Hye Sook Han, M.D., Ph.D.
Division of Medical Oncology, Department of Internal Medicine,
College of Medicine and Medical Research Institute, Chungbuk National University
Human Epidermal Growth Factor Receptor 2 (HER2)
HER1, HER2, HER3, and HER4 are transmembrane tyrosine kinase receptors that normally regulate cell growth and survival, as well as adhesion, migration, differentiation, and other cellular responses.
HER2 also referred to as HER2/neu or ErbB-2, a 185-kD receptor first described more than two decades ago.
Hudis CA. N Eng J Med 2007;357:39
Extracellular binding domain
HER2 signaling
HER2-positive metastatic breast cancer
HER2-positive metastatic gastric cancer
Principles of HER2 testing
Immunohistochemistry & in situ hybridization
M/63
Abdominal pain, weight loss
Case 1
1Abdomen & pelvic CT
Endoscopic biopsy: HER2 immunohistochemistry Esophagogastroduodenoscopy
Endoscopic biopsy (H&E stain):
Tubular adenocarcinoma, moderate differentiated
Case 1
2What are you going to do next?
1. Retesting by HER2 IHC 2. HER2 FISH
3. Trastuzumab + FP or XP
4. Trastuzumab + Docetaxel
5. XELOX
F/48
2010.04 Breast cancer (IDC), Lt
s/p Breast conserving surgery, pT2N2M0, ER/PR (+/-), HER2 IHC 2+/FISH (-) s/p AC#4 followed by paclitaxel#4
s/p Adjuvant radiotherapy on Adjuvant tamoxifen
Case 2
1Case 2
2What are you going to do first?
1. HER2 retesting by IHC with primary breast tumor 2. HER2 retesting by FISH with primary breast tumor 3. Liver biopsy
4. Trastuzumab + docetaxel
5. Paclitaxel
Liver needle biopsy
Case 2
3*** Results of Immunohistochemistry ***
Antigen Reactivity Comment Pattern
ER 2+/3 90% Nucleus
PR - -
C-erb B2 2+/3 70% membrane
Ki-67 + 70% nucleus
P53 3+/3 > 95% nucleus
INVASIVE DUCTAL CARCINOMA, nuclear grade 2/3
*** HER2 FISH evaluation result ***
- Specimen adequacy (more than 20 cells of invasive tumor cells): YES - Number of invasive tumor cell countered : 40
- Number of observed : two
- Tumor cell heterogeneity : absence
- Number of tumor cells with HER2 amplification : 21/40 - Polysomy: absence
- Average number of HER2 signals/nucleus : 4.14
- Average number of CEP17 chromosome probes/nucleus : 1.97 -Ratio of HER2 signals/CEP17 probe signals :
2.10
Case 2
4What are you going to do next?
1. Retesting by HER2 IHC
2. Counting of additional cells 3. Retesting by HER2 SISH
4. HER2-targeted therapy + chemotherapy
5. Chemotherapy
HER2-positive = HER2 overexpression
HER2 overexpression occurs in 20 to 30% of breast cancers / in 15 to 20% of gastric cancers.
HER2 overexpressing tumors are associated with a more aggressive phenotype and poor prognosis.
HER2 protein overexpression by IHC 3+ HER2 gene amplification by ISH
IHC, immunohistochemistry; ISH, in situ hybridization
HER2 IHC in breast cancer
Wolff AC, et al. J Clin Oncol 2013;31:3997
HER2 IHC in gastric cancer
HER2 testing in gastric cancer differs from testing in breast cancer due to inherent differences in tumor biology; gastric cancer more frequently shows HER2 heterogeneity (focal staining) and incomplete membrane staining.
Breast cancer
vs
Focal staining can be designated as positive, especially in endoscopic biopsy.
Baso-lateral staining should be accepted as complete staining.
