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Chemotherapy -Targeted Therapy
BBM 15-10-2010
Luc DirixMedical Oncology - IridiumNetwerk
Antwerp
Signal Transduction by the HER Family and Potential Mechanisms of Action of Trastuzumab.
Hudis CA. N Engl J Med 2007;357:39-51.
HER-2 directed agents
• Trastuzumab• Lapatinib• Neratinib• T-DM1• Pertuzumab• …
HER-2 directed agents: TrastuzumabBO20652: OHERA
• HER2 positive• EBC• Trastuzumab therapy• N = 3800• Cardiac evaluation study
– Symptoms : NYHA ; 5 years – LVEF : US, MUGA, MRI q 3/12 during therapy
• Post-T : 6/12, 12/12, 24/12
HER-2 directed agents: TrastuzumabThe Synergism Or Long Duration (SOLD) Study
• HER-2 + ( CISH/FISH/3+)• T1b and > grade 1• TxN1(including micro-met > 0.2 mm)• Not isolated TC• EJF > 50%• RT institutional• Primary endpoint DFS:
– Local, contralat, distant, other ca, death
In both Arms:
_RT (according to the institutional practise )
_Endocrine therapy for a minimum of 5 yrswhen ER/PgR +ve
SOLD Design FE75C3-weekly trastuzumab (H)
RANDOMIZE
Docetaxel80 or 100 mg/m 2
H 3-weekly x 14
H for 9 wks
H for 9 wks
(to complete 1 year)
HER-2 directed agents: TrastuzumabThe Synergism Or Long Duration (SOLD) Study
HER-2 directed agents: TrastuzumabThe Synergism Or Long Duration (SOLD) Study
• A superiority assumption is made between the study treatments. It is assumed that the survival rate after 5 years of follow-up will be 84% in the better arm and 80% in the worse arm
• Prof. R. Paridaens PI in Belgium.
HER-2 directed agents
• Small molecules; Lapatinib
• Preclinical studies : lapatinib induces apoptosis in trastuzumab-resistant BC cell lines
• In a randomized phase 3 clinical trial in women with HER2-positive advanced breast cancer who had previously been treated with an anthracycline, taxane, and trastuzumab, the addition of lapatinib significantly improved time to progression (TTP) (8.4 vs 4.4 months; P< .001) with a trend toward less CNS disease progression in the combination arm (4 vs 11 months)
• Lapatinib in combination with capecitabine was approved for patients with advanced or metastatic HER2-positive breast cancer.
• Ongoing trials (ALTTO study) are evaluating its use in early-stage breast cancer in the curative setting.
Lapatinib
Nat Rev Clin Oncol. 2010 Feb;
Protein – protein interactions in response to trastuzumab and lapatinib treatment is an active area of investigation.
PFS from Breast Cancer and OS , and Cumulative Incidence of PD or death from BC
Geyer CE et al. N Engl J Med 2006;355:2733-2743.
• Patients with ER or PgR-positive tumours receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started after the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 years
• Radiotherapy if indicated
Trastuzumab3-weekly
(For 52 weeks)
Lapatinib
(For 52 weeks)
Trastuzumab Weekly
(For 12 weeks)
Lapatinib
+Trastuzumab
3-weekly(For 52 weeks)
Centrally-determined HER2+; ER and PgR
Surgery, complete (neo)adjuvant anthracycline-based chemotherapy (selected from an approved list)
LVEF ≥ 50%
Locally-determined HER2-positive invasive breast cancer
Washout (6 weeks)
Lapatinib (34 weeks)
DESIGN 1: Completion of ALL (neo)adjuvant chemotherapy prior to
targeted therapy
Max 12 w
52
WEEKS Lapatinib
+ Trastuzumab
3-weekly
40 weeks
Lapatinib +
TrastuzumabWeekly
12 weeksê
TrastuzumabWeekly
12 weeksê
Lapatinib
52 weeks
Trastuzumab3-weekly
40 weeks
Lapatinib
34 weeks
PaclitaxelWeekly
12 weeksê
+/-Radio-therapy
PaclitaxelWeekly
12 weeksê
+/-Radio-therapy
PaclitaxelWeekly
12 weeksê
+/-Radio-therapy
Washout 6 weeks
PaclitaxelWeekly
12 weeksê
+/-Radio-therapy
TrastuzumabWeekly
12 weeksê
