Hovav Nechushtan Hadassah Hebrew University Medical center
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Currently we are not curing stage 4 cancer the approach of one
cure fits all does not seem to work Perhaps a new general drug is
on the horizon but most of us are skeptic.. I will describe in this
short lecture some case reports which illustrate our hopes and also
current shortcomings
Have We Approached the Ceiling for Chemotherapy in Advanced
NSCLC? Schiller et. al., NEJM 2002 MST ~ 8 mos.
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Bevacizumab -based therapy extends survival beyond historical
benchmark of 1 year 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0
06121824303642 Duration of survival (months) OS estimate Sandler,
et al. NEJM 2006 E4599 overall patient population CP (n=444)
Avastin 15mg/kg + CP (n=434) HR (95% CI) 0.79 (0.670.92) p
value0.003 Median OS (months)10.312.3 10.3 CP (n=444) Avastin
15mg/kg + CP (n=434) HR (95% CI) 0.79 (0.670.92) p value0.003
Median OS (months)10.312.3
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Pemetrexed in Breast Cancer Clinical Response by Baseline TS
mRNA % responders N=34N=17
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FIGURE 3. KaplanMeier plots of PFS (A) and OS (B) in patients
with low and high nuclear TS expression (H- score) (n = 60). High
and low TS immunohistochemical expression in the nucleus: TS
nucleus H-score less than 70 and more than or equal to 70,
respectively. OS, overall survival, PFS, progression-free survival;
TS, thymidylate synthase. Copyright 2013 Journal of Thoracic
Oncology. Published by Lippincott Williams & Wilkins.8
Thymidylate Synthase Expression and Outcome of Patients Receiving
Pemetrexed for Advanced Nonsquamous NonSmall-Cell Lung Cancer in a
Prospective Blinded Assessment Phase II Clinical Trial Thymidylate
Synthase Expression and Outcome of Patients Receiving Pemetrexed
for Advanced Nonsquamous NonSmall-Cell Lung Cancer in a Prospective
Blinded Assessment Phase II Clinical Trial Nicolson, Marianne C.;
Fennell, Dean A.; Ferry, David; OByrne, Kenneth; Shah, Riyaz;
Potter, Vanessa; Skailes, Geraldine; Upadhyay, Sunil; Taylor, Paul;
Andr, Valerie; Nguyen, Tuan S.; Myrand, Scott P.; Visseren- Grul,
Carla; Das, Mayukh; Kerr, Keith M. Journal of Thoracic Oncology.
8(7):930-939, July 2013. doi: 10.1097/JTO.0b013e318292c500
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Overall Survival in Pts with Adenocarcinoma or Large Cell Ca.
Overall Survival for all Pts HR=0.81 Approved in US by FDA in 10/08
for non-squamous ca
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FIGURE 4. Utility of routine IHC markers to identify putative
NR and R to Pemetrexed therapy. The expression of eight IHC markers
in 68 of 90 NSCLC and two normal lung tissues (G0) was detected by
TMA and used for cluster analysis. High staining is shown in red
and low staining is shown in green. Failed IHC staining is shown in
purple. NSCLC cases are annotated with predominantly present
expression profile-assigned subgroup(s) (G1 to G6) on the right and
predicted Pemetrexed responsiveness (resistant case [NR]: gray;
sensitive case [R]: orange) on the left. IHC, immunohistochemistry;
NR, nonresponder; R, responder; NSCLC, non-small cell lung cancer.
Copyright 2012 Journal of Thoracic Oncology. Published by
Lippincott Williams & Wilkins.10 Expression Profiling-Based
Subtyping Identifies Novel Non-small Cell Lung Cancer Subgroups and
Implicates Putative Resistance to Pemetrexed Therapy Expression
Profiling-Based Subtyping Identifies Novel Non-small Cell Lung
Cancer Subgroups and Implicates Putative Resistance to Pemetrexed
Therapy Hou, Jun; Lambers, Margaretha; den Hamer, Bianca; den
Bakker, Michael A.; Hoogsteden, Henk C.; Grosveld, Frank; Hegmans,
Joost; Aerts, Joachim; Philipsen, Sjaak Journal of Thoracic
Oncology. 7(1):105- 114, January 2012. doi:
10.1097/JTO.0b013e3182352a45
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Main approaches semi- available today 1) Find expression of a
small number of markers ( usually derived from enzymatic markers )
for tailoring the right chemo ( arrays not yet available) 2) Find
the gene for which there is oncogene addiction and target it ! 3)
Find the overactive signal transduction pathways and target them
4)Utilize alternative approaches such as vaccines/cytokine
inhibitors etx 5) Use animal models!
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a non smoker ! 57yr old -woman Alcian blue - - .CK5/6+, P63+,
TTF-1+(on some cells ) Favoring SCC
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NOT relevant anymore >>>>!
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Relevance of circulating biomarkers for the therapy monitoring
and follow-up investigations in patients with non- small cell lung
cancer. Barak V, Holdenrieder S, Nisman B, Stieber P Barak
VHoldenrieder SNisman BStieber P Int J Biol Markers. 2012 Jul
19;27(2):e139-46. doi: 10.5301/JBM.2012.9141. Int J Biol Markers.
Cytokeratin-19 fragments, nucleosomes and neuron-specific enolase
as early measures of chemotherapy response in non-small cell lung
cancer. Alm El-Din MA, Farouk G, Nagy H, Abd Elzaher A, Abo El-Magd
GH Alm El-Din MAFarouk GNagy HAbd Elzaher A Abo El-Magd GH .