Gastric cancer
HER2 IHC scoring criteria for gastric cancer
Score Surgical specimen-staining pattern Biopsy specimen-staining pattern HER2 overexpression assessment 0 No reactivity or membranous
reactivity in < 10% of cancer cells
No reactivity or no membranous reactivity in any cancer cells
Negative
1+ Faint/barely perceptible
membranous reactivity in ≥ 10% of cancer cells; cells are reactive only in part of their membrane
Cancer cell cluster with a faint/barely
perceptile membranous reactivity irrespective of percentage of cancer cells stained
Negative
2+ Weak to moderate complete, basolateral or lateral membranous reactivity in ≥ 10% of cancer cells
Cancer cell cluster with a weak to moderate complete, basolateral or lateral membranous reactivity irrespective of percentage of
cancer cells stained
Equivocal
3+ Strong complete, basolateral or lateral membranous reactivity in ≥ 10% of cancer cells
Cluster of five or more cancer cellswith a strong complete, basolateral or lateral membranous reactivity irrespective of percentage of cancer cells stained
Positive
Ruschoff J, et al. Virchows Arch 2010;457:299; Bang YJ, et al. Lancet 2010;376:687
HER2 dual color in situ hybridization (ISH)
Fluorescence in situ hybridization (FISH)
Silver in situ hybridization (SISH) Chromogeic in situ hybridization (CISH)
HER2 ISH NCCN Guidelines Version 1.2012
ratio > 2.2
HER2 ISH NCCN Guidelines Version 2.2013
ratio ≥ 2.0
HER2 ISH NCCN Guidelines Version 3.2014
ratio ≥ 2.0
M/63
Abdominal pain, weight loss
Case 1
3Esophagogastroduodenoscopy Abdomen & pelvic CT
1. Retesting by HER2 IHC 2. HER2 SISH
3. Trastuzumab + FP or XP 4. Trastuzumab + Docetaxel 5. XELOX
What are you going to do next?
Endoscopic biopsy: HER2 immunohistochemistry
Liver needle biopsy
Case 2
5*** Results of Immunohistochemistry ***
Antigen Reactivity Comment Pattern
ER 2+/3 90% Nucleus
PR - -
C-erb B2 2+/3 70% membrane
Ki-67 + 70% nucleus
P53 3+/3 > 95% nucleus
INVASIVE DUCTAL CARCINOMA, nuclear grade 2/3
*** HER2 FISH evaluation result ***
- Specimen adequacy (more than 20 cells of invasive tumor cells): YES - Number of invasive tumor cell countered : 40
- Number of observed : two
- Tumor cell heterogeneity : absence
- Number of tumor cells with HER2 amplification : 21/40 - Polysomy: absence
- Average number of HER2 signals/nucleus : 4.14
- Average number of CEP17 chromosome probes/nucleus : 1.97 -Ratio of HER2 signals/CEP17 probe signals : 2.10
What are you going to do next?
1. Retesting by HER2 IHC
2. Counting of additional cells 3. Retesting by HER2 FISH
4. HER2-targeted therapy + chemotherapy
5. Chemotherapy
HER2 testing for treatment selection
Lordick F, et al. Future Oncol 2011;7:187-99
Immunohistochemistry HER2
IHC score 0/1 IHC score 2 IHC score 3
Chemotherapy HER2-targeted therapy
FISH -
FISH-Test HER2
FISH +
Ratio of HER2 gene/CEP17 probe signals ≥ 2.0
Palliative Therapy for Metastatic Breast Cancer
F/45
Chief complaint> Breast mass with ulceration, Rt
Case 3
1F/45
Rt Breast mass / liver needle biopsy
Case 3
2ER/PR/HER2 (+/+/3+)
HER2 IHC H&E stain
What kind of treatment would you give for this patient in first-line therapy?
Case 3
31. Trastuzumab + Docetaxel
2. Trastuzumab + Pertuzumab + Decetaxel 3. Trastuzumab + Letrozole
4. Lapatinib + Letrozole
5. Letrozole alone
What kind of treatment would you give for this patient in first-line therapy?