DESIGN 2: Paclitaxel concurrent with targeted therapy after any A-based
(neo)adjuvant chemotherapyLocally-determined HER2-positive invasive breast cancer
Centrally-determined HER2+; ER and PgR
Surgery, complete (neo)adjuvant chemotherapy(selected from an approved list)
LVEF ≥ 50%
Max 6 w
Lapatinib and Pazopanib in IBC
• HER-2 + IBC• Elaborate protocol of skin involvement in IBC
(“evaluable lesion”)• Post-Trastuzumab treatment
– Pazopanib + Lapatinib– Lapatinib– Pazopanib
Laptem
• Academic Study: IJ Bordet• Lapatinib has activity in HER2 BM• Temozolomide in GBM, MM, BM MM• Logic and oral combination• Phase I study
A Randomized, Open-Label, Phase III Study of Taxane Based Chemotherapy With Lapatinib or Trastuzumab as First-Line
Therapy for Women With HER2/Neu Positive MBC
• Patients are stratified according to prior neoadjuvant/adjuvant anti-HER2/neu-targeted therapy (yes vs no), prior neoadjuvant/adjuvant taxane chemotherapy, planned taxane therapy (paclitaxel vs docetaxel), and liver mets (yes vs no).
• Arm I: – Patients receive either paclitaxel IV on days 1, 8, and 15;– Alternatively, patients may receive docetaxel IV on day 1; – These patients also receive filgrastim (G-CSF) – All patients receive oral lapatinib once daily during taxane treatment and
continue after completion of taxane treatment.• Arm II:
– Patients receive paclitaxel IV on days 1, 8, and 15 and trastuzumab IV on days 1, 8, 15, and 22.
– Alternatively, patients may receive docetaxel IV and trastuzumab IV – After completion of taxane chemotherapy and trastuzumab, all patients
receive trastuzumab alone IV once every 3 weeks in the absence of disease progression or unacceptable toxicity.
• Primary endpoint : PFS • Formalin-fixed paraffin-embedded tissue samples are analyzed for ER, PgR,
EGFR, CK5/6, Ki67, and other molecular biomarkers by tissue microarray and immunohistochemistry.
Structure of HKI-272, Neratinib
Rabindran S K et al. Cancer Res 2004;64:3958-3965
HER-2 directed agents : Neratinib
• Oral, irreversible HER1,HER2 antagonist• Activity in HER2 BC, minimal in NSCLC• Mainly diarrhea, DLT• MTD 320 mg, RDPII 240 mg/day• Minimal skin toxicity• No cardiac toxicity, no QT-effect• Less food effect on absorption
Clinical outcomes of patients with prior trastuzumab (T) or no prior T treatment
Burstein H J et al. JCO 2010;28:1301-1307
HER-2 directed agents : Neratinib
• Extensive program– In adjuvant post-trastuzumab– Phase I combo with vinrelbine, paclitaxel– Phase III capetabine– Phase III paclitaxel
• Double-blind, placebo control• Primary Endpoint: DFS• Stratification by: nodes, ER/PR, prior chemo/trastuzumab (concurrent vs
sequential)• 3300 patients needed worldwide
Neratinib Protocol 3004
Placebo po qd x 1 year
Neratinib 240 mg po qd x 1 year
• ErbB-2+ breast cancer patients• Stage II/III disease• Completed prior adjuvant therapy with trastuzumab within 1 yr prior to randomization• Lymph node + or neoadjuvant with residual invasive disease and node -• ER/PR+/-
Ran
dom
ize
1:1
• Open-label, active control• Primary Endpoint: PFS• Stratification by: prior adjuvant trastuzumab / lapatinib
exposure, ER/PR, region• ~1200 pts needed worldwide
Neratinib 1st Line Trial Summary
Trastuzumab + paclitaxel
Neratinib + paclitaxel•Prior adjuvant taxane/trastuzumab/lapatinib permitted -but-
•Progression Free Interval ≥12 months after adjuvant systemic (other than endocrine) therapy
•No prior treatment for locally recurrent or metastatic disease (except hormonal)
•Measurable disease
Ran
dom
ize
1:1
T-DM1• Trastuzumab-DM1 (T-DM1) is a novel anti-HER2
antibody drug–conjugate in development for the treatment of HER2+ metastatic breast cancer (MBC).
