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  • 1
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    Online Resource
    5-day dosing schedule of temozolomide in relapsed sensitive or refractory small cell lung cancer (SCLC) and methyl-guanine-DNA methyltransferase (MGMT) analysis in a phase II trial.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 7052-7052
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 7052-7052
    Abstract: 7052 Background: MGMT promoter methylation and loss of MGMT activity are associated with improved sensitivity to alkylating agents. We recently reported that the oral alkylating agent temozolomide is active in 2nd- and 3rd-line treatment of relapsed SCLC at 75mg/m 2 /day for 21 out of 28 days (Pietanza et al, Clin Can Res 2012). Here we evaluate the 5-day dosing schedule of temozolomide in a second cohort of patients and analyze MGMT activity in both cohorts of patients on the same study. Methods: Patients with disease progression after 1 or 2 prior chemotherapy regimens received temozolomide at 200mg/m 2 /day for 5 out of 28 days (n=25). Those with sensitive (S-SCLC, n=16) and refractory (R-SCLC, n=9) disease were enrolled to assess safety. Available tumor tissue from patients treated according to either schedule was assessed for MGMT promoter methylation status by PCR and MGMT expression by immunohistochemistry (IHC). Results: An overall response rate of 12% was noted (3 partial responses: 1 S-SCLC, 2 R-SCLC). 4 patients had stable disease for at least 3 cycles. Median progression-free survival and overall survival for all patients were 1.3 months and 7.9 months, respectively. Grade ≥3 thrombocytopenia and neutropenia was observed in 20% with a shorter mean duration of myelosuppression compared to the 21-day schedule. Results from MGMT evaluation of tumor samples from both dosing schedules were combined. Promoter methylation of MGMT was not significantly associated with response (p=0.23). However, patients that lacked MGMT expression by IHC had a higher response rate compared to those with MGMT-positive tumors (43% vs. 13%, p = 0.052; see table). Conclusions: The 5-day dosing schedule of temozolomide is both active and safe in patients with relapsed SCLC. A strong trend toward increased response was demonstrated in patients with MGMT-negative tumors compared to patients with MGMT-positive tumors by IHC. A trial combining temozolomide with the PARP inhibitor, ABT888, is planned. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.7052
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    Local therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 7527-7527
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 7527-7527
    Abstract: 7527 Background: The utility of EGFR directed therapy for the treatment of EGFR mutant lung cancer is limited by the development of acquired resistance (AR) to EGFR tyrosine kinase inhibitor (TKI) therapy, which occurs after a median of 16 months (mos). There are no approved targeted therapies after disease progression on EGFR TKI therapy. Local therapy for oligometastatic disease is used with regularity in other solid tumors, and can lead to long term survival in selected individuals. EGFR mutant lung cancers with AR to TKI therapy can follow an indolent course that is amenable to local therapy to treat progression of disease when used in conjunction with continued EGFR inhibition. Outcomes following local therapy in this setting have not been assessed. Methods: Patients (pts) with AR to EGFR TKI’s who received local therapy excluding treatment of CNS metastases or local therapy prior to AR were identified in an IRB-approved prospective registry of 184 pts with AR enrolled from August 2004- November 2011. We collected treatments as well as progression free survival (PFS) and overall survival (OS) after local therapy. Results: 18 pts received local therapy. Treatments included surgical resection and radiation to lung, lymph nodes, adrenal gland or bone. Median age was 57, 56% were women, and 61% were never smokers. 14 had EGFR Exon 19 deletions, and 4 L858R. The median time to development of AR on TKI was 19 mo (range 5-33). Known mechanisms of AR included T790M (11 pts), MET amplification (1 pt) and small cell transformation (1 pt). The median PFS after local therapy was 10 mo (95% CI: 4-NA), median time from local therapy until change in systemic therapy was 22 mo (95%CI: 6 - 30), and median OS from local therapy was 41 mo (95% CI: 26-NA). Local therapy was tolerated well, with 85% of pts restarting TKI therapy within one month of completing local therapy. Conclusions: Local therapy is well tolerated and in combination with continued EGFR TKI therapy prolongs time until change in systemic therapy is required and may lead to outcomes that are superior to currently available treatment options in selected individuals.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.7527
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Online Resource
    Comparison of the KRAS/EGFR mutation profile and survival of “collegiate smokers” and never smokers with advanced lung cancers.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 7580-7580