Case 3
41. Trastuzumab + Docetaxel
2. Trastuzumab + Pertuzumab + Decetaxel 3. Trastuzumab + Letrozole
4. Lapatinib + Letrozole 5. Letrozole alone
(Do not consider insurance reimbursement and cost)
Trastuzumab (Herceptin ® )
Hudis CA. N Eng J Med 2007;357:39
Potential mechanisms of action of trastuzumab
Trastuzumab in first-line HER2-positive MBC
1. Slamon et al. N Eng J Med 2001;344:783; 2. Marty et al. J Clin Oncol 2005; 3. Pegram et al. J Clin Oncol 2007; 4. Robert et al. J Clin Oncol 2006 IHC, immunohistochemistry
P, Paclitaxel (Taxol); H, trastuzumab (Herceptin) T. Docetaxel (Taxotere); C, carboplatin
Current standard treatment in Korea Trastuzumab + Taxane
Lapatinib (Tykerb ® )
Oral small molecule dual inhibitor of HER2 and EGFR tyrosine kinase The mechanism of action of trastuzumab and lapatinib
Binds to intracellular ATP binding site of EGFR and HER2 preventing phosphorylation and activation.
Blocks downstream signaling through homodimers and heterodimers of EGFR and HER2.
Dual blockagde of signaling may be more effective than the single-target inhibition provided by agents
such as trastuzumab.
Lapatinib in HER2-positive MBC
Geyer CE. N Eng J Med 2006;355:2733
Lapatinib plus capecitabine for HER2-positive metastatic breast cancer
Lapatinib plus capecitabine is superior to capecitabine alone in women with HER2-positive advanced breast cancer that has progressed after treatment with regimens that included ananthracycline, a taxane, and trastuzumab.
Pertuzumab (Perjeta ® )
The mechanism of action of trastuzumab and pertuzumab
Metzger-Filho O, et al. Clin Cancer Res 2013;19:5552
Preferentially inhibits ligand-independent HER2 signaling Prevents shedding of HER2 extracellular domain
Falgs cells for destruction by the immune system
Trastuzumab
Inhibits HER2 forming dimer pairs
Suppresses multiple HER2 signaling pathways, leading to a more comprehensive blockade of HERs signaling
Falgs cells for destruction by the immune system
Pertuzumab
HER2:HER3 dimers Escape mechanism from trastuzumab
Tzahar et al. Mol Cell Biol 1996; Sergina et al. Nature 2007
Homodimers Heterodimers
Signaling activity
CLEOPATRA Clinical Evaluation of Pertuzumab and Trastuzumab
Baselga J, et al. N Eng J Med 2012;366:109
Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer
Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance Docetaxel: 75 mg/m2, escalating to 100 mg/m2if tolerated
every 3 weeks
Patients with HER2-positive MBC
Centrally confirmed (N = 808)
R 1:1
Stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not)
*< 6 cycles allowed for unacceptable toxicity or PD;
> 6 cycles allowed at investigator discretion
Placebo + Trastuzumab
Docetaxel*
PD
Pertuzumab + Trastuzumab
Docetaxel*
PD n=406
n=402
Primary endpoint Progression-free survival
Secondary endpoint
Overall survival, objective response rate, and safety
Independently assessed PFS Primary endpoint
Baselga J, et al. N Eng J Med 2012;366:109
The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positivie metastatic breast cancer, significantly prolonged progression-free survival.
