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CT Predicts Local Recurrence and Survival for Squamous Cell Carcinoma of the Anus
S34
International Journal of Radiation Oncology Biology Physics
Conclusions: In this cohort, referral hospital was an independent predictor of cCR regardless of stage, but interestingly not DFS or OS. These results suggest that HIV+ patients are prone to health disparities in anal cancer outcomes. Further, these data support that SES factors are important in determining treatment outcome, independent of treatment course characteristics. Recognizing the prognostic implication of SES factors may lead to a better understanding and improvement of the clinical outcomes for anal cancer. Author Disclosure: D.S. Bitterman: None. D. Grew: None. C.G. Leichman: None. L. Leichman: None. K.L. Du: None.
66
65 Quantitative FDG-PET/CT Predicts Local Recurrence and Survival for Squamous Cell Carcinoma of the Anus M.L. Cardenas, C.R. Spencer, T.A. DeWees, S. Hunt, R.J. Myerson, M. Silviera, R. Jain, P.J. Parikh, B. Tan, P.W. Grigsby, F. Dehdashti, and J.R. Olsen; Washington University, Saint Louis, MO Purpose/Objective(s): FDG-PET/CT imaging is recommended for staging and treatment planning of anal cancer, although quantitative pre- and post-treatment metrics predictive of recurrence are unknown. We evaluated the association between pre- and post-treatment FDG-PET/CT parameters and outcome for patients with squamous cell carcinoma of the anus (SCCA). Materials/Methods: The records of 110 patients treated between 2003 and 2013 with definitive radiotherapy for SCCA were reviewed under an IRBapproved protocol. The median radiotherapy dose was 50.4 Gy (Range, 35-60 Gy). Concurrent chemotherapy was administered for 109/110 patients and generally consisted of 5-FU in combination with mitomycin C (n Z 94). All patients underwent pre-treatment FDG-PET/CT and 100/110 also underwent post-treatment FDG-PET/CT 3 months following completion of radiotherapy. Pre-treatment and post-treatment FDG-PET/ CT parameters including the maximum standardized uptake value (SUVmax) and SUVmax normalized to blood pool uptake (nSUVmax) were analyzed in addition to multiple patient and treatment factors (age, T-stage, N-stage, stage group, gender, and HIV status) by univariate and multivariate Cox regression for correlation with local recurrence (LR) and overall survival (OS). Results: The median follow-up time was 28.6 months. LR occurred in 1/15 (6.7%), 5/47 (10.6%), and 6/48 (12.5%) patients with stage I, II, and III disease, respectively. A significant association was observed on univariate analysis between reduced LR and pre-treatment SUVmax > 7.1 (p Z 0.029), and between reduced LR and post-treatment nSUVmax < 3.2 (p Z .015). A significant univariate association was also observed between increase OS and pre-treatment SUVmax > 7.1 (p Z 0.046), and between increased OS and post-treatment nSUVmax (p Z 0.016). On multivariate analysis, a significant association was observed between reduced LR and pre-treatment SUVmax > 7.1 (p Z 0.010) and between reduced LR and post-treatment nSUVmax < 3.2 (p Z 0.003). A significant multivariate association was also observed between increased OS and pre-treatment SUVmax > 7.1 (p Z 0.026), post-treatment nSUVmax (p Z 0.027), and less advanced nodal disease (p Z 0.0020). Conclusions: A higher pre-treatment SUVmax > 7.1, and lower posttreatment nSUVmax < 3.2 are associated with reduced LR and increased OS following definitive chemoradiation therapy for SCCA. FDG-PET/CT metrics correlated with outcome independently of T and N stage on multivariate analysis and maybe useful for patient selection and stratification in clinical trials. Greater follow-up is required to confirm association with late patterns of failure, and further study is required to determine if this association may be due to tumor hypoxia, p16 status, or other mechanism. Author Disclosure: M.L. Cardenas: None. C.R. Spencer: None. T.A. DeWees: None. S. Hunt: None. R.J. Myerson: None. M. Silviera: None. R. Jain: None. P.J. Parikh: None. B. Tan: None. P.W. Grigsby: None. F. Dehdashti: None. J.R. Olsen: G. Consultant; Dfine, Inc.