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 7580-7580
    Abstract: 7580 Background: In practice, we encounter patients (pts) with lung cancers who state they smoked only while in college. The impact of this degree of tobacco use on cancer biology is unknown. We have shown that EGFR mutations are less common in pts who smoked 〉 15 pack years (PY). We hypothesize that among pts with lung cancer the KRAS / EGFR mutation profile and overall survival (OS) of “collegiate smokers” (former smokers who smoked between 101 lifetime cigarettes and 5 PY) will be distinct from never smokers and former smokers with ≥ 15 PY. Methods: We collected age, sex, stage, and survival for pts evaluated from 2004 - 2009 with stage IIIB/IV lung cancer with known KRAS and EGFR status. ALK testing was not available routinely during this time. Smoking history was obtained using a patient completed survey. The Fisher exact test was used to compare mutation profiles. The log rank test was used to compare OS. Results: Smoking history and clinical data were available for 852 pts with Stage IIIB/IV lung cancer with known KRAS and EGFR status: 307 never smokers, 178 current smokers, and 367 former smokers. Of the former smokers, 55 were “collegiate smokers”, 61 had smoked 5-15 PY, and 251 had smoked ≥ 15 PY. The KRAS / EGFR mutation profiles by smoking history are shown below (Table). The KRAS / EGFR mutation profile of “collegiate smokers” is distinct from those of pts who were never smokers (p 〈 .001) and former smokers with ≥ 15 PY (p 〈 .001) but similar to that of pts who were former smokers with 5-15 PY (p = 0.9). Median OS after diagnosis of stage IIIB/IV lung cancer for “collegiate smokers” was 25 months (mos), compared to 32 mos for never smokers (p = 0.4) and 21 mos for former smokers with ≥ 15 PY (p = 0.63). Conclusions: “Collegiate smokers” are a distinct group of pts with a higher incidence of KRAS mutations and lower incidence of EGFR mutations compared to never smokers. These data suggest that even a small amount of cigarette smoking influences the biology of lung cancer. These findings reinforce the importance of doing mutation testing routinely for all pts with lung cancer to guide clinical care. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.7580
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 4
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    Online Resource
    KIF5B-RET : Discovery of a novel fusion oncogene in lung adenocarcinomas by a systematic screen for tyrosine kinase fusions and identification of patients for a RET targeted therapy trial.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 7578-7578
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 7578-7578
    Abstract: 7578 Background: The mutually exclusive pattern of major targetable driver oncogenes in lung adenocarcinomas (ADC) suggests that other similar driver oncogenes may exist. We therefore performed a systematic screen for tyrosine kinase (TK) fusions in cases without known driver oncogenes by measuring aberrantly high RNA expression of kinase domain (KD) exons relative to more 5’ exons. Methods: We studied 74 patients whose lung ADC lacked mutations in KRAS, EGFR, BRAF, HER2, and ALK fusions. A NanoString-based assay was designed to query the transcripts of 90 TKs at two points: 5’ to the KD and within or 3’ to the KD. Tumor RNAs were hybridized to the NanoString probes and analyzed for outlier 3’ to 5’ expression ratios. The assay was validated on samples with known ALK and ROS fusions. Presumed novel fusion events were followed up by rapid amplification of cDNA ends (RACE) and confirmatory RT-PCR. Results: The NanoString assay identified aberrant 5’ to 3’ ratios in ROS and RET in 2 cases, respectively, out of 74. RACE analysis isolated a novel GOPC-ROS fusion in the former and a novel KIF5B-RET fusion in the latter, both confirmed by RT-PCR. Further screening by RT-PCR for KIF5B-RET identified one more positive sample in the study set that had not been detected by NanoString. At the RNA level, both fusions joined exon 15 of KIF5B to exon 12 of RET, thus retaining a portion of the dimerization domain of KIF5B and the entire KD of RET, analogous to RET fusions in papillary thyroid carcinoma (TC). One KIF5B-RET patient was a 60 y.o. female never smoker, the other, a 73 y.o. male former smoker. Conclusions: The novel KIF5B-RET fusion described here and also recently reported by Ju YS et al. (Genome Res, Dec 22, 2011) defines a new subset of lung ADC with a potentially targetable driver oncogene. Based on these genetic data and the preclinical activity of the RET inhibitor XL184 (Exelixis) in papillary TC and its known activity in medullary TC with RET mutations, we have initiated prospective testing for KIF5B-RET as part of our lung ADC screening panel in anticipation of a planned phase 2 trial with XL184 in patients with KIF5B-RET or related variant RET fusions.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.7578
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    Prospective study of tumor suppressor gene (TSG) methylation as a prognostic biomarker in surgically resected non-small cell lung cancer (NSCLC).
