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Caris Centers of Excellence Virtual Molecular Tumor Board - July 13, 2015

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Slide deck from Caris Life Science's Virtual Molecular Tumor Board hosted by Levine Cancer Institute - Carolinas Healthcare System

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Caris Centers of Excellence Virtual Molecular Tumor Board - July 13, 2015

  1. 1. Today’s VMTB Presented by Edward Kim, M.D. Chair, Solid Tumor Oncology at Levine Cancer Institute - Carolinas Healthcare System Agenda Patient 1 – metastatic adenocarcinoma, gallbladder Patient 2 – metastatic NSCLC Patient 3 – bladder cancer Patient 4 – metastatic colorectal cancer Patient 5 – adenoid cystic carcinoma Housekeeping Please identify yourself and organization when asking or responding to questions 1The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  2. 2. Case 1 The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  3. 3. Clinical History • Female in mid-40’s, Caucasian, never smoker • At diagnosis: Presented with pain, CT showed ill-defined mass involving medial segment of left hepatic lobe adjacent to gallbladder, necrotic lymph node in portal hepatis indicating concern of primary gallbladder malignancy with local tumor invasion and small lesions in hepatic lobes • Metastatic adenocarcinoma of gallbladder, wedge resection of liver lesion Gemcitabine + cisplatin, 6 cycles with eventual progressive disease • at 2 months: CT showed marked decrease gallbladder and liver lesions, CA19-9 = 70 Palliative gemcitabine + cisplatin • At 3 months: Laparoscopy for tissue for Caris testing, CA 19-9 = 114 The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  4. 4. Pathology H & E HER2 IHC • Liver biopsy: adenocarcinoma of liver, segments 3 & 4A • Gallbladder: moderately differentiated adenocarcinoma of gallbladder The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  5. 5. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  6. 6. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  7. 7. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  8. 8. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  9. 9. Molecular Tumor Summary • HER2 positivity by IHC and amplified by CISH • TP53 mutation • Cytotoxic markers suggesting response: – Gemcitabine – Taxanes – Irinotecan – Anthracyclines The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  10. 10. Current Treatment • At 6 months: Xeloda + herceptin + oxaliplatin, 3rd cycle CA 19-9 = 509 (5/1/15) • At 7 months: CA 19-9 decreased (509326) • At 8 months: Intrahepatic lesions increased, stable lymph node, abnormal significant bowel wall thickening involving ileum and distal ileum The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  11. 11. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  12. 12. Discussion Points • Her2+ and subsequent treatment • RRM1- • Gemcitabine may be useful due its inhibition of ribonucleotide reductase activity • Progression, what’s next? The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  13. 13. Case 2 The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  14. 14. Clinical History • Female, early 70’s, Caucasian, NSCLC, never smoker • PMH: Hypertension, hyperlipidemia, renal insufficiency, asthma • Initial diagnosis: Presented with musculoskeletal pain in right chest wall with history of stage IV NSCLC (adenocarcinoma, EGFR L858R+) • CT: 4.7x3.7cm right hilar poorly differentiated adenocarcinoma, 2.4x1.7cm lower lobe mass • PET: 3.6x3.9cm high lower lobe mass, multiple bilateral mediastinal hilar lymph nodes, right pleural effusion, and hepatic metastasis of 1.3x1.4cm  Started Tarceva  partial response • At 13 months: Progression, treated with carb/pem 4 cycles • At 19 months: Maintenance pemetrexed, quickly progressed in lung/liver • Liver biopsy  EGFR L858R+ and T790M+ poorly differentiated adenocarcinoma  Began clinical trial AZD9291 • At 29 months: CT showed continued response to AZD9291 • At 32 months: CT showed left hepatic lesion increasing • Surgical resection of hepatic lesion; sent to Caris The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  15. 15. Pathology H&E EGFR IHC • At diagnosis: FNA hilar lesion – poorly differentiated adenocarcinoma, ALK-, EGFR L858R+; lymph nodes showed no carcinoma • At 2 years: poorly differentiated metastatic adenocarcinoma of liver, EGFR T790M+, L858R+ • At 2.75 years: metastatic adenocarcinoma, poorly differentiated The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  16. 16. Pathology EGFR L585R specific EGFR deletion-specific The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  17. 17. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  18. 18. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  19. 19. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  20. 20. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  21. 21. Molecular Tumor Summary • ATM pathogenic mutation • CMET amplification • CMET IHC+ • EGFR pathogenic mutation exon 21, L858R • EGFR H-score positive • TP53 pathogenic mutation, exon 5, A159V The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  22. 22. Discussion Points • EGFR L858R+: IHC and prior treatment • cMET amplification and IHC+: Possible clinical trial? • What’s next? The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  23. 