Mace L. Rothenberg, M.D.
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Transcript of Mace L. Rothenberg, M.D.
Mace L. Rothenberg, M.D.
Professor of MedicineIngram Professor of Cancer Research
Developing a Patient-Tailored Strategy to Stratify and Treat Patients with
Pancreatic Cancer
Conflict of Interest DisclosureConsultant or Advisory Role
Antigenics OSI
Array BioPharma Pfizer
Bristol Myers-Squibb Roche
Genentech sanofi-aventis
Idera Synta
ImClone Takeda
Johnson & Johnson Zymogenetics
Novacea
Stock OwnershipSynta Targeted Therapeutics
Patient-Tailored Strategy for Pancreatic Cancer Treatment
• Development of a more robust preclinical model
• Pharmacogenomics
• Randomized Phase II clinical trial
• Patterns of gene expression and amplification
How Are These Presentations Related?
• Each looks at a different, and complementary approach to the development of improved therapy
• Tumor genetics, host genomics, effect of therapy in the mouse, effect of therapy in the patient
A prospective validation of a direct tumor xenograft model in pancreatic ductal
adenocarcinoma (PDA)
Antonio Jimeno, Ignacio Garrido-Laguna, Maria Uson-Olaso, Dante Trusty, Ralph Hruban, Richard
Schulick, John Cameron, Anirban Maitra, and Manuel Hidalgo
Patient-Tailored Strategy for Pancreatic Cancer Treatment
Abstract #4500
Direct Tumor Xenograft Model in Pancreatic Cancer
What Did They Do and Why is it Important?
• Obtained fresh pancreatic ductal carcinoma from the operating room which were then implanted directly into nude mice
• This maintains the genetic integrity of the original tumor over multiple passages
• Evaluated response of tumor explants to drugs to determine if this model has promise in predicting
• clinical response to the agent in the patient
• potential activity of investigational drugs against pancreatic cancer
Direct Tumor Xenograft Model in Pancreatic Cancer
Key Findings
• Explantation and propagation of human pancreatic ductal adenocarcinomas in nude mice is feasible
• In a limited number of patients, information from this model was be used to select treatment upon relapse
• In 4 patients, there was concordance between ex vivo sensitivity and clinical response
• Concordance between ex vivo sensitivity and gene expression patterns of tumor cell lines known to be sensitive to gemcitabine and docetaxel
Direct Tumor Xenograft Model in Pancreatic Cancer
Limitations and Challenges
• Only 20% of all consenting patients yielded successful xenografts• Model lacks certain elements that may be critical in determining treatment response
• Immune system• Tumor-stromal-vascular interactions
• Very few drugs have demonstrated greater activity than the standard agent used to treat this disease: gemcitabine
• Clinical “successes” consisted of 2 pts with SD x 4 and 6 months• Can PD at 100 days be considered a success?
• Poor correlation between ex vivo sensitivity and PFS with adjuvant gemcitabine: R2 = .08
Patient-Tailored Strategy for Pancreatic Cancer Treatment
Abstract #4501
Significant Effect of Single Nucleotide Polymorphisms of Gemcitabine Metabolic Genes on Pancreatic Cancer Survival and
Drug Toxicity
Milind Javle, Taro Okazaki, Robert Wolff, Chris Crane, Linus Ho, Gauri Varadhachary, Douglas B. Evans,
James L. Abbruzzese, Donghui Li.
Correlation of Gemcitabine Metabolic SNPs and Clinical Outcome
What Did They Do and Why is it Important?
• Identified SNPs in gemcitabine-associated cellular transporter, anabolic and catabolic genes
• Correlated SNP patterns (haplotypes) with therapeutic outcomes as well as patterns and severity of toxicity
• This approach has the potential to identify patients at increased risk of harm as well as patients more likely to benefit from treatment
Correlation of Gemcitabine Metabolic SNPs and Clinical Outcome
Key Findings• Grade 3-4 ANC was increased 2-3 fold for those patients with CT or TT genotype at position 111 in the cytidine deaminase gene or the CC/CT genotype in position 1205 in the deoxycytidine kinase gene.
• Longer survival was observed in those patients with the same genotype in the cytidine deaminase gene or with an AA or AG genotype in position 42 of the ribonucleotide reductase M1 gene.
• Two models, one comprised of selected haplotypes of metabolic genes and the other with selected haplotypes of transporter genes, were associated different patterns of survival
Correlation of Gemcitabine Metabolic SNPs and Clinical Outcome
Limitations and Challenges
• Data generated from a relatively small dataset (120 patients)• Combined data from 2 clinical trials with different chemotherapy regimens
• Gemcitabine alone (54 patients)• Gemcitabine + cisplatin (66 patients)
• All patients received radiation in addition to chemotherapy• Was the predictive value of these SNPs still seen in multivariate analysis that included known clinical prognostic variables such as tumor grade, baseline CA19-9, + or - margin or LN?