•T-DM1 combines the HER2-targeting properties of trastuzumab with targeted delivery of a highly potent anti-microtubule derivative, DM1.– It is hypothesized that after binding to HER2, T-DM1
undergoes receptor-mediated internalization, resulting in intracellular release of DM1.
ADC Development Considerations
• High in tumor tissue, low in normal tissue• Lack of down-regulation
Target Expression
• Highly potent• Suitability for conjugation• Non-immunogenic
Cytotoxic Agent
• Systemically stable• Susceptible to local release mechanisms
Linker
Conjugation of T–DM1 Components Increases Efficacy
Parsons, et al. AACR Annual Meeting, Los Angeles, California, April 14–18, 2007 (Abstract 649)
0
500
1000
1500
0 5 10 15 20 25 30
Vehicle
Trastuzumab–DM1 15 mg/kg / 817 µg/m2
Trastuzumab 15 mg/kg
Trastuzumab 15 mg/kg + free DM1 817 µg/m2
Free DM1 817 µg/m2
Free DM1 (near MTD) 1947 µg/m2
Mea
n tu
mor
vol
ume
(mm
3 )±
SEM
Time (days)IV dosing
T–DM1 demonstrated a rapid and durable reduction in tumor volume in the Fo5 animal breast cancer model, which was specifically
engineered to be insensitive to trastuzumab
A Phase II Study of Trastuzumab-DM1 (T-DM1), a HER2 Antibody-Drug Conjugate, in Patients with HER2-Positive Metastatic Breast
Cancer
C.L. Vogel,1 H. A. Burris,2 S. Limentani,3 R. Borson,4 J. O’Shaughnessy,5S. Vukelja,6 S. Agresta,7 B. Klencke,7 B. Tong,7 H.S. Rugo8
TDM4258g
Anti-Tumor Activity in All Treated Patients (n=112)
IRFn (%)
Investigatorn (%)
Best Objective ResponseCRPRSDPDUnable to Evaluate
028 (25.0)54 (48.2)21 (18.8)9 (8.0)
3 (2.7)40 (35.7)43 (38.4)22 (19.6)
4 (3.6)
ORR95% CI
28 (25.0)17.5–33.6
43 (38.4)29.8–47.5
Clinical Benefit Rate95% CI
39 (34.8)26.1–43.9
50 (44.6)35.5–54.3
Duration of trastuzumab-DM1 (T-DM1) therapy and best responses.
Assessment IRFn=67
INVn=67
Patients with OR, n (%)95% CI for OR
16 (23.9)14.3–35.4
24 (35.8)25.2–48.2
Patients with Clinical Benefit*, n (%)95% CI for Clinical Benefit
24 (35.8)25.2–48.2
30 (44.8)32.8–56.9
Overall Response in Patients Previously Treated with Lapatinib
CI=confidence interval, INV=investigator, IRF=independent review facility, OR=objective response* Includes patients who achieved an objective CR, PR, or SD of ≥6 months.
Mean levels of trastuzumab-DM1, total trastuzumab, and DM1 over time at the maximum-tolerated does of 3.6 mg/kg.
