(CONFERENCE CONTINUES) PANCREATIC CANCER UPDATE:

*FOLFIRINOX definitely in control as first choice for first line
but this option is too toxic in the elderly so a modified version is adopted by some
.*new IMPACT STUDY,  GEMZAR-ABRAXANE is being rapidly adopted as an alternative to FOLFIRINOX for this same and very  reason (Toxicity of Folfirinox)
This combination was reportedly tried in selected clinics (including Eastern Europe) in a Phase III trial, was tried against Gemzar alone
and gave Progression free survival of 5.5 months Vs 3.7 months
                                                      Overall survival 8.5 months Vs 6.7 months     (Von Hoff DD et al.)

Abraxane given at 125 mg/m2 and Gemzar at 1000mg/m2 Q3/4 in the combination arm
----------------------------------------------------------------------------------------------
3rd choice of course was GEMZAR-ERLOTINIB follwed by GEMZAR ALONE.
===========================================================

NOTABLY NO TARGET THERAPY DISCUSSED WHICH NEEDS TO BE CORRECTED FAST!

TODAY'S CONFERENCE NEWS!

One thing is for sure: current clinical practice of Oncology is miles away from the cutting edge science advancing before it and there is a reason to this fact, only what is clearly established and approved by national institutions reaches the practicing Oncologist.  And clearly, it is important that speakers during Oncology conferences reinvent themselves deep enough to understand the flow of information coming through.  It is easy to tell who knows fully and who is trying to keep up among speakers.   Navigating the world of research while keeping up with clinical studies is the challenge our speakers face.

1.  In lung cancer
-------------------
*In Adenocarcinoma:  Pemetrex +Cisplatin based treatment is still King prior to gene Mutation determination, in Metastatic setting and first line
*But when EGFR and positive is known, Erlotinib came on top! And when progression occurs,
continuing ERLOTINIB, but adding a chemotherapy doublet won!
*Despite great achievements by Target therapy in lung cancer, most of the time it is hard to prove survival benefits because most studies allow cross-over of those failing the chemotherapy-alone arm.
*Afatinib was superior to Cisplatin-Pemetrex in those with Del 19/L858R (EGFR mutation positive)
with Progression free survival 13.6 months Vs 6.9 months in metastatic setting.
*Increasingly, re-biopsy at recurrence is occurring to reassess the status of common Mutations.
It has noted that tumors which were EGFR positive, once they become resistant, they adopt small cell features and respond to Small cell regimens.
* When using a EGFR, continue the drug beyond resistance because in a limited MSKCC series, up to 25% of cancers experience a "FLARE" when TKI (Tyrosine Kinase Inhibitors) were discontinued.  So, while considering options for 2nd line therapy, do not stop TKI.

*Currently tested Mutations:
EGFR, EML4-ALK fusion, MET amplification by FISH (not so much by IHC), ROS-1, PIK3CA (sometime FGFR1)
*"PROXIMITY" TO ROS1 WITH INSULIN RECEPTOR discussed
*IF EGFR positive, rarely you will find KRAS (exclusivity rule discussed)
*in lung cancer :
you find ROS1 in 1.5% of cases,
             ALK + in 5% of cases
             RET + in 2% of cases
             EGFR + in 18% of cases
             HER-2 in 2 % of cases
*Acinar Morphology a cue for ALK positive? and CRIZOTINIB is the answer!

*Now comes OR HAS ARRIVED THE PRACTICE OF "MULTIPLEX TESTING" FOR IDENTIFICATION OF SPECIFIC MUTATIONS.
*Of note: the study showing Taxotere equivalent to Gefitinib in lung cancer cases unscreened for EGFR mutation at onset of trial are challenging the notion of Early EGFR identification!

NEW GANETESPID (+TAXOTERE), THIS IS AN INHIBITOR OF HSP90, A CHAPERONE MOLECULE AND PD-L1   BMS936558

WITH THIS FRAME OF INFORMATION - GO TO WORK!

NEXT: METASTATIC MELANOMA

WAKE UP AND SMELL THE COFFEE.  THE STORY OF DDR2

ONE OF THE MOST POWERFUL PAPERS

« ASCO issues Provisional Clinical Opinion on EGFR testing in Non-Small-Cell Lung Cancer | Main | Systems biology for studying cancer »

