Dr. Luis M. Zetina Toaché Oncomédica. Multimédica
GENOMICA EN CANCER DE PULMON
Clin
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20
20092013
Updates in Community Oncology 2011: A Focus on Non-Small-Cell Lung Cancer
20142015
“ It is much more important to know what kind of patient has a disease, than to know what kind of disease a patient has”
Caleb Parry. 18th Century physician, Bath.
“We used to think our fate was in our stars. Now we know, in large measure, our fate is in our genes”
J.D Watson. Time Magazine 20 March 1989
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
65-yr-old malesmoker,
squamous
KRAS Mt
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
In 2012: Most oncologists would agree that these patients have very different malignancies
Most oncologists would agree that these patients should receive different therapy
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
39-yr-old female
never-smoker,adenoca
EGFR Mt
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
In 2012: Most oncologists would agree that these patients have very different malignancies
Most oncologists would agree that these patients should receive different therapy
65-yr-old malesmoker,
squamous
KRAS Mt
ALK fusion
54-yr-old malenever-smoker,
adenoca
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
Most oncologists would agree that these patients have very different malignancies
Most oncologists would agree that these patients should receive different therapy
39-yr-old female
never-smoker,adenoca
EGFR Mt
65-yr-old malesmoker,
squamous
KRAS Mt
Non-small-cell lung cancer (NSCLC)
Presented By Daniel Costa at 2014 ASCO Annual Meeting
Only a fraction of molecular aberrations are clinically relevant
Presented By David Gerber at 2014 ASCO Annual Meeting
Competition is fierce
Report, Medicines in Development for Cancer, PhRMA, www.phrma.org,
136
136
GENOMICA EN CANCER DE PULMON
OBJETIVOS DE LA CONFERENCIA1. Epidemiologia (CA y Caribe)2. Historia del Dx. y Tx. ( Pesimismo) 3. Blancos terapéuticos (Genómica)4. Resultados de Terapia Blanco
(Optimismo)5. Inmunoterapia.. (El Futuro…)6. Optimismo…..
30 million ptes living with cancer 2015
CA&C: 255,900 CASES
173
134
TER
CER
O IN
CID
ENC
IA
PR
IME
RO
MO
RTA
LID
AD
581 328 390
235 299 349
2182
6943
5333 985 425
148 22 30
TOTAL
case
s of L
ung Cance
r: 9
125
TOTAL
case
s of C
ancer:
101900
(11%)
QT 1era linea NSCLC avanzado llego
“PLATEAU”
Urgente necesidad de Nuevos opciones de
tratamiento
1990s
Schiller JH, et al. N Engl J Med 2002;346:92–8
1.0
0.8
0.6
0.4
0.2
0
0 5 10 15 20 25 30Meses
Cisplatino/paclitaxel (R)Cisplatino/gemcitabineCisplatino/docetaxelCarboplatino/paclitaxel (R)
dis
trib
uti
on
fu
nct
ion
SV
ida
1930 1940 1950 1960 1970 1980 1990 2000 2010
Sv ½ 7.9mTR: 19%
Carcinoma PulmonarHistoria . E1594 (n=1155)
. Adapted from Hanahan and Weinberg. Cell. 2000;100:57.
Evadingapoptosis
Self-sufficiency in growth signals
Tissue invasionand metastasis
Limitless replicative potential
Sustainedangiogenesis
Insensitivity to antigrowth signals
Cancercells
Fundamental Hallmarks of Cancer
Updates in Community Oncology 2011: A Focus on Non-Small-Cell Lung Cancer
History of Therapy in Advanced NSCLC: FDA Approval Dates
First lineSecond lineThird lineMaintenanceNot approved
1970 1980 1990 2000
MedianOS (mos)
12+
~ 6~ 2-4
BSC Single-agent platinum Doublets
Bevacizumab + PC
Carboplatin*1989
ErlotinibPemetrexed
2004
Docetaxel1999
PaclitaxelGemcitabine
1998
Vinorelbine1994
Docetaxel2002
Bevacizumab2006
Gefitinib2003
Standard therapies
*Label does not include NSCLC-specific indication Pemetrexed
2008/2009
Histology-directed therapy
~ 8-10
Cisplatin*1978
1. FDA Web site. 2. NCCN. Clinical practice guidelines in oncology. v.3.2011. 3. Schrump, et al. Non-small cell lung cancer. In: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.
. Adapted from Hanahan and Weinberg. Cell. 2000;100:57.
Evadingapoptosis
Self-sufficiency in growth signals
Tissue invasionand metastasis
Limitless replicative potential
Sustainedangiogenesis
Insensitivity to antigrowth signals
Cancercells
Fundamental Hallmarks of Cancer
Numerous driver mutations have been identified in NSCLC
Presented By David Gerber at 2014 ASCO Annual Meeting
KRAS mutations are the most common genomic alteration in lung adenocarcinoma
Presented By David Gerber at 2014 ASCO Annual Meeting
Epidermal growth factor receptor (EGFR) pathway
Presented By Daniel Costa at 2014 ASCO Annual Meeting
Prevalence of EGFR Mutations by Smoking Status
EGFR mutation status (exons 19 and 21) determined in 2142 adenocarcinoma samples from Memorial Sloan- Kettering Cancer Center
Incidence of EGFR mutations in tumors– 52% of never smokers– 15% of former smokers– 6% of current smokers
D’Angelo SP, et al. J Clin Oncol. 2011;29:2066-2070.