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described by Rossel Seems to predict ddp response May predict
response to taxanes
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Cyfra 21-1 reduced to normal levels from being more than x20 of
normal Ca125 reduced from over 3000 to around 100
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A term coined by the late IB Weinstein Describes a situation
whereby the tumor is still addicted to an overactivity of a
specific oncogene Some impressing successes yet up to now
Resistance has nearly always appeared Still the whole concept is
very appealing
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An Evolving View of Adenocarcinoma KRAS 1999 Pending EGFR BRAF
PIK3CA EML4-ALK FGFR4 HER2 2009
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69 yr old male Light smoker from a perypheral town in Israel a
clerk on pension After first line taxane and carbo After brain
irradiation Tumor progressing -2010 at that time Only around 50
patients have been reported in prelimenary reports of Crizotinib in
ALK translocated patients
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Pre-Treatment (FLT-PET) Pre-Treatment (FLT-PET) After 4 weeks
of PF-02341066 After 4 weeks of PF-02341066 43 yo Male Non-Smoker
with NSCLC positive for ALK 43 yo Male Non-Smoker with NSCLC
positive for ALK
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Tumor Responses to PF-02341066, In NSCLC with ALK fusion
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45 yr old non smoker Will describe here only a few aspects of
his very complex story
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cadherin Translation kinesin coiled coil tyrosine kinase a) RET
KIF5B b) KIF5B (exons 16-25) RET (exons 1-11) KIF5B (exons 1-15)
RET (exons 12-20) ATG 32,316,377 bps Not Expressed Expressed Figure
3. (a) Schematic representation of the 11,294,741 bp inversion in
NSCLC (TEVA) that generates an in-frame KIF5B-RET gene fusion (not
to scale). The inverted region of chromosome 10 starts at
32,316,377 bps (within KIF5B intron 15) and ends at 43,611,118 bps
(within RET intron 11). (b) Protein domain structure of the
RET-KIF5B and KIF5B-RET gene fusions. The cadherin domain of RET is
included in the predicted RET-KIF5B protein. The kinesin and coiled
coil domains of KIF5B and the tyrosine kinase domain of RET are
included in the KIF5B-RET fusion protein. RT-PCR of primer designed
to RET exon 11 and KIF5B exon 16 yielded no product. RT-PCR of
primer designed to KIF5B exon 15 and RET exon 12 yielded a strong
product (data not shown). 43,611,118 bps KIF5B-RETRET-KIF5B ATG
break
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Foundation test on recurrent disease Foundation test on
recurrent disease reveal two additional gene mutations
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SURGERY FIRST ROUND PATIENT EXPANSIONTREATMENT TUMORGRAFT
RESECTION RECOVERY ENGRAFTME NT
There is a phase 1 trial combining PI3K inhibitor with MEK Not
in Israel did not answer us ( perhaps we could have tried harder)
So we made our combination sorafenib for kras and everolimus for
mtor/PI3 K inhibition Suffers from pneumonia responds to
antibiotics See ct
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( not our patients MRI)
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perhaps our therapy led to the spreading of new and eventually
lethal brain mets or At least was inactive in the brain A reccurent
theme our therapies are not nave and induce sometime unpredicted
tumor responses Are the drugs we use really doing their job?
Epidemiologic Characteristics and Therapeutic Perspectives
Julien Mazie`res, Solange Peters, Benoit Lepage, Alexis B. Cortot,
Fabrice Barlesi, Michele Beau- Faller, Benjamin Besse, Hele`ne
Blons, Audrey Mansuet- Lupo, Thierry Urban, Denis Moro-Sibilot,
Eric Dansin, Christos Chouaid, Marie Wislez, Joachim Diebold,
Enriqueta Felip, Isabelle Rouquette, Julie D. Milia, and Oliver
Gautschi Jco 7-2013
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Garraway and colleagues did full exome seq on 180 lung cancer
samples No HER2 mutations!!! Perhaps not critical as a driver
mutation .
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Specifically, we observed a DCR of 93% for trastuzumab-based
therapies (n = 15) and a DCR of 100% for afatinib (n = 3) but no
response to other HER2-targeted drugs (n = 3). Progression-free
survival for patients with HER2 therapies was 5
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42 yr old non smoker Severe aspirin induced asthma Previously
treated with anti IGE antibodies
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Diagnosis with large lung mass Small brain met Several small
liver mets Bone met
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Avastin alimta carbo Feels better less cough Abdominal abcess
probably microperforation Slowly got better Brain irradaition
radiosurgery only
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Irreversible inhibitor Available in Israel Used in this group
of patients Started on full dose although there was the
microperforation
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Was feeling ok But MRI multiple brain mets Body less uptake but
some tumors did grow bigger So We moved him to herceptin + afatinib
(Her2 staining in tumor very low)
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A non smoker 70 yr old Metastatic Adenocarcinoma PR to Alimta
+carbo Due to proteinuria we did not start with avastin After 4
cycles a major CVA Treated with TPA After rehab started again
alimta
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Stabilizes under the new treatment A few bone met and lung
tumor General condition got much better No biopsy available so he
was sent for a new biopsy Very small sample so we did not send for
ALK but for Foundation
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Is this a bona fide driver mutation ? Not sure Can treatment
with HER2 inhibitors help? Probably but might depend on the patient
and some characterization of the patients other mutations might
help So definetly a drug target in NSCLC but results are probably
less exiting than those with EGFR mutations
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The Kras story is important represents a large part of our
NSCLC patients And the other mutations we note can probably ( no
one checked in humans) greatly influence the tumor response HER2
story again complex perhaps also greatly influenced by other driver
mutations? So we are left with many questions but would like to
present new possibilities to our patients