May 06, 2011

DDR2 Kinase Mutations in Lung Squamous Cell Carcinoma

Yes--you read that right!
The journal Cancer Discovery reports in a publish ahead-of-print article (abstract) the discovery of mutations in the discoidin domain receptor 2 tyrosine kinase (DDR2) gene in a series of lung squamous cell carcinomas (SQC) that may identify a  potential therapeutic target similar to those described for lung adenocarcinomas.  Interestingly, DDR2 is a receptor kinase that normally binds collagen as its ligand and has been shown to promote cell migration, proliferation, and survival when activated by ligand binding and phosphorylation.
While subtypes of lung adenocarcinoma (ADC) have been increasingly better defined and characterized on multiple levels with respect to identifying therapeutic targets/responses, minimal progress has been made with squamous cell carcinoma.
The authors of this study used conventional Sanger sequencing of 201 genes, including the entire tyrosine kinome, in an initial set of 20 primary lung SQC and matched normal controls and identified 2 samples with DDR2 mutations; a secondary screen of 48 lung SQC samples identified an additional 4 DDR2 mutations.  Following this, the authors sequenced DDR2 in a validation cohort of 222 primary lung SQC samples and identified 5 additional samples with mutations.  Excluding samples from lung SQC cell lines, there was an overall frequency of 3.2% of DDR2 mutations in primary lung SQC samples--about the same frequency reported for ALK fusion mutations in lung ADC.
The authors analyzed the TKIs imatinib and dasatinib, previously reported to inhibit DDR2, to evaluate whether targeting DDR2 mutated in SQC might be a potential therapeutic strategy.  Dasatinib showed particular efficacy in inhibiting proliferation and promoting cell death through apoptosis in SQC cell ines with DDR2 mutations.  In addition, they report one of 7 subjects from an early-phase trial of dasatinib or combination dasatinib and erlotinib with advanced stage lung SQC cancer who exhibited significant shrinkage in tumor size while receiving the dasatinib/erlotinib combination.  The authors were able to perform direct sequencing of DDR2 in a pretreatment tumor specimen from this individual and identified a novel DDR2 kinase mutation.
This is an intriguing paper that you might well keep in mind.  Hopefully, this may stimulate other investigators to not only look for other potential genomic alterations that either drive SQC and/or represent targetable proteins but also go back and scrutinize histological and other clinicopathological characteristics of lung SQC that may have therapeutic or prognostic importance.

Posted at 11:40 AM in Lung Cancer, Lung Squamous Cell Carcinoma, Molecular Pathology, Prognostic/Predictive Cancer Markers | Permalink

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AT CRBCM WE BELIEVE

ONE OF THE MOST POWERFUL TREATMENT AGAINST A DISEASE IS TO FIND THE TARGET THAT INITIATED IT.  THE STRONGEST EVIDENCE THAT A TARGET MOLECULE IS A CRITICAL MOLECULE IS WHEN ITS MUTATION SHORTENS A LIMB IN INDIVIDUALS AND DDR2 MUTATION DOES EXACTLY THAT !!!!
It reminds me of the story of Thalidomide.  And the 2 can be linked.  I am only 50% of this! And whenever a limb is missing, your Angiogenesis and Differentiation are not very far and sure enough, Dasatinib, Imitanib and most likely Thalidomid are not far, lurking in the neighborhood!

SPONDYLO META EPIPHYSEAL DYSPLASIA (SMED) IS THE CONDITION OF SHORT STATURE AND SMALL LIMBS THAT IS RELATED TO DDR2 MUTATION!
SCIENTISTS DID NOT SLEEP, THEY LOOKED IN LUNG CANCER WHAT DASATINIB WOULD DO IN THESE PATIENTS WITH DDR2 MUTATION AND SURE ENOUGH, DASATINIB WORKS. The proof of concept is there in the pudding.

Now don't go out hunting for any short stature individual to test their gene.  But nature has given us a clue that all short stature gene found in a cancer cell, should not only tell us that the gene is targetable by an anti-VEGF and related kinase.  WE SHOULD BE TESTING ALL CANCER FOR DDR2, AND TREAT WITH DASATINIB. CURE IN THOSE CASES IS REACHABLE!  And may be we can prevent all stature with these drug.   One thing for sure, let's find DDR 2 in triple negative breast cancer, and we know what to give pronto now!

Attended Mark G Kris lecture on Lung Cancer  (KRIS IS FROM MSKCC)

Now genetic sequencing is important

Prescribe the following

1)  EGFR-------------ERLOTINIB, GEFITINIB
2)  ALK-----------------CRIZOTINIB
3) HER-2--------------HERCEPTIN, LAPATINIB
4) BRAF -------------------VEMURAFENIB
5) ROS-1-----------------CRIZOTINIB  (AGAIN)
6) RET--------------------------VANDETANIB  (CABOZANTINIB)
7)MET------------------------CRIZOTINIB (AGAIN)

NICE THE PRESCRIPTION SPELLING OUT ONLY THE GENE SEQUENCING, AND LET YOUR PHARMACIST DO THE REST.
QUESTION: COULD THESE DRIVER GENE ABNORMALITIES BE THE SAME IN TRIPLE NEGATIVE BREAST CANCER?