The Radiogenomic Landscape of Cancer M. Abazeed,1 D. Adams,2 P. Tamayo,2 B. Yard,3 J. Loeffler,4 J. Suh,1 M. Meyerson,5 P. Hammerman,5 and S. Schreiber6; 1Cleveland Clinic Foundation, Cleveland, OH, 2Broad Institute, Cambridge, MA, 3Cleveland Clinic, Cleveland, OH, 4Massachusetts General Hospital, Boston, MA, 5 Dana Farber Cancer Institute, Boston, MA, 6Harvard University, Cambridge, MA Purpose/Objective(s): There have not been extensive systematic analyses of the correlation between therapeutic sensitivity and genomic parameters. We report on a large-scale effort to functionally characterize genetic alterations driving radiotherapeutic resistance across 22 solid tumor lineages. Materials/Methods: We developed a systematic high-throughput method for profiling radiation sensitivity and benchmarked this method against the conventional clonogenic survival assay. In the largest study of its kind, we have measured the sensitivity of 533 genomically characterized cancer cell lines to radiation. We combined results from this high-throughput assay with genomic parameters to identify parameters that predict radiation sensitivity. Genomic correlates of radiosensitivity were explored by accessing the Cancer Cell Line Encyclopedia, the COSMIC database of the Cancer Genome Project, The Cancer Genome Atlas, Gene Set Enrichment Analysis, and GISTIC2.0. Results: Radiation survival sensitivity across lineages largely reflected clinical experience. Importantly, intra-lineage variation in radiation survival was significant (6-7 fold variation), reflecting underlying genetic diversity. We showed that major pathways of radiation resistance include the activation of growth factor receptors (HER2, BRAF, EGFR, IGF-1R), pro-growth kinases (PIK3CA, AKT, mTOR, JAK-STAT), and transcription factors (AR, ER, WNT, NFE2L2) whereas deficiencies in DNA repair (TP53, TP53BP1, PRKDC, BRCA1/BRCA2), chromatin remodeling (SMARCA4) and mRNA processing were strong predictors of radiation sensitivity. In lineage confined analyses, we showed that: 1) HER2 and ER activity is predictive of radiation resistance and identified AR expression as a novel predictor of radiation resistance in breast cancer; 2) select BRAF mutations confer radiation resistance in lung adenocarcinoma; and 3) novel HER2 kinase domain mutations confer radiation resistance in endometrial cancer. We demonstrated that small molecules that target genetic alterations driving therapeutic resistance including enzalutamide (AR), sorafenib (BRAF), and lapatinib (HER2) effect genotype selective radiosensitization, establishing a preclinical basis for personalized radiotherapeutic regimens. Conclusions: Our methods utilize novel and robust pre-clinical evaluation of markers of therapeutic sensitivity that will generate unique information that will inform future trials of personalized radiation. This dataset is an important resource that can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs given concurrently with radiation matched to patients by their cancer genotype, thereby enhancing efficacy and limiting toxicity in the context of a new approach of precision radiotherapy. Author Disclosure: M. Abazeed: None. D. Adams: None. P. Tamayo: None. B. Yard: None. J. Loeffler: None. J. Suh: None. M. Meyerson: G. Consultant; M.M. is a consultant to Foundation Medicine. R. Ownership Other; M.M. is an equity holder in Foundation Medicine. P. Hammerman: G. Consultant; P.S.H. reports consulting fees from ARIAD. S. Schreiber: None.
