergistic activity with docetaxel in KRAS-mutant cancers. We did a prospective, randomised, phase 2 trial to assess selumetinib plus docetaxel in previously treated patients with advanced KRAS-mutant NSCLC. METHODS: Eligible patients were older than 18 years of age; had histologically or cytologically confirmed stage IIIB-IV KRAS-mutant NSCLC; had failed first-line therapy for advanced NSCLC; had WHO performance status of 0-1; had not received previous therapy with either a MEK inhibitor or docetaxel; and had adequate bone marrow, renal, and liver function. Patients were randomly assigned (in a 1:1 ratio) to either oral selumetinib (75 mg twice daily in a 21 day cycle) or placebo; all patients received intravenous docetaxel (75 mg/m(2) on day 1 of a 21 day cycle). Randomisation was done with an interactive voice response system and investigators, patients, data analysts, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival, analysed for all patients with confirmed KRAS mutations. This study is registered with ClinicalTrials.gov, number NCT00890825. FINDINGS: Between April 20, 2009, and June 30, 2010, we randomly assigned 44 patients to receive selumetinib and docetaxel (selumetinib group) and 43 to receive placebo and docetaxel (placebo group). Of these, one patient in the selumetinib group and three in the placebo group were excluded from efficacy analyses because their tumours were not confirmed to be KRAS-mutation positive. Median overall survival was 9·4 months (6·8-13·6) in the selumetinib group and 5·2 months (95% CI 3·8-non-calculable) in the placebo group (hazard ratio [HR] for death 0·80, 80% CI 0·56-1·14; one-sided p=0·21). Median progression-free survival was 5·3 months (4·6-6·4) in the selumetinib group and 2·1 months (95% CI 1·4-3·7) in the placebo group (HR for progression 0·58, 80% CI 0·42-0·79; one-sided p=0·014). 16 (37%) patients in the selumetinib group and none in the placebo group had an objective response (p<0·0001). Adverse events of grade 3 or higher occurred in 36 (82%) patients in the selumetinib group and 28 (67%) patients in the placebo group. The most common grade 3-4 adverse events were neutropenia (29 [67%] of 43 patients in the selumetinib group vs 23 [55%] of 42 patients in the placebo group), febrile neutropenia (eight [18%] of 44 patients in the selumetinib group vs none in the placebo group), dyspnoea (one [2%] of 44 patients in the selumetinib group vs five [12%] of 42 in the placebo group), and asthenia (four [9%] of 44 patients in the selumetinib group vs none in the placebo group). INTERPRETATION: Selumetinib plus docetaxel has promising efficacy, albeit with a higher number of adverse events than with docetaxel alone, in previously treated advanced KRAS-mutant NSCLC. These findings warrant further clinical investigation of selumetinib plus docetaxel in KRAS-mutant NSCLC. FUNDING: AstraZeneca.
    The Lancet Oncology 11/2012; · 25.12 Impact Factor
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    ABSTRACT: PURPOSE Investigate if CT tumor volume analysis provides quantitative parameters that are associated with overall survival of advanced NSCLC patients with sensitizing EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs). METHOD AND MATERIALS Among a cohort of 101 advanced NSCLC patients with sensitizing EGFR mutations treated with first-line erlotinib or gefitinib, 56 patients had baseline and at least one follow-up chest CT, and at least one measurable lung lesion. Tumor volume of the dominant lung lesion was measured on baseline and follow-up CT scans using a FDA-approved software (Vitrea ® 2, version 4.0, Vital Images), and were analyzed for association with overall survival. RESULTS Among 56 eligible patients, 86% were female, median age was 63 years (range 35-84), 46% were never smokers, 57% had distant metastasis, 50% had exon 19 del and 91% received erlotinib. The median number of follow-up CT scans during TKI therapy was 7 (range 1-35 scans). The median tumor volume was 17.8 cc (range: 1.3-172.7 cc) at baseline, 4.8 cc (range: 0.2-62.3 cc) at the nadir (the smallest volume since baseline) and 7.1 cc (range: 0.4-62.3 cc) at 8 weeks. The median proportional volume decrease was 58.5% at 8 weeks and 70.5% at the nadir compared to the baseline. The median time from the initiation of therapy to the nadir was 5.5 months. The baseline volume did not correlate with overall survival from baseline (p=0.57). In 49 patients with follow-up chest CT at 8 weeks of therapy, proportional volume decrease was associated with overall survival (Cox model, p=0.02). Using the cut-off value of 38% (75th percentile) for proportional volume decrease at 8 weeks, patients with proportional volume decrease >38% (n=37) had a median survival of 43.5 months compared to 16.3 months among those with proportional volume decrease ≤38% (n=12) (log-rank p=0.01). Proportional volume decrease at the nadir did not appear to be associated with overall survival in this patient population (p=0.23). CONCLUSION In EGFR-mutant advanced NSCLC patients treated with the first-line EFGR-TKIs, the proportional volume decrease at 8 weeks is associated with overall survival. CLINICAL RELEVANCE/APPLICATION The proportional volume decrease at 8 weeks of therapy serves as a marker for survival in advanced NSCLC patients harboring EGFR mutations treated with the first-line EGFR-TKIs.
    Radiological Society of North America 2012 Scientific Assembly and Annual Meeting; 11/2012
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    ABSTRACT: The clinical efficacy of EGFR kinase inhibitors gefitinib and erlotinib is limited by the development of drug resistance. The most common mechanism of drug resistance is the secondary EGFR T790M mutation. Strategies to overcome EGFR T790M mediated drug resistance include the use of mutant selective EGFR inhibitors, including WZ4002, or by the use of high concentrations of irreversible quinazoline EGFR inhibitors such as PF299804. In the current study we develop drug resistant versions of the EGFR mutant PC9 cell line which reproducibly develops EGFR T790M as a mechanism of drug resistance to gefitinib. Neither PF299804 resistant (PFR) nor WZ4002 resistant (WZR) clones of PC9 harbor EGFR T790M. Instead, they demonstrate activated IGF1R signaling as a result of loss of expression of IGFBP3 with the IGF1R inhibitor, BMS 536924, restoring EGFR inhibitor sensitivity. Intriguingly, prolonged exposure to either PF299804 or WZ4002 results in the emergence of a more drug resistant subclone which exhibits ERK activation. A MEK inhibitor, CI-1040, partially restores sensitivity to the EGFR/IGF1R inhibitor combination. Moreover, an IGF1R or MEK inhibitor used in combination with either PF299804 or WZ4002 completely prevents the emergence of drug resistant clones in this model system. Our studies suggest that more effective means of inhibiting EGFR T790M will prevent the emergence of this common drug resistance mechanism in EGFR mutant NSCLC. However, multiple drug resistance mechanisms can still emerge. Preventing the emergence of drug resistance, by targeting pathways that become activated in resistant cancers, may be a more effective clinical strategy.
    Cancer Research 11/2012; · 9.28 Impact Factor
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    ABSTRACT: Lung adenocarcinoma, the most common subtype of non-small cell lung cancer, is responsible for more than 500,000 deaths per year worldwide. Here, we report exome and genome sequences of 183 lung adenocarcinoma tumor/normal DNA pairs. These analyses revealed a mean exonic somatic mutation rate of 12.0 events/megabase and identified the majority of genes previously reported as significantly mutated in lung adenocarcinoma. In addition, we identified statistically recurrent somatic mutations in the splicing factor gene U2AF1 and truncating mutations affecting RBM10 and ARID1A. Analysis of nucleotide context-specific mutation signatures grouped the sample set into distinct clusters that correlated with smoking history and alterations of reported lung adenocarcinoma genes. Whole-genome sequence analysis revealed frequent structural rearrangements, including in-frame exonic alterations within EGFR and SIK2 kinases. The candidate genes identified in this study are attractive targets for biological characterization and therapeutic targeting of lung adenocarcinoma.
    Cell 09/2012; 150(6):1107-20. · 31.96 Impact Factor
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    ABSTRACT: The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here, we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of extracellular signal-regulated kinase (ERK) signaling caused by either an amplification of mitogen-activated protein kinase 1 (MAPK1) or by downregulation of negative regulators of ERK signaling. Inhibition of MAP-ERK kinase (MEK) or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib-resistant EGFR-mutant non-small cell lung carcinoma patient. In addition, the WZ4002-resistant MAPK1-amplified cells also show an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials.
    Cancer Discovery 09/2012; 2(10):934-947. · 15.93 Impact Factor