Efficacy and Safety of Trastuzumab-DM1 Versus Trastuzumab plus Docetaxel in HER2-Positive Metastatic Breast Cancer Patients with no Prior
Chemotherapy for Metastatic Disease: Preliminary Results of a Randomized, Multicenter, Open-Label
Phase 2 Study
EA Perez,1 L Dirix,2 J Kocsis,3 L Gianni,4 J Lu,5 J Vinholes,6 V Ng,7 C Linehan,7 S Agresta,7 S Hurvitz8
TDM4450g
• Randomized, phase II, international, open-label study• HER2+ (IHC3+ and/or FISH amplified per local lab) measurable disease
required• Stratification factors:
– World region (U.S., ROW)– Prior adjuvant trastuzumab therapy (yes, no)– Disease-free interval (≤ 24 months, > 24 months)
• Primary endpoint: PFS by INV• Secondary endpoints: ORR, CBR, OS, 1-year survival rate, and safety
Study Design
1:1 First line HER2+
mBC or recurrent locally
advanced patients (n=137)
T-DM13.6 mg/kg Q3W until PD
Trastuzumab 8 mg/kg dose; 6 mg/kg Q3W
+ Docetaxel 75 or 100 mg/m2 after
trastuzumab, Q3W
CrossoverT-DM1PD
Grade ≥3 AEs: ≥ 10% Difference in Incidence Safety Evaluable Patients
MedDRA Preferred Term NCI CTCAE Grade
Trastuzumab + Docetaxel
(n=68)T-DM1(n=67)
Neutropenia - Total -
3 4
36 (52.9%)6 (8.8%)
30 (44.1%)
(0.0%)(0.0%)(0.0%)
Leukopenia - Total -
3 4
17 (25.0%)12 (17.6%)5 (7.4%)
(0.0%)(0.0%)(0.0%)
Febrile neutropenia- Total -
3 4
7 (10.3%)6 (8.8%)1 (1.5%)
(0.0%)(0.0%)(0.0%)
Summary of Efficacy ResultsRandomized Patients
Trastuzumab + Docetaxel T-DM1
Objective Response (ORR; [95% CI*]) 29/70 (41.4%; [30.2%, 53.8%]) 32/67 (47.8%; [35.4%, 60.3%])
Prior Trastuzumab and/or Taxane Therapy 11/31 (35.5%; [20.0%, 53.4%]) 13/24 (54.2%; [33.9%, 74.5%])
No Prior Trastuzumab and/or Taxane Therapy 18/39 (46.2%; [30.1%, 61.7%]) 19/43 (44.2%; [29.5%, 60.1%])
* 95% CI was computed using Blyth-Still-Casella exact confidence interval method.
Clin Cancer Res. 2009 Dec
Pertuzumab, an anti-HER2 humanized mAb that binds to an epitope located in domain 2 of HER2.
It sterically blocks a binding pocket necessary for receptor dimerization and signaling.
It therefore prevents HER2 dimerization, including HER2/HER3 heterodimerization.
Pertuzumab
• Pertuzumab is active against HER2 overexpressing cell lines and xenografts.
• In preclinical studies, there was potential synergism with trastuzumab resulting in induction of apoptosis in vitro.
• Pertuzumab binds to the dimerization epitope of the HER2 receptor, inhibits HER dimerization and signal transduction, and induces ADCC.
• Phase 2 trial of pertuzumab in combination with trastuzumab in patients with HER2-overexpressing metastatic breast cancer with disease progression on trastuzumab have suggested good tolerance and clinical activity of the combination.
Pertuzumab
Nat Rev Cancer. 2009 Jul;9
1st Line mBC Phase III MARIANNE Study: BO22589/TDM4788g
Patients with HER2 positive progressive or recurrent locally advanced breast cancer or previously untreated metastatic breast cancer
Primary endpoints: PFS as assessed by IRF; SafetySecondary endpoints: OS; PFS by investigator; PRO analyses; BiomarkersSuperiority design with a Non-inferiority analysis between each of the experimental arms and the control armInterim futility analysis: Option to drop experimental arm
Arm A
Arm B
Arm C
Trastuzumab + taxane (until PD)n=364
T-DM1 + pertuzumab (until PD)n=364
T-DM1 + pertuzumab placebo (until PD)n=364
n=1092
Patients stratified by: World regionNeo/Adjuvant therapy (Y/N)
Trastuzumab and/or lapatinib based therapy (Y/N)
Visceral disease (Y/N)
FPI July 6 2010
• The proposed mechanisms of action of trastuzumab and lapatinib is inhibition of PI3K activity and activity of the downstream kinases in HER2 amplified breast cancer. Thus are potentially attractive targets.
• Up-regulation of this pathway is also an important mediator of resistance to HER2 directed therapy.
• Inhibitors of this pathway has shown synergistic activity with trastuzumab in preclinical studies.
• Novel inhibitors of this pathway are in clinical development in combination with trastuzumab.