23. Case 3 The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  24. 24. Clinical History • Female, Caucasian, in mid-70’s • PMH: Diabetes without neuropathy, coronary artery disease post bypass graft • At diagnosis: Microhemoturia, nocturia, urinary frequency and urgency 1st TURBT/cystoscopy , 1.5 cm high-grade papillary urothelial carcinoma with superficial and angliolymphatic invasion, without muscularis invasion BCG, one round, difficulty tolerating • At 4 months:CT, cytourethroscopy/fulgration showed T2 N0 M0 high-grade urothelial carcinoma of the bladder, nested variant with prominent propria invasion and muscularis propria invasion  Recommended neoadjuvant chem followed by radical cystectomy but patient requested bladder preservation and started Tx w/concurrent 5FU/mitomycin C/ radiation • At 8 months: Mild increased size of right posterior lateral wall thickness, extension into right ureter causing marked right hydronephrosis consistent with progression but not metastasis • At 10 months: Post-radiation radical cystectomy, extended pelvic lymph node dissection The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  25. 25. Pathology H & E At diagnosis: Urothelial carcinoma, nested variant, prominent lamina propria and muscularis propria invasion, indeterminate for lymph-vascular space invasion At 10 months: High-grade urothelial carcinoma of the bladder, focal nested features, pathologic state pT3b pN3; metastatic carcinoma involving 1/3 right obturator pelvic and 1/1 paracaval lymph nodes with extranodal extensions The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  26. 26. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  27. 27. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  28. 28. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  29. 29. Caris Molecular Intelligence Profile The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  30. 30. Caris Molecular Intelligence Profile The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  31. 31. Molecular Tumor Summary • No Pathogenic Mutations on NGS • IHC findings: – Suggest benefit with: platinums, taxanes, anti- androgen, temozolomide – Suggest lack of benefit with: 5-FU, capecitabine, irinotecan, anti-HER2, anthracyclines The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  32. 32. Discussion Points • Prior Treatment w/concurrent 5FU/mitomycin C/ radiation • Patient is: • AR+: Treatment with anti-androgens? • ERCC1 -: Treatment with platinums? • MGMT-: Treatment with temozolomide? • PGP, TLE3, TUBB3+: Treatment with taxanes? • PD-1+: Treatment with immunotherapy? • EGFR +: Cetuximab? • Clinical trials? • What’s next? The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  33. 33. Case 4 The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  34. 34. Clinical History • Female, Caucasian, in her late 60’s, Smoker ~2 packs/day, 60 yrs • Family history: Father colorectal and prostate cancer • PMH: Diabetes mellitus w/neuropathy, GERD; sick sinus syndrome w/ pacemaker, hypertension, hyperlipidemia • At diagnosis: Patient presented with chronic abdominal pain • CT: Thickening/irregularities in ascending colon at the hepatic flexure; • Biopsy: mucinous adenocarcinoma of hepatic flexure • Right hemicolectomy • Stage IIIB pT3 pN1 M0 colorectal adenocarcinoma • Began 5FU, discontinued in at month 4 due to GI side effects; surveillance • In 6 years: persistent RUQ pain, CT/PET showed 13 x 9 cm right hepatic lobe • Neo-adjuvant irinotecan/bev, 2 cycles, partial response • In 4 months: CT showed 12.2 x 8.9 cm prominent lesion right hepatic lobe • Metastatic – adenocarcinoma, liver • Right partial hepatic resection, • Post-resection CT showed 4.8x4.2 cm right hepatic lobe • Completed 1/ 4 cycles 5FU/leucovorin/irinotecan/bev; side effects required switching to irinotecan + bev The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  35. 35. Pathology H & E • Initial diagnosis: 9 cm moderately differentiated, low grade mucinous adenocarcinoma; metastatic, 2/15 lymph nodes; pathologic stage pT3, pN1 pMX Resection: Metastatic adenocarcinoma of liver, NRAS/KRAS negative • Recurrence at 6 years: Right partial hepatic resection, loss of MLH1, PMS2 nuclear positivity, BRAF V600E+ The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  36. 36. Pathology PMS2 MLH1 The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  37. 37. Pathology BRAF V600E-specific IHC The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  38. 38. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  39. 39. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  40. 40. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  41. 41. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  42. 42. Molecular Tumor Summary • Pathogenic Mutations on NGS: – APC N1455fs, T1556fs – PTEN K267fs – BRAF V600E – VHL P138L • IHC findings predict benefit for: – 5-FU / Capecitabine – Gemcitabine The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  43. 43. Discussion Points • TOPO1 negative: May not respond to irinotecan • KRAS/NRAS/PIK3CA/PTEN negative: Cetuximab, panitumimab? • BRAF V600E+: Vemurafenib, dabrafenib? • TS-: Capecitibaine, fluorouracil, pemetrexed? • RRM1-: Gemicitabine? • What’s next? The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  44. 