Publication Stats

18k Citations
2,211.36 Total Impact Points

Institutions

  • 2004–2014
    • Harvard Medical School
      • • Department of Medicine
      • • Department of Pathology
      • • Department of Biological Chemistry and Molecular Pharmacology
      • • Department of Radiation Oncology
      Boston, Massachusetts, United States
  • 2002–2014
    • Dana-Farber Cancer Institute
      • • Carole M. and Philip L. Lowe Center for Thoracic Oncology
      • • Department of Medical Oncology
      Boston, Massachusetts, United States
  • 2012
    • Institute for Cancer Research and Treatment
      • Molecular Genetics Division
      Torino, Piedmont, Italy
    • Centre Hospitalier Lyon Sud
      Lyons, Rhône-Alpes, France
  • 2011
    • Institut de Cancérologie Gustave Roussy
      Île-de-France, France
  • 2009–2011
    • Kinki University
      • Faculty of Medicine
      Ōsaka-shi, Osaka-fu, Japan
    • Memorial Sloan-Kettering Cancer Center
      • Human Oncology & Pathogenesis Program
      New York City, NY, United States
  • 2005–2010
    • Massachusetts General Hospital
      • Department of Pathology
      Boston, Massachusetts, United States
  • 2008
    • University of Milan
      Milano, Lombardy, Italy
  • 2007
    • Eli Lilly
      • Lilly Research Laboratories
      Indianapolis, Indiana, United States
    • Istituto Clinico Humanitas IRCCS
      • Department of Oncology and Hematology
      Rozzano, Lombardy, Italy
  • 2006
    • Brigham and Women's Hospital
      • Department of Medicine
      Cambridge, MA, United States