Trastuzumab Emtansine (T-DM1)
1
st-in-class HER2 antibody-drug conjugate (ADC)
Mechanism of T-DM1
T-DM1 selectively delivers a highly toxic payload to HER2-postive tumor cells
T-DM1 binds to the HER2 protein on cancer cells
Receptor T-DM1 complex is internalised into HER2-positive cancer cells
Potent antimicrotubule agent is released once inside the HER2-positive tumor cells
: Inhibition of microtubule polymerization
EMILIA
Verma S, et al. N Eng J Med 2012;367:1783
Trastuzumab Emtasine for HER2-Positive Advanced Breast Cancer
Stratified by geographic region, number of prior chemotherapy regimens for MBC or unresectable
LABC, presence of visceral disease
HER2-positive (central) LABC or MBC
(N=991)
• Prior taxane and trastuzumab
• Progression on metastatic treatment or within 6 months of adjuvant treatment
R 1:1
T-DM1
3.6 mg/kg q 3 weeks IV
PD
Capecitabine
1000 mg/m2orally bid, days 1-14 q 3 weeks
Lapatinib
1250 mg/day orally qd
PD n=496
n=495
Primary endpoint
Progression-free survival, overall survival, and safety
Secondary endpoint
Objective response rate and time to symptom progression
Independently assessed PFS Primary endpoint
Verma S, et al. N Eng J Med 2012;367:1783
Overall survival Secondary endpoint
Verma S, et al. N Eng J Med 2012;367:1783
T-DM1 significantly prolonged progression-free survival and overall survival than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane.
Lapatinib plus Letrozole HR-positive and HER2-positive
Johnston S, et al. J Clin Oncol 2009;27:5538; Schwartzberg LS, et al. Oncologist 2010;15:122
Lapatinib plus Letrozole as First-line Therapy for HR-Positive, HER2-Positive Metastatic Breast Cancer
Kaufman B, et al. J Clin Oncol 2009;27:5529
Trastuzumab Plus Anastrozole Versus Anastrozole Alone for the Treatment of Postmenopausal Women With Human Epidermal Growth Factor Receptor 2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer
: Results From the Randomized Phase III TAnDEM Study
TAnDEM Trastuzumab and Anastrozole Directed Against ER-Positive Mammary Carcinoma
Conclusion HER2-positive metastatic breast cancer
Current available treatment in Korea: Trastuzumab + Taxane
NCCN guideline level 1: Pertuzumab + Trastuzumab + Docetaxel First-line treatment
Current available treatment in Korea: Lapatinib + Capecitabine NCCN preferred option: T-DM1
Second-line treatment
Other HER2-targeted therapy: T-DM1 or Pertuzumab or Lapatinib + Capecitabine Third-line or greater treatment
HR positive and HER2 positive
HER2-targeted therapy + Chemotherapy
(OS benefit)or Endocrine therapy
(PFS benefit)Current available option in Korea: Lapatinib + Letrozole
Endocrine therapy alone: low disease burden, non-visceral disease, long DFS
HER2-targeted therapy
HER2-targeted therapy
HER2-targeted therapy
What kind of treatment would you give for this patient in first-line therapy?
Case 3
51. Trastuzumab + Docetaxel
2. Trastuzumab + Pertuzumab + Decetaxel 3. Trastuzumab + Letrozole
4. Lapatinib + Letrozole
5. Letrozole only
What kind of treatment would you give for this patient in first-line therapy?
Case 3
61. Trastuzumab + Docetaxel
2. Trastuzumab + Pertuzumab + Decetaxel 3. Trastuzumab + Letrozole
4. Lapatinib + Letrozole 5. Letrozole only
(Do not consider insurance reimbursement and cost)
Palliative Therapy for Advanced Gastric Cancer
M/57
Chief complaint> Abdominal discomfort
Case 4
1Esophagogastroduodenoscopy Abdomen & pelvic CT PET-CT
HER2 immunohistochemistry Tubular adenocarcinoma,
well-differentiated
What kind of treatment would you give for this patient in first-line therapy?