Downstream targetting
Trastuzumab and mTOR Signaling
• Inhibition of both PI3K and mTOR downstream of PI3K appears to be required for maximum effect of trastuzumab on cell proliferation
• Inappropriate mTOR signaling will drive trastuzumab resistance. Activation of mTOR renders cells resistant to HER2 inhibition
• Combining trastuzumab with an mTOR inhibitor synergistically inhibited in vitro and in vivo growth of breast cancer cells
PI3K
mTOR
AKT
Cell Proliferation
TSC2 TSC1
Cell Growth
Metabolism
Angiogenesis
EGFRHER3HER4
HER2
Everolimus
PTEN
Everolimus: Oral mTOR Inhibitor
Everolimus
O O OH
O OON
OO
O O
O
OH
O
HO
1. O’Donnell et al. J Clin Oncol. 2008;26:1588.2. Tabernero et al. J Clin Oncol. 2008;26:1603.3. Data on file.4. Motzer et al. Lancet. 2008;372:449.
§ Active rapamycin derivative
§ Orally bioavailable; T1/2 ≈30 hours; CYP3A4 metabolism
§ Sustained inhibition of mTOR through daily administration1,2
§ Crosses the BBB3
§ Broad antitumor activity– Inhibits cell growth and angiogenesis– Potential synergy with chemotherapy, radiation,
and other targeted agents– Demonstrated single-agent efficacy and safety
in a phase 3 trial in renal cell carcinoma4
§ Investigated in >9000 patients with cancer
10 mg / 5 mg
BOLERO-1 (J2301): Phase 3 First-linePaclitaxel + Trastuzumab ± Everolimus
a After a loading dose of 4 mg/kg on day 1, cycle 1 (1 cycle = 28 days).
N=7052:1
(everolimus:placebo)
RANDOMIZATION
RANDOMIZATION
Everolimus 10.0 mg PO dailyPaclitaxel 80 mg/m2 IV on days 1, 8, and 15Trastuzumab 2 mg/kga IV on days 1, 8, 15, and 22
Everolimus 10.0 mg PO dailyPaclitaxel 80 mg/m2 IV on days 1, 8, and 15Trastuzumab 2 mg/kga IV on days 1, 8, 15, and 22
Placebo PO dailyPaclitaxel 80 mg/m2 IV on days 1, 8, and 15Trastuzumab 2 mg/kga IV on days 1, 8, 15, and 22
Placebo PO dailyPaclitaxel 80 mg/m2 IV on days 1, 8, and 15Trastuzumab 2 mg/kga IV on days 1, 8, 15, and 22
PFSResponseSurvivalSafety
Assessment q8 week
PFSResponseSurvivalSafety
Assessment q8 week
Stratification by prior adjuvant or neoadjuvant trastuzumab and by
§ Patients with HER2-overexpressing, unresectable, locally advanced, recurrent, or metastatic BC; no prior therapy for locally advanced or recurrent disease except hormonal therapy§ Stratification by prior adjuvant or neoadjuvant trastuzumab and by
presence of visceral metastasesScreen <14 days prior to day 1
BOLERO-3 (W2301): Phase 3 Second-lineVinorelbine + Trastuzumab ± Everolimus
a Following a 4-mg/kg loading dose on day 1, cycle 1.
Everolimus:placebo1:1 (N=572)
RANDOMIZE
RANDOMIZE
Everolimus (5 mg PO daily)Vinorelbine (25 mg/m2 weekly)Trastuzumab (2 mg/kg weeklya)
Everolimus (5 mg PO daily)Vinorelbine (25 mg/m2 weekly)Trastuzumab (2 mg/kg weeklya)
Continue treatment until PD or
intolerable toxicity
Continue treatment until PD or
intolerable toxicity
Placebo (PO daily)Vinorelbine (25 mg/m2 weekly)
Trastuzumab (2 mg/kg weeklya)
Placebo (PO daily)Vinorelbine (25 mg/m2 weekly)
Trastuzumab (2 mg/kg weeklya)Tumor assessment according to RECIST
using CT or MRI scans q6 weeks
SCREEN
SCREEN
§ Patients with HER2+, locally advanced MBC who have received prior taxane therapy and whose disease is resistant to trastuzumab§ Stratification by prior use of lapatinib
(yes or no)
Primary end point§ PFSSecondary end points§ OS, ORR, CBR, safety, PK, biomarkers
Follow-up for survival q3 mo
until 384 deaths have been recorded
Follow-up for survival q3 mo
until 384 deaths have been recorded
Tumor size is dependent on angiogenesis
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Gimbrone et al. NEJM 1972
Angiogenic switch
• In normal tissue, anti-angiogenic factors dominate over pro-angiogenic factors
• In tumors, there is a “switch” from non-angiogenic (“dormant”) to angiogenic phenotype
QuickTime™ en een-decompressor
zijn vereist om deze afbeelding weer te geven.
