Repurposing therapies for treatment of HER2-amplified pancreatic cancer
Mark J Cowley1^ Angela Chou1^ N...
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Repurposing Therapies for Treatment of HER2 Amplified Pancreatic Cancer - Cowley Mark


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Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal, and molecularly diverse malignancies, with few therapeutic options. We have used next generation sequencing to define the molecular features of PDAC. Repurposing of therapeutics that target specific molecular mechanisms in different disease types offers considerable potential for rapid improvements in outcome. Herceptin®, a monoclonal antibody targeting HER2 has been successfully used to treat HER2-amplified breast cancer, and has recently been repurposed for gastric cancer; the incidence of HER2-amplified PDAC is poorly understood.

Through a combination of whole exome, whole genome, copy number and microarray analysis, we identified 1/99 PDAC tumours with a ~1MB high-level amplification, affecting HER2, resulting in high mRNA and protein expression. From an archival cohort of 369 PDAC tissues, and using IHC and SISH, we identified 10 patients (2.1%) with high-level HER2-amplification, and defined standardized guidelines for identifying HER2-amplified PDAC.

Strikingly, the distribution of metastatic sites in HER2 amplified PDAC showed strong preference to brain and lung, over the normal pattern of liver (P<5E-7; relative to non-HER2-amplified PDAC), similar to that observed in HER2-amplified breast cancer.

The substantial molecular heterogeneity of PDAC implies that with an incidence of 2.1%, HER2-amplification potentially represents a valuable therapeutic target. Since collecting these data, we observed a significant response to Herceptin therapy in a patient with HER2-amplified PDAC. We have established the IMPACT clinical trial to assess the efficacy of three genotype-guided therapies in PDAC, including Herceptin.

Authors: Mark J Cowley, Angela Chou, Nicola Waddell, David K Chang, Jiamin Wu, Mark Pinese, Lorraine Chantrill, Amber L Johns, Katia Nones, Ann-
Marie Patch, Sean M Grimmond, Andrew V Biankin

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Repurposing Therapies for Treatment of HER2 Amplified Pancreatic Cancer - Cowley Mark

