Repurposing Therapies for Treatment of HER2 Amplified Pancreatic Cancer - Cowley Mark
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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. HER2- amplification confirmed by IHC (3+ staining; F) SISH (G) and FISH (H). Aims 1) Determine the prevalence of HER2-amplified PDAC 2) Assess clinical response to targeted therapeutics Conclusions PANCREATIC CANCER Repurposing therapies for treatment of HER2-amplified pancreatic cancer Mark J Cowley 1^ Angela Chou 1^ Nicola Waddell 2^ David K Chang 1 Jiamin Wu 1 Mark Pinese 1 Lorraine Chantrill 1 Amber L Johns 1 Katia Nones 2 Ann- Marie Patch 2 APGI 3 Sean M Grimmond 2 Andrew V Biankin 1 1 Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia. 2 Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, St Lucia, QLD, Australia. 3 Australian Pancreatic Cancer Genome Initiative, for a list of members, please visit http://www.pancreaticcancer.net.au/apgi/collaborators ^these authors contributed equally Background The 5 year survival rate of pancreatic ductal adenocarcinoma (PDAC) is a dismal 3-5%. 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 HER2- amplified gastric cancer. Establishment of a genotype-guided clinical trial • 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. HER2-amplified pancreatic cancer 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. 2.1% of PDAC is HER2-amplified Figure 2: Algorithm for Diagnostic testing of HER2-amplification in PDAC 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) Prevalence of any HER2-amplified cancer Cancer Type TCGA frequency of HER2 gain (%) es;mated new cases 2012 es;mated new cases in 2012 with HER2 gain es;mated deaths 2012 es;mated deaths in 2012 with HER2 gain Breast Invasive Carcinoma (TCGA, Nature 2012) 12.9 229,060 29,549 39,920 5,150 Stomach Adenocarcinoma (TCGA, Provisional) 12.9 21,320 2,750 10,540 1,360 Bladder Urothelial Carcinoma (TCGA, Provisional) 6.8 73,510 4,999 14,880 1,012 Uterine Corpus Endometrioid Carcinoma (TCGA, Provisional) 5.5 47,130 2,592 8,010 441 Cervical Squamous Cell Carcinoma (TCGA, Provisional) 4.4 12,170 535 4,220 186 Colon and Rectum Adenocarcinoma (TCGA, Nature 2012) 3.1 143,460 4,447 51,690 1,602 Head and Neck Squamous Cell Carcinoma (TCGA, Provisional) 2.4 52,610 1,263 38,380 921 Lung & bronchus cancer 2.4 226,160 5,428 160,340 3,848 Ovarian Serous Cystadenocarcinoma (TCGA, Nature 2011) 2.2 22,280 490 15,500 341 PancreaUc Ductal Adenocarcinoma (ICGC, Nature 2012) 2.1 43,920 922 37,390 785 Kidney & renal pelvis cancer 1.3 64,770 842 13,570 176 Thyroid Carcinoma (TCGA, Provisional) 0.4 56,460 226 1,780 7 Brain & other nervous system 0 22,910 13,700 Liver Hepatocellular Carcinoma (TCGA, Provisional) 0 28,720 20,550 Prostate Adenocarcinoma (MSKCC, Cancer Cell 2010) 0 241,740 28,170 Sarcoma (MSKCC/Broad, Nature GeneUcs 2010) 0 10,700 3,800 Skin Cutaneous Melanoma (TCGA, Provisional) 0 76,250 9,180 total, all cancer types sequenced by TCGA/ICGC 3.94% 1,373,170 54,043 471,620 15,829 total, excluding Breast & Stomach, and cancers with 0% HER2 amp 2.93% 742,470 21,744 345,760 9,319 HER2-amplified PDAC has an unusual pattern of metastasis & responds to targeted therapy Table 2: Clinicopathological characteristics of HER2- amplified PDAC. A preponderance of lung, without liver metastases (χ 2 P=5e-7) Acknowledgements The authors thank all the members of the Australian Pancreatic Cancer Genome Initiative (www.pancreaticcancer.net.au/apgi/collaborators) 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. 1 2 3 5 4 Figure 3 Case Report 42yo lady, primary PDAC, resected & standard first line adjuvant therapy Recurred 14mo later, with liver metastasis Confirmed pancreatic origin, strongly HER2- amplified (IHC 3+) Received 24 weeks of Capecitabine and Trastuzumab + 5 cycles of Epirubuicin Further Trastuzumab for 34 weeks Alive at 4 years since recurrence
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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
Transcript of Repurposing Therapies for Treatment of HER2 Amplified Pancreatic Cancer - Cowley Mark
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. HER2-amplification confirmed by IHC (3+ staining; F) SISH (G) and FISH (H).