The “other ones” involved … get used to their names
Upregulation of VEGF by HER2Confirmed at transcript and protein level
Epstein, et al. SABCS 2003
Rationale for Bevacizumab + Trastuzumab
Increased number of vessels– vessel dilation– vessel tortuosity
HER2-negative
HER2-positive
Angiogenesis Inhibition: Anti-VEGF and Anti-HER2: BETH
• Study recently closed
• HER-2 + EBC • CT + H followed by H vs • CT + H + B followed by H + B
Angiogenesis Inhibition LMM
• Increasing in incidence • No “optimal” standard of care change since ….• Case reports and personal experience • Combination CDDP + Bevacizumab• MTX-refractory LMM in HER2- BC• PK in CSF • PI: L. Dirix , IKN
Angiogenesis Inhibition: RTKI + Capecitabine
• Sunitinib results • Sorafenib + Capecitabine
– SOLTI-0701: A Multinational Double-Blind, Randomized Phase 2b Study Evaluating the Efficacy and Safety of Sorafenib Compared to Placebo When Administered in Combination with Capecitabine in Patients with Locally Advanced or Metastatic Breast Cancer (BC)
– Promising results – Peculiar similar in toxicity profile
QuickTime™ en een-decompressor
zijn vereist om deze afbeelding weer te geven.
Angiopoetins
QuickTime™ en een-decompressor
zijn vereist om deze afbeelding weer te geven.
Antitumor efficacy of AMG 386.
Herbst R S et al. JCO 2009;27:3557-3565
Angiogenesis Inhibition: Angiopoeitins
• Phase 2 Study of AMG 386 Plus Paclitaxel With or Without Bevacizumab as First Line Therapy in Her2-Negative Breast Cancer Patients
• Tolerability and efficacy of the combinatiopn of anti-VEGF and and-angiopoeitin strategy in combination with paclitaxel
BRCA 1 mutation associated Breast tumors with basal-like features
Sorlie et al.Pnas.2003
All tumors from Patients carrying BRCA 1 mutations fell within the basal subgroup
Two BRCA 2 tumors showed luminal A expression
Mechanism of Cell Death from Synthetic Lethality, as Induced by Inhibition of Poly(Adenosine Diphosphate [ADP]–Ribose)
Polymerase 1 (PARP1).
Iglehart JD, Silver DP. N Engl J Med 2009;361:189-191.
PARP• Poly(ADP-ribose) polymerases (PARPs) 1 and 2 are central to
specific type of DNA damage, especially single stranded breaks.• PARP -1 is a major component of the BER pathway.• The BER pathway is central in repair of endogenous DNA damage.• PARP inhibitors may induce “synthetic lethality” in tumors with defects
in BRCA-dependent DNA repair pathway• Synthetic lethality is a phenomenon whereby cell death results from
loss of function of 2 different gene products.• Somatic mutations in BRCA1 and 2 are rare in non-hereditary breast or
ovarian cancer.• Loss of heterozygosity of genomic regions not uncommon• Reduced expression of BRCA1 protein; somatic BRCA1 promoter
hypermethylation or downregulation is noted in non-hereditary breast cancer• They usually do not express estrogen or progesterone receptors and do not
overexpress HER2 (TNBC).• Many TNBC demonstrate a basal-like gene expression and as do most
tumors arising in BRCA1 mutation carriers.
Combination of platinum with PARP agents
Bipar science
PARP-Inhibition
• Phase I/II AZD8931/Paclitaxel in Treatment of Advanced Solid Tumours (Phase I) and Advanced Breast Cancer (Phase II) (THYME)
Prospective Validation of Mammaprint: The MINDACT Trial
Accrual started 2/07 and is expected to be finished within 3 years
6,000 LN- patients
High risk àChemo +Endocrine
Risk assessed viaClinicopathologicalFactors (adjuvant)+ Mammaprint
Low risk àEndocrine
Discordant cases:random assignmentto follow genomicvs clinicopathologicresult
Cardoso, F. JCO, 2008.