Case 4
21. Trastuzumab + XP
2. Trastuzumab + FOLFIRI 3. Trastuzumab + Docetaxel 4. Lapatinib + XELOX
5. Lapatinib + Paclitaxel
ToGA Trastuzumab for Gastric Cancer study
Bang YJ, et al. Lancet 2010;376:6
Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric of gastro-esophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial
Primary end point Overall survival
3807 patients screened810 HER2-positive*
HER2-positive advanced GC
(n=584)
R
XP or FP
‡(n=290)
§XP or FP
‡+ trastuzumab
(n=294)
§Capecitabine 1000 mg/m2twice a day for 14 days Cisplatin 80mg/m2on day 1
Fluorouracil 800 mg/m2/day on days 1-5
every 3 weeks (for six cycles)
Trastuzumab 8 mg/kg on day 1 of the 1stcycle, followed by 6 mg/kg (until progression) Capecitabine 1000 mg/m2twice a day for 14 days Cisplatin 80mg/m2on day 1
Fluorouracil 800 mg/m2/day on days 1-5
(for six cycles) every 3 weeks
*594 patients randomised, 10 patients never received treatment;
‡Chosen at investigator’s discretion: 87.5% of patients had capecitabine;
§ITT population; R = randomization
Overall Survival
Bang YJ, et al. Lancet 2010;376:6
Overall Survival IHC 2+ and FISH+ or IHC 3+
Bang YJ, et al. Lancet 2010;376:6
Trastuzumab in combination with chemotherapy can be considered as a new standard option for patients with HER2-positive advanced gastric or gastro-esophageal junction cancer.
TRIO-013/LoGiC
Overman MJ, et al. 2013 ASCO Annual Meeting
Lapatinib in combination with capecitabine plus oxaliplatin (CapeOx) in HER2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma (AC): The TRIO-013/LOGiC Trial
Primary end point
Overall survival in the PEP*
1. Confirmed histology 2. Local/central HER-2+
3. Confirmed eligibility
R
CapeOx + Lapatinib
Day 1: Oxaliplatin 130 mg/m2
Day 1-14: Capecitabine 850 mg/m2, bid Day 1-21: Lapatinib 1250 mg, qd
(one cycle = 21 days)
CapeOx
Day 1: Oxaliplatin 130 mg/m2
Day 1-14: Capecitabine 850 mg/m2, bid Day 1-21: Placebo, qd
(one cycle = 21 days)
Tumor tissue sent to central lab
Stratification factors
• Prior (neo)adjuvant therapy
• Region (Asia, North America, Rest of the world)
Primary Efficacy Population (PEP)
(HER-2 amplification confirmed by FISH centrally)
Overall survival
Overman MJ, et al. 2013 ASCO Annual Meeting
Lapatinib and capecitabine/oxaliplatin (CapeOx+P) did not lead to a significant survival advantage
over capecitabine/oxaliplatin (CapeOx).
TyTAN Tykerb With Taxol in Asian HER2-Positive Gastric Cancer
Satoh T, et al. J Clin Oncol 2014
Lapatinib Plus Paclitaxel Versus Paclitaxel Alone in the Second-Line Treatment of HER2-Amplified Advanced Gastric Cancer in Asian Populations: TyTAN-A Randomized, Phase III study
Intention-to-treat population HER2 IHC 3+ patients
Lapatinib plus paclitaxel demonstrated activity in the second-line treatment of patients with HER2 FISH-positive IHC 3+ advanced gastric cancer butdid not significantly improve overall survival in the intention-to-treat population.
Clinical trials targeting HER2 in AGC
Phase I Phase II Phase III
ASLAN001 HN781-36B MGAH22 MM-111
Dacomitinib Afatinib
Lapatinib (LOGiC)
Pertuzumab (JACOB)
TDM-1 (GATSBY)
Conclusion HER2-positive advanced gastric cancer
Trastuzumab plus fluoropyrimidine/platinum is the standard in HER2-positive AGC.
The ToGA trial must be characterized as a landmark in the treatment of gastric cancer and it has paved the way for a number of new HER2-targeted therapies such as pertuzumab, T-DM1, lapatinib, afatinib, and dacomitinib, which are currently undergoing phase II and III clinical testing.
HER2-positive MBC HER2-positive
AGC