67 High-Throughput RNAi Screening Platform Identifies Novel Regulators of DNA Double-Strand Break Repair Pathways A.F. Salem, Y. Surovtseva, R.K. Sundaram, and R.S. Bindra; Yale University, New Haven, CT Purpose/Objective(s): Ionizing radiation (IR) induces DNA doublestrand breaks (DSBs) which are repaired by two main pathways, homologous recombination (HR) and non-homologous end joining (NHEJ). Although many core regulators of DSB repair are known, recent studies
International Journal of Radiation Oncology Biology Physics
Conclusions: In this cohort, referral hospital was an independent predictor of cCR regardless of stage, but interestingly not DFS or OS. These results suggest that HIV+ patients are prone to health disparities in anal cancer outcomes. Further, these data support that SES factors are important in determining treatment outcome, independent of treatment course characteristics. Recognizing the prognostic implication of SES factors may lead to a better understanding and improvement of the clinical outcomes for anal cancer. Author Disclosure: D.S. Bitterman: None. D. Grew: None. C.G. Leichman: None. L. Leichman: None. K.L. Du: None.
66
65 Quantitative FDG-PET/CT Predicts Local Recurrence and Survival for Squamous Cell Carcinoma of the Anus M.L. Cardenas, C.R. Spencer, T.A. DeWees, S. Hunt, R.J. Myerson, M. Silviera, R. Jain, P.J. Parikh, B. Tan, P.W. Grigsby, F. Dehdashti, and J.R. Olsen; Washington University, Saint Louis, MO Purpose/Objective(s): FDG-PET/CT imaging is recommended for staging and treatment planning of anal cancer, although quantitative pre- and post-treatment metrics predictive of recurrence are unknown. We evaluated the association between pre- and post-treatment FDG-PET/CT parameters and outcome for patients with squamous cell carcinoma of the anus (SCCA). Materials/Methods: The records of 110 patients treated between 2003 and 2013 with definitive radiotherapy for SCCA were reviewed under an IRBapproved protocol. The median radiotherapy dose was 50.4 Gy (Range, 35-60 Gy). Concurrent chemotherapy was administered for 109/110 patients and generally consisted of 5-FU in combination with mitomycin C (n Z 94). All patients underwent pre-treatment FDG-PET/CT and 100/110 also underwent post-treatment FDG-PET/CT 3 months following completion of radiotherapy. Pre-treatment and post-treatment FDG-PET/ CT parameters including the maximum standardized uptake value (SUVmax) and SUVmax normalized to blood pool uptake (nSUVmax) were analyzed in addition to multiple patient and treatment factors (age, T-stage, N-stage, stage group, gender, and HIV status) by univariate and multivariate Cox regression for correlation with local recurrence (LR) and overall survival (OS). Results: The median follow-up time was 28.6 months. LR occurred in 1/15 (6.7%), 5/47 (10.6%), and 6/48 (12.5%) patients with stage I, II, and III disease, respectively. A significant association was observed on univariate analysis between reduced LR and pre-treatment SUVmax > 7.1 (p Z 0.029), and between reduced LR and post-treatment nSUVmax < 3.2 (p Z .015). A significant univariate association was also observed between increase OS and pre-treatment SUVmax > 7.1 (p Z 0.046), and between increased OS and post-treatment nSUVmax (p Z 0.016). On multivariate analysis, a significant association was observed between reduced LR and pre-treatment SUVmax > 7.1 (p Z 0.010) and between reduced LR and post-treatment nSUVmax < 3.2 (p Z 0.003). A significant multivariate association was also observed between increased OS and pre-treatment SUVmax > 7.1 (p Z 0.026), post-treatment nSUVmax (p Z 0.027), and less advanced nodal disease (p Z 0.0020). Conclusions: A higher pre-treatment SUVmax > 7.1, and lower posttreatment nSUVmax < 3.2 are associated with reduced LR and increased OS following definitive chemoradiation therapy for SCCA. FDG-PET/CT metrics correlated with outcome independently of T and N stage on multivariate analysis and maybe useful for patient selection and stratification in clinical trials. Greater follow-up is required to confirm association with late patterns of failure, and further study is required to determine if this association may be due to tumor hypoxia, p16 status, or other mechanism. Author Disclosure: M.L. Cardenas: None. C.R. Spencer: None. T.A. DeWees: None. S. Hunt: None. R.J. Myerson: None. M. Silviera: None. R. Jain: None. P.J. Parikh: None. B. Tan: None. P.W. Grigsby: None. F. Dehdashti: None. J.R. Olsen: G. Consultant; Dfine, Inc.