EGFR Mutations Detected
Never (n = 302)
Current (n = 20)
Former (n = 181)
36%
4%
60%
Gefitinib as first line therapy for EGFR mutated NSCLC: Legacy of the IPASS (IRESSA Pan-Asia Study) trial
Presented By Daniel Costa at 2014 ASCO Annual Meeting
EGFR TKIs as first line therapy for EGFR mutated NSCLC: <br />gefitinib (NEJ 002) and erlotinib (EURTAC) vs chemotherapy
Presented By Daniel Costa at 2014 ASCO Annual Meeting
Trial Treatment N RR, % Median PFS, Mos Median OS, Mos
TKI Chemo TKI Chemo TKI Chemo
NEJ002[1] Gefitinib vs carboplatin/paclitaxel
230 74 31 10.8 5.4 30.5 23.6
WJTOG3405[2] Gefitinib vs cisplatin/docetaxel
172 62 32 9.2 6.3 30.9 Not reached
OPTIMAL[3] Erlotinib vs carboplatin/gemcitabine
165 83 36 13.1 4.6 NR Not reported
EURTAC[4] Erlotinib vs platinum-based
doublet174 58 15 9.7 5.2 NR Not
reported
Prospective Trials of EGFR TKIs vs Chemotherapy in EGFR-Mutated Patients
1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 3. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 4. Rosell R, et al. ASCO 2011. Abstract 7503.
Evidence-based use of EGFR TKIs (gefitinib, erlotinib and afatinib) for EGFR-L858R or exon 19 deletions mutated advanced NSCLCs as first line systemic therapy
Presented By Daniel Costa at 2014 ASCO Annual Meeting
Slide 5
Presented By Leena Gandhi at 2014 ASCO Annual Meeting
Crizotinib in Patients With Advanced ALK-Positive NSCLC
Crizotinib (PF-02341066)– Dual selective inhibitor of ALK and c-MET
• ATP-competitive inhibitor• Orally available small molecule
– Potent inhibition of cell growth and induction of apoptosis in NSCLC cell lines
– Demonstrated safety in dose-escalation study
1. Tan W, et al. ASCO 2010. Abstract 2596.
RESPONSES SEEN TO CRIZOTINIB, AN ALK AND C-MET INHIBITOR, IN ALK-REARRANGED NSCLC PATIENTS ON PHASE I TRIAL
Presented By Leena Gandhi at 2014 ASCO Annual Meeting
EML4-ALK FUSION???
Slide 10
Presented By Leena Gandhi at 2014 ASCO Annual Meeting
Kinase inhibitors in driver oncogene mutant cancers: <br />EGFR TKIs in comparison to other approved inhibitors
Presented By Daniel Costa at 2014 ASCO Annual Meeting
TARGETED THERAPY FOR ONCOGENIC DRIVER ALTERATIONS
Presented By Leena Gandhi at 2014 ASCO Annual Meeting
The immunoediting hypothesis suggests that clinically evident cancer arises when the control mechanisms of the immune system are breached thus leading to escape and a
cascade of tumor proliferation associated with relative immune paresis.
Patrick M. Forde et al. The Oncologist 2013;18:1203-1213
©2013 by AlphaMed Press
CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma
Yuan J et al. PNAS 2008;105:20410-20415
Polyfunctional NY-ESO-1 antigen-specific T cells secreted higher levels of IFN-γ after anti-CTLA-4 antibody treatment.
Immune checkpoint modulation for advanced NSCLC.
Patrick M. Forde et al. The Oncologist 2013;18:1203-1213
©2013 by AlphaMed Press
Why Perform Molecular Testing?
Outcomes of Molecular Testing
For predictive and prognostic value
Predictive: Who is likely to do better with a particular therapy?
Prognostic: Who is likely to do better or worse, independent of therapy?
To improve clinical outcomes
Give best treatments first (eg, consider timing of EGFR TKI)
Provide access to agent (eg, crizotinib for ALK-positive NSCLC)
Identify subsets who might benefit from targeted therapy (eg, cetuximab)
To facilitate clinical research
May improve patient outcomes Better understanding of molecular oncology
Diagnosis Tumor is resected and measured
Stage IA+B: Observation
Stage II-IIIA: Adjuvant therapy
Early-Stage NSCLC Treatment Protocol
Who to treat? 27% of stage IA and 42% of stage IB patients recur and die
– Q: How to identify individuals at higher risk? 41% of patients with stage II NSCLC are cured with surgery alone and
do not need adjuvant treatment– Q: How to identify patients that can be cured by surgery alone?– Q: How can patient selection among those given adjuvant
therapy improve HR and cure rate?
Importance of Molecular Staging
LUNG
COMPROBACION POR IHQ
thyroid transcription factor 1
RESPONSE TO TK
EGFR MUTATION ANALYSYSCENTRAL & CARIBBEAN
CDDP
TK
PEMETREXED
CETUXIMAB
Muchas GraciasThank you
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