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 7066-7066
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 7066-7066
    Abstract: 7066 Background: In the New England Journal of Medicine, Brock et al. (2008) published a nested case-control study which tested the association between early recurrence of NSCLC after surgical resection, and TSG promoter methylation in tumor and lymph nodes detected by methylation-specific PCR (MSP). They reported that promoter methylation of the TSGs p16, CDH13, RASSF1A, and APC was significantly associated with early recurrence in 51 patients with stage I NSCLC compared to matched patients without early recurrence. We attempted to confirm these findings. Methods: In a prospective study, fresh frozen tumor tissue was acquired after surgical resection in 107 patients with stage I-IIIA NSCLC between 2003-2008. The promoter methylation status of the same 4 genes examined by Brock, et al (p16, CDH13, RASSF1A, APC), as well as 6 additional TSGs (MGMT, WIF-1, METH-2, GSTP1, SOCS3, DAPK) were assessed in the tumor tissue using quantitative MSP (MethyLight assay), with any amount of methylation scored as positive. Methylation status was correlated with clinical features, pathologic stage, disease-free survival (DFS), and overall survival (OS). Results: No significant associations were observed between promoter methylation of individual TSGs and DFS. No significant associations were observed between the number of methylated TSGs and DFS, or OS. Increased RASSF1A methylation was observed in poorly-differentiated and undifferentiated tumors compared to tumors that were well- or moderately-differentiated (p=0.031). Increased WIF-1 methylation and GSTP1 methylation were associated with increasing T (p=0.01) and N stage (p=0.028), respectively. Squamous cell carcinomas (SQCCs) were characterized by increased p16 methylation (p=0.0314) and decreased APC methylation (p=0.0146) compared to tumors of non-SQCC histologies. Conclusions: In this prospective study, we did not confirm that the promoter methylation of p16, CDH13, RASSF1A, and APC, or 6 other TSGs, was prognostic for early recurrence in surgically resected NSCLC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.7066
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 6
    Online Resource
    Online Resource
    Screening for RET and ROS1 fusions in an enriched cohort of pan-negative never-smokers with advanced lung adenocarcinomas to identify patients for treatment in targeted therapy trials.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 8067-8067
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 8067-8067
    Abstract: 8067 Background: RET and ROS1 fusions have been identified pre-clinically as drivers of tumor growth in lung adenocarcinomas. In addition, based on response to crizotinib in ROS1-positive tumors and emerging data on RET inhibition in some tumors, these fusions represent druggable targets. While each occurs in 1-2% of unselected patients, a screening paradigm based on testing never-smokers whose tumors have no known oncogenic mutations or fusions may enrich identification for ongoing clinical trials. Methods: Patients with a never-smoking history ( 〈 100 lifetime cigarettes) and advanced pan-negative lung adenocarcinomas (absence of mutations in EGFR, KRAS, NRAS, BRAF, HER2, PIK3CA, MEK1, and AKT, and ALK fusions) were selected for testing. Screening for RET and ROS1 fusions was performed in real-time via dual-probe FISH breakapart assays, RT-PCR, and next-generation sequencing in selected cases. We enrolled patients onto a phase II trial of cabozantinib for RET fusion-positive lung cancers (NCT01639508) and, as part of the Lung Cancer Mutation Consortium (LCMC), a phase I trial of crizotinib for ROS1-positive lung cancers (NCT00585195). Results: Thirty five (n=35) never-smokers with advanced pan-negative lung adenocarcinomas were identified. A RET or ROS1 fusion was found in 31% [n=10/32, 95% CI, 15-47%] of patients. RET and ROS1 fusions were found in 15% [n=5/34, 95% CI, 3% - 27%] and 15% [n=5/33, 95% CI, 2%-27%] of patients, respectively. 1 patient had a novel TRIM33-RET fusion. 3 of 5 patients with RET fusion-positive tumors were eligible for treatment with cabozantinib, 2 of which had partial responses to therapy. 1 of 5 patients with ROS1 fusion-positive tumors was treated on-protocol with crizotinib and achieved a partial response. Conclusions: 31% of never-smokers with pan-negative advanced lung adenocarcinomas harbor a gene fusion involving either RET or ROS1. Until multiplexed mutation and fusion testing is routinely available, targeting this population for screening represents an interim enrichment strategy for patient identification and enrollment on clinical trials where responses are already being documented.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.8067
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 7
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    Online Resource
    Clinical characteristics of patients with multiple primary lung cancers: Moving beyond the Martini and Melamed criteria.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 7570-7570
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 7570-7570
    Abstract: 7570 Background: Deciding to operate for lung cancer in patients with a prior lung cancer resection is influenced by the extent of disease at 1st resection and the certainty that the new lesion is a 2nd primary lung cancer. While the Martini and Melamed (M & M) criteria (J Thorac Cardiovasc Surg 1975) guide the decision whether a new lesion represents a 2nd lung cancer, improvements, incorporating detailed clinical and molecular analyses, are needed. Methods: From a prospective database, we identified 130 patients who underwent two curative resections from 1995 to 2009 for non-small cell lung cancers. We examined associations between clinical factors and patterns of recurrence/DFS/OS following 2nd surgery. Results: Patient characteristics: median age 66; 42% men; and 8% never smokers. See Table for stage, histology, and completeness of resection. DFS and OS were not associated with smoking status, surgical procedure, and histology. Stage at 1st resection was not associated with patterns of recurrence (none vs local vs distant, p=0.77), DFS (p=0.61), or OS (p=0.37). Earlier stage at 2nd resection was associated with improved DFS (p 〈 0.001) and OS (p 〈 0.001), as well as a trend toward less distant recurrence (p=0.06). As many surgeries predated routine genotyping, very few patients (5%) had genotyping from both resections. 38% of 2nd resection stage IA lung cancers recurred distantly. 20% had a third lung cancer and 47% had at least one other malignancy. Conclusions: Outcomes after 2nd primary lung cancers are unaffected by the stage of the 1st lung cancer. Pursuit of curative interventions should not be influenced by the stage of the 1st cancer. We need more detailed molecular analysis to help correctly identify new primaries. We also need additional features to help discriminate among those at most risk for another lung cancer vs local recurrence vs distant recurrence. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.7570
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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