The Radiogenomic Landscape of Cancer M. Abazeed,1 D. Adams,2 P. Tamayo,2 B. Yard,3 J. Loeffler,4 J. Suh,1 M. Meyerson,5 P. Hammerman,5 and S. Schreiber6; 1Cleveland Clinic Foundation, Cleveland, OH, 2Broad Institute, Cambridge, MA, 3Cleveland Clinic, Cleveland, OH, 4Massachusetts General Hospital, Boston, MA, 5 Dana Farber Cancer Institute, Boston, MA, 6Harvard University, Cambridge, MA Purpose/Objective(s): There have not been extensive systematic analyses of the correlation between therapeutic sensitivity and genomic parameters. We report on a large-scale effort to functionally characterize genetic alterations driving radiotherapeutic resistance across 22 solid tumor lineages. Materials/Methods: We developed a systematic high-throughput method for profiling radiation sensitivity and benchmarked this method against the conventional clonogenic survival assay. In the largest study of its kind, we have measured the sensitivity of 533 genomically characterized cancer cell lines to radiation. We combined results from this high-throughput assay with genomic parameters to identify parameters that predict radiation sensitivity. Genomic correlates of radiosensitivity were explored by accessing the Cancer Cell Line Encyclopedia, the COSMIC database of the Cancer Genome Project, The Cancer Genome Atlas, Gene Set Enrichment Analysis, and GISTIC2.0. Results: Radiation survival sensitivity across lineages largely reflected clinical experience. Importantly, intra-lineage variation in radiation survival was significant (6-7 fold variation), reflecting underlying genetic diversity. We showed that major pathways of radiation resistance include the activation of growth factor receptors (HER2, BRAF, EGFR, IGF-1R), pro-growth kinases (PIK3CA, AKT, mTOR, JAK-STAT), and transcription factors (AR, ER, WNT, NFE2L2) whereas deficiencies in DNA repair (TP53, TP53BP1, PRKDC, BRCA1/BRCA2), chromatin remodeling (SMARCA4) and mRNA processing were strong predictors of radiation sensitivity. In lineage confined analyses, we showed that: 1) HER2 and ER activity is predictive of radiation resistance and identified AR expression as a novel predictor of radiation resistance in breast cancer; 2) select BRAF mutations confer radiation resistance in lung adenocarcinoma; and 3) novel HER2 kinase domain mutations confer radiation resistance in endometrial cancer. We demonstrated that small molecules that target genetic alterations driving therapeutic resistance including enzalutamide (AR), sorafenib (BRAF), and lapatinib (HER2) effect genotype selective radiosensitization, establishing a preclinical basis for personalized radiotherapeutic regimens. Conclusions: Our methods utilize novel and robust pre-clinical evaluation of markers of therapeutic sensitivity that will generate unique information that will inform future trials of personalized radiation. This dataset is an important resource that can be used to develop novel therapeutic hypotheses and to accelerate discovery of drugs given concurrently with radiation matched to patients by their cancer genotype, thereby enhancing efficacy and limiting toxicity in the context of a new approach of precision radiotherapy. Author Disclosure: M. Abazeed: None. D. Adams: None. P. Tamayo: None. B. Yard: None. J. Loeffler: None. J. Suh: None. M. Meyerson: G. Consultant; M.M. is a consultant to Foundation Medicine. R. Ownership Other; M.M. is an equity holder in Foundation Medicine. P. Hammerman: G. Consultant; P.S.H. reports consulting fees from ARIAD. S. Schreiber: None.
67 High-Throughput RNAi Screening Platform Identifies Novel Regulators of DNA Double-Strand Break Repair Pathways A.F. Salem, Y. Surovtseva, R.K. Sundaram, and R.S. Bindra; Yale University, New Haven, CT Purpose/Objective(s): Ionizing radiation (IR) induces DNA doublestrand breaks (DSBs) which are repaired by two main pathways, homologous recombination (HR) and non-homologous end joining (NHEJ). Although many core regulators of DSB repair are known, recent studies