Correlation of Gemcitabine Metabolic SNPs and Clinical Outcome
Conclusions
• These findings should be validated in an independent cohort involving a larger number of patients
• Agree (this has been the downfall of prior efforts)
• But does the model need further refinement first?
• Prospectively select SNPs based on biological pathways (for gemcitabine and/or other drugs)
• Agree
Results are encouraging but more work needs to be done before it is likely to have a major clinical impact
on patient management
Patient-Tailored Strategy for Pancreatic Cancer Treatment
Abstract #4502
Final analysis of a randomized phase II trial of bevacizumab and gemcitabine plus cetuximab
or erlotinib in patients with advanced pancreatic cancer
Hedy Lee Kindler, Tara Gangadhar, Theodore Karrison, Howard Hochster, Malcolm Moore, Kenneth Micetich, Weijing Sun, Daniel Catenacci, Walter M Stadler, and
Everett E Vokes for the University of Chicago Phase II Consortium
Addition of EGFR Inhibitors to Gemcitabine + Bevacizumab in Advanced Pancreatic Cancer
What Did They Do and Why is it Important?
• Tried to build upon exciting early clinical data for gemcitabine + VEGF inhibitor (bevacizumab) and gemcitabine + EGFR inhibitor (erlotinib or cetuximab)
• Promising preclinical data on the effect of simultaneous inhibition of multiple growth factor signaling pathways
• Randomized Phase II design could help identify if either of these regimens should be taken to Phase III
Addition of EGFR Inhibitors to Gemcitabine + Bevacizumab in Advanced Pancreatic Cancer
Key Findings
• Primary endpoint of RR ≥ 35% for either arm was not met• Is RR the best indicator of activity in this disease?
• Both regimens were relatively well tolerated• Patients with better PS and locally advanced disease did best• Appearance of rash during treatment correlated with PFS for GBE but not for GBC group• Early HTN may predict for response but not for PFS or OS• Neither VEGF nor soluble VEGFR2 correlated with clinical outcome
Addition of EGFR Inhibitors to Gemcitabine + Bevacizumab in Advanced Pancreatic Cancer
Issues to Consider
• Interference between VEGF inhibitor and EGFR inhibitor• biologically• pharmacologically
• Presence of KRAS mutation in >90% of all pancreatic cancers
• Likely to be a cause of resistance to EGFR inhibitors in CRC and NSCLC• But why was NCIC PA.3 study positive? (Death HR = 0.81, p = .028 for combination of gemcitabine + erlotinib).• Is there a definable subset of patients with PDAC who benefit from an EGFR inhibitor?
Addition of EGFR Inhibitors to Gemcitabine + Bevacizumab in Advanced Pancreatic Cancer
Two Alternative Interpretation of Results
1. The trial didn’t meet protocol-specified endpoint for success
2. With >90% of PDAC carrying KRAS mutations, the lack of benefit is not surprising
3. In mCRC, the addition of an EGFR inhibitor to chemotherapy and bevacizumab doesn’t improve outcomes
1. Requirement of a RR ≥35% was unrealistic
2. RR is not a reliable indicator of efficacy in PDAC
3. OS = 7-8 months compares favorably with gemcitabine (6 mo), gem + erlotinib (6.4 mo), gem + bevacizumab (5.7 mo), and gem + cetuximab (6.4 mo)
Trial was a Failure Trial was a Success
Patient-Tailored Strategy for Pancreatic Cancer Treatment
Abstract #4503
Whole Genome Expression Analysis of Pancreatic Adenocarcinoma Predicts
Prognosis after Surgery
Eric A. Collisson, R. Mori, A.C. Hoffmann, G.E. Kim, R.Hajnal, P.V. Danenberg, J. Cooc, K.D.
Danenberg, M.A. Tempero
Whole Genome Expression Analysis in PDAC
What Did They Do and Why is it Important?
• Tried to identify a genetic signature that distinguished long from short survivors following Whipple resection of PDAC
• Performed this on gross and microdissected tumor
• Also evaluated tumors for differences in gene copy number
Key Findings
• Expression pattern of PDAC differs dramatically from NL pancreas• Gene expression profile differences identified from microdissected specimens were not maintained when gross tumor was analyzed• Only 3 of >700 genes overlapped suggesting dilutional effect of stroma and acini
• Two genetic loci appear to be amplified disproportionately in patients with PDAC and short survival: 6p21.1-21.3 and 8p12 - 8p11.23 (LETM2)
Whole Genome Expression Analysis in PDAC
Issues to Consider• Was the genetic signature an independent predictive or prognostic tool after taking known clinical factors into account?
• Although adjuvant therapy is the only statistically significant difference, there are notable imbalances in gender, and histologic grade.
• The short surviving patients survived a median of 3 months; why so short?
• Does this analysis include death from any cause or just disease-specific death?
• Will either model hold up in a larger, independent cohort?• What are the biological consequences of the overexpressed or amplified genes?
Whole Genome Expression Analysis in PDAC