Aims 1) Determine the prevalence of HER2-amplified PDAC 2) Assess clinical response to targeted therapeutics
Conclusions
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 Ann-Marie 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 http://www.pancreaticcancer.net.au/apgi/collaborators ^these authors contributed equally
Background
The 5 year survival rate of pancreatic ductal adenocarcinoma (PDAC) is a dismal 3-5%.
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 HER2-amplified gastric cancer.
Establishment of a genotype-guided clinical trial
• 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 1: Integrated genomic analysis identified 1/99 patients with focal amplification of HER2 (A). This resulted in up-regulated of gene expression (B). Whole exome sequencing identified somatic mutations, whole genome sequencing identified structural variationss. A 1.9MB stretch of chromosome 17 was amplified, including HER2 (ERBB2(.
HER2-amplified pancreatic cancer
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.
2.1% of PDAC is HER2-amplified
Figure 2: Algorithm for Diagnostic testing of HER2-amplification in PDAC
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)
Prevalence of any HER2-amplified cancer
Cancer Type
TCGA frequency of HER2 gain (%)
es;mated new cases
2012
es;mated new cases in 2012
with HER2 gain
es;mated deaths 2012
es;mated deaths in 2012 with HER2 gain
Breast Invasive Carcinoma (TCGA, Nature 2012) 12.9 229,060 29,549 39,920 5,150 Stomach Adenocarcinoma (TCGA, Provisional) 12.9 21,320 2,750 10,540 1,360 Bladder Urothelial Carcinoma (TCGA, Provisional) 6.8 73,510 4,999 14,880 1,012 Uterine Corpus Endometrioid Carcinoma (TCGA, Provisional) 5.5 47,130 2,592 8,010 441 Cervical Squamous Cell Carcinoma (TCGA, Provisional) 4.4 12,170 535 4,220 186 Colon and Rectum Adenocarcinoma (TCGA, Nature 2012) 3.1 143,460 4,447 51,690 1,602 Head and Neck Squamous Cell Carcinoma (TCGA, Provisional) 2.4 52,610 1,263 38,380 921 Lung & bronchus cancer 2.4 226,160 5,428 160,340 3,848 Ovarian Serous Cystadenocarcinoma (TCGA, Nature 2011) 2.2 22,280 490 15,500 341 PancreaUc Ductal Adenocarcinoma (ICGC, Nature 2012) 2.1 43,920 922 37,390 785 Kidney & renal pelvis cancer 1.3 64,770 842 13,570 176 Thyroid Carcinoma (TCGA, Provisional) 0.4 56,460 226 1,780 7 Brain & other nervous system 0 22,910 -‐ 13,700 -‐ Liver Hepatocellular Carcinoma (TCGA, Provisional) 0 28,720 -‐ 20,550 -‐ Prostate Adenocarcinoma (MSKCC, Cancer Cell 2010) 0 241,740 -‐ 28,170 -‐ Sarcoma (MSKCC/Broad, Nature GeneUcs 2010) 0 10,700 -‐ 3,800 -‐ Skin Cutaneous Melanoma (TCGA, Provisional) 0 76,250 -‐ 9,180 -‐
total, all cancer types sequenced by TCGA/ICGC 3.94% 1,373,170 54,043 471,620 15,829 total, excluding Breast & Stomach, and cancers with 0% HER2 amp 2.93% 742,470 21,744 345,760 9,319
HER2-amplified PDAC has an unusual pattern of metastasis & responds to targeted therapy
Table 2: Clinicopathological characteristics of HER2-amplified PDAC. A preponderance of lung, without liver metastases (χ2 P=5e-7)
Figure 3: HER2-amplified patient response to an EGFR inhibitor, Tarceva® (Erlotinib). HER2 heterodimerises with EGFR.
Acknowledgements The authors thank all the members of the Australian Pancreatic Cancer Genome Initiative (www.pancreaticcancer.net.au/apgi/collaborators) 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.
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Figure 3
Case Report 42yo lady, primary PDAC, resected & standard first line adjuvant therapy Recurred 14mo later, with liver metastasis Confirmed pancreatic origin, strongly HER2-amplified (IHC 3+) Received 24 weeks of Capecitabine and Trastuzumab + 5 cycles of Epirubuicin Further Trastuzumab for 34 weeks Alive at 4 years since recurrence
Case Report