  1. 1. PANCREATIC CANCER Repurposing therapies for treatment of HER2-amplified pancreatic cancer Mark J Cowley1^ Angela Chou1^ Nicola Waddell2^ David K Chang1 Jiamin Wu1 Mark Pinese1 Lorraine Chantrill1 Amber L Johns1 Katia Nones2 AnnMarie Patch2 APGI3 Sean M Grimmond2 Andrew V Biankin1 1Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. 2Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, St Lucia, QLD, Australia. 3Australian Pancreatic Cancer Genome Initiative, for a list of members, please visit ^these authors contributed equally Background 1 The 5 year survival rate of pancreatic ductal adenocarcinoma (PDAC) is a dismal 3-5%. HER2-amplified pancreatic cancer Only 10% of patients with PDAC demonstrate any clinical response to the standard therapy, gemcitabine. We recently performed whole exome sequencing of 142 primary PDAC tumours, which revealed extensive molecular heterogeneity. Defining clinically actionable molecular subtypes of PDAC is vital. Trastuzumab (Herceptin®), a monoclonal antibody targeting HER2 has been successfully used to treat HER2-amplified breast cancer. Trastuzumab has recently been repurposed for HER2amplified gastric cancer. Aims 1)  Determine the prevalence of HER2-amplified PDAC 2)  Assess clinical response to targeted therapeutics 2 Figure 1: A) Copy number analysis on SNP arrays identified 1/99 patients with focal amplification of HER2. B) whole genome sequencing resolved the breakpoints to a 1.0 MB region, containing HER2. C) This resulted in extreme up-regulation of gene expression. D) Whole exome sequencing identified 23 non-synonymous somatic variants; whole genome sequencing identified additional structural variations. E) Genes within the 1.0 MB amplicon. HER2amplification confirmed by IHC (3+ staining; F) SISH (G) and FISH (H). 2.1% of PDAC is HER2-amplified 3 HER2-amplified PDAC has an unusual pattern of metastasis & responds to targeted therapy Case Report Table 1: HER2-amplification was assessed by IHC and FISH in an archival cohort of 469 PDAC tumours. Diagnostic criteria for detecting HER2-amplified PDAC were established. 4 Figure 2: Algorithm for Diagnostic testing of HER2-amplification in PDAC Establishment of a genotype-guided clinical trial Table 2: Clinicopathological characteristics of HER2amplified PDAC. A preponderance of lung, without liver metastases (χ2 P=5e-7) 42yo lady, primary PDAC, resected & standard first line adjuvant therapy Recurred 14mo later, with liver metastasis Confirmed pancreatic origin, strongly HER2amplified (IHC 3+) Received 24 weeks of Capecitabine and Trastuzumab + 5 cycles of Epirubuicin Further Trastuzumab for 34 weeks Alive at 4 years since recurrence Conclusions •  2.1% of PDAC is HER2-amplified •  8% will stain as 2+/3+ by IHC & warrant further testing by FISH •  Like breast cancer, HER2-amplified PDAC has unusual pattern of metastasis •  1 patient with strong response to Trastuzumab •  Clinical trial established to determine efficacy of Trastuzumab in HER2-amplified PDAC •  HER2-amplifications identified in other cancers; potential for pan-cancer clinical trials. Figure 3 5 Prevalence of any HER2-amplified cancer Cancer  Type   Breast  Invasive  Carcinoma  (TCGA,  Nature  2012)   Stomach  Adenocarcinoma  (TCGA,  Provisional)   Bladder  Urothelial  Carcinoma  (TCGA,  Provisional)   Uterine  Corpus  Endometrioid  Carcinoma  (TCGA,  Provisional)   Cervical  Squamous  Cell  Carcinoma  (TCGA,  Provisional)   Colon  and  Rectum  Adenocarcinoma  (TCGA,  Nature  2012)   Head  and  Neck  Squamous  Cell  Carcinoma  (TCGA,  Provisional)   Lung  &  bronchus  cancer   Ovarian  Serous  Cystadenocarcinoma  (TCGA,  Nature  2011)   PancreaUc  Ductal  Adenocarcinoma  (ICGC,  Nature  2012)   Kidney  &  renal  pelvis  cancer   Thyroid  Carcinoma  (TCGA,  Provisional)   Brain  &  other  nervous  system   Liver  Hepatocellular  Carcinoma  (TCGA,  Provisional)   Prostate  Adenocarcinoma  (MSKCC,  Cancer  Cell  2010)   Sarcoma  (MSKCC/Broad,  Nature  GeneUcs  2010)   Skin  Cutaneous  Melanoma  (TCGA,  Provisional)   total,  all  cancer  types  sequenced  by  TCGA/ICGC   total,  excluding  Breast  &  Stomach,  and  cancers  with  0%  HER2  amp   es;mated   new  cases   TCGA   frequency    es;mated   in  2012    es;mated   of  HER2   new  cases   with  HER2   deaths   gain   gain  (%)   2012     2012     12.9   12.9   6.8   5.5   4.4   3.1   2.4   2.4   2.2   2.1   1.3   0.4   0   0   0   0   0   3.94%   2.93%    229,060      21,320      73,510      47,130      12,170      143,460      52,610      226,160      22,280      43,920      64,770      56,460      22,910      28,720      241,740      10,700      76,250      1,373,170      742,470      29,549      2,750      4,999      2,592      535      4,447      1,263      5,428      490      922      842      226      -­‐          -­‐          -­‐          -­‐          -­‐          54,043     21,744    39,920      10,540      14,880      8,010      4,220      51,690      38,380      160,340      15,500      37,390      13,570      1,780      13,700      20,550      28,170      3,800      9,180      471,620      345,760     es;mated   deaths  in   2012  with   HER2  gain    5,150      1,360      1,012      441      186      1,602      921      3,848      341      785      176      7      -­‐          -­‐          -­‐          -­‐          -­‐          15,829     9,319   Figure 4: Prevalence of HER2-amplified (>4 copies) cancer, from TCGA and ICGC. 54,000 new cases of HER2-amplified cancer are expected in 2012, in USA alone (22,000 excluding breast and gastric) Acknowledgements The authors thank all the members of the Australian Pancreatic Cancer Genome Initiative ( for their continuing support with provision of biospecimens. We also thank Mary-Anne Brancato, Michelle Thomas, Sarah Rowe and Mona Martyn-Smith for maintenance of the APGI database and biospecimen resource, Gerard hammond, Warren Kaplan, Derrick Lin, Ajaya Sharma and Jim McBride for database, high performance computing and IT support. The work is supported by the National Health and Medical Research Council of Australia (NHMRC; 631701, 535903, 535914); Australian Government: Department of Innovation, Industry, Science, Research and Tertiary Education (DIISRTE); Australian Cancer Research Foundation (ACRF); Queensland Government (NIRAP); University of Queensland; Cancer Council NSW (SRP06-01; ICGC09-01; SRP11- 01); Cancer Institute NSW (06/ ECF/1-24, 09/CDF/2-40, 07/CDF/1-03, 10/CRF/1-01, 08/RSA/1-15, 10/CDF/2-26,10/FRL/2-03, 06/RSA/1-05, 09/RIG/1-02, 10/TPG/1-04, 11/REG/ 1-10, 11/CDF/3-26); Garvan Institute of Medical Research; Avner Nahmani Pancreatic Cancer Foundation; R.T. Hall Trust; Jane Hemstritch in memory of Philip Hemstritch; Gastroenterological Society of Australia (GESA); Royal Australasian College of Surgeons (RACS); Royal Australasian College of Physicians (RACP); Royal College of Pathologists of Australasia (RCPA) and the St Vincent’s Clinic Foundation.