44. Case 5 The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  45. 45. Clinical History • Female, Caucasian, in her late 60’s • Initial diagnosis:Treated for unresectable myoepithelial carcinoma • Chemoradiation (carboplatin + taxol, 7 weeks) • Total thyroidectomy for papillary carcinoma, 0.6 cm, T1a N0 • In 3 years: CT/PET showed recurrence in left masticator space and abnormal area in right lobe of liver • Confirmed with biopsy metastatic head and neck and liver cancer • Left parotid, skin cheek, mandible, zygoma, maxillary wall resected • CT showed stable right lobe hepatic lesion and small portal lymph nodes • Radiation with concomitant cisplatin • Ablation of liver lesion followed by chemoradiation and resection; found 2.4 cm metastatic adenoid cystic carcinoma with negative margin • Reduction of hypodense right hepatic lobe lesion • Follow-up: No evidence of recurrent disease by PET, FDG activity in right hepatic lobe suggestive of necrosis; metastatic disease portacaval lymph node The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  46. 46. Pathology H & E ERCC1 IHC • Initial diagnosis: Salivary gland neoplasm with basaloid features, cKit+ • At 3 years, recurrence: Adenoid cystic carcinoma or parotid, 3.8 cm, with admixed bone (tissue over left medial zygoma), perineural invasion in pes anserinus of left facial nerve, adenoid cystic carcinoma of left maxillary mucosa, no lymph node involvement • 2.4 cm metastatic adenoid cystic carcinoma right hepatic lobe, margin negative The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  47. 47. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  48. 48. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  49. 49. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  50. 50. Molecular Tumor Summary • No mutations detected by NGS • EGFR IHC+ • Cytotoxic IHC markers predicteding response to: – Capecitabine, 5-FU – Gemcitabine – Taxanes – Carboplatin – Temozolomide The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  51. 51. Discussion Points • Previous treatment with platinums, taxol, radiation • ERCC1-: Treatment with platinums? • PCP, TLE3, TUBB3-: Treatment with taxanes? • TS-: Treatment with capecitabine? • RRM1-: Treatment with gemcitabine? • EGFR+: Cetuximab trial? • PD-1+: Immunotherapy trial? The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  52. 52. Summary The next VMTB will be presented by Elisabeth Heath, M.D., of the Barbara Ann Karmanos Cancer Center Date: July 27, 2015 Time: 5:00 pm EST Look for an Outlook invitation in the next week Please direct any questions regarding the VMTB to cariscentersofexcellence@carisls.com 52The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  53. 53. References: Case 1 • Javle 2015 “HER2/neu-directed therapy for biliary tract cancer”, J Hemotol Oncol, 8:58. – A retrospective analysis of biliary tract cancer patients carrying Her2 aberrations: 8 out of 9 patients showed gene amplification or overexpression, 3 showed SD, 4 PR and 1 CR. 1 patient carrying mutation had a mixed response. • Law 2012 “Dramatic response to trastuzumab and paclitaxel in a patient with human epidermal growth factor receptor 2-positive metastatic cholangiocarcinoma.” J Clin Oncol. 2012 30(27):e271-3 – A case report of a gallbladder cancer • Sorscher 2013 “Marked radiographic response of a HER-2-overexpressing biliary cancer to trastuzumab”, Cancer Management and Research 2014:6 1–3 The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  54. 54. References: Case 2 • Brugger W, et al. Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol. 2011 Nov 1;29(31):4113-20. • Engelman JA, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007 May 18;316(5827):1039-43. – Resistance to gefitinib with cMET amplification • Douillard JY, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014 Jul;25(7):1346- 55. – Cetuximab benefit in high expressing EGFR patients is not limited by concomitant EGFR mutations • Bhattacharya N et al. Frequent alterations of MCPH1 and ATM are associated with primary breast carcinoma: clinical and prognostic implications. Ann Surg Oncol. 2013 – ATM-altered patients had poor prognosis when treated with DNA-interacting drugs The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  55. 55. References: Case 3 • ASCO GU 2015. Systematic review and meta-analysis on ERCC1 in urothelial CA: http://meetinglibrary.asco.org/content/141786-159. • ASCO GU 2015, on androgen deprivation therapy to prevent bladder CA recurrence: http://meetinglibrary.asco.org/content/141184-159. • Powles T, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014 Nov 27;515(7528):558-62. The information contained in these slides is provided for educational purposes only and has been permanently de-identified
  56. 56. References: Case 5 • Dahse R, et al. KRAS status and epidermal growth factor receptor expression as determinants for anti-EGFR therapies in salivary gland carcinomas. Oral Oncol. 2009. Sep;45(9):826-9. – supports EGFR and KRAS status as determinant for anti-EGFR • Popovtzer, et al. BioMed Research International 2015 – TUBB3/PGP for taxanes The information contained in these slides is provided for educational purposes only and has been permanently de-identified

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