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ASCO 2010: Erlotinib plus novel cMET inhibitor in NSCLC

I was attending the 2010 ASCO Annual Meeting this past weekend, June 5-6, and will post some blogs about my "highlights."  This is a perk of living in Chicago since the meetings were here from 2006-2008 and will be here for the next ten meetings!

Dr. Joan H. Schiller, from the University of Texas Southwestern Medical Center, presented the findings of the the ARQ 197-209 Clinical Trial Group during Saturday’s Clinical Science Symposium on “Molecularly Targeted Trials in Lung Cancer” (Abstract LBA7502).  ARQ 197-209 is an investigational agent that is an inhibitor of c-MET, a high-affinity tyrosine kinase receptor for hepatocyte growth factor.  The c-MET receptor is an attractive anticancer target in NSCLC given that c-MET gene amplification correlates with a poor prognosis in NSCLC and is also a mechanism for resistance to EGFR inhibitors such as erlotinib.

This was a phase II, randomized, double-blind, placebo-controlled trial that studied 167 patients with locally advanced or metastatic NSCLC who were randomly assigned 1:1 to treatment with erlotinib plus either ARQ 197 or placebo.  The primary objective of the study was to compare PFS between the two arms. Although study participants had received at least one prior chemotherapy regimen, all were required to be naïve to EGFR inhibitors for study inclusion.

Results.  The addition of ARQ 197 to erlotinib significantly prolonged PFS by a median of 6.4 weeks after adjustment for key prognostic factors in the Cox regression model (p < 0.05).  

An additional interesting finding was that the benefits of adding ARQ 197 to erlotinib were more marked when analyses were restricted to the 111 patients with non-squamous cell histology. Patients in this subgroup who received ARQ 197/erlotinib as compared with erlotinib alone demonstrated a significant 9.2-week improvement in PFS (adjusted HR = 0.61; p < 0.05), as well as a significant 13.7-week improvement in OS (adjusted HR = 0.58; p < 0.05).

Another provocative finding was found in their exploratory analyses based on NSCLC molecular features which suggest that ARQ 197 also yields particularly prominent PFS improvements in KRAS mutant disease, most commonly found in smokers, and perhaps EGFR wild-type disease as well.

Abstracts solicited for Pathology Informatics 2010 Conference

Dr. Bruce Friedman at LabSoftNews blog has announced a call for abstracts for the Pathology Informatics 2010 Conference in Boston on September 19-22, 2010.

The conference Web site is up which has links for additional information about the conference, online registration, abstract submission, etc.  This really is a premier conference and well-worth the time and expense!  Please check out the Web site--it is pretty amazing what this conference has evolved into since I attended my first conference in 2000 (ouch!).

Part 3. Molecular testing in lymphoma: USCAP 2010

Final recap from Dr. Adam Bagg's lecture at USCAP 2010 on molecular testing in lymphoma.  The highpoint of the lecture for me was his comments on diffuse large B-cell lymphoma (DLBCL) since this is the most common lymphoma type we see in our practice.  It so happens that there have been some recent papers that I've read that complement Dr. Bagg's lecture notes and I cite those below.  I think if you consider his comments and have a look at these papers, you should be well-prepared for the next DLBCL you see.

DLCBL is the most common lymphoma in adults but it is a heterogeneous clinical, morphological, immunophenotypic, molecular, and genetic "category."  Some differences in clinical behavior can be predicted by the recognition of certain between-defined morphological subtypes and/or clinical parameters.  This presentation focused on current attempts to use molecular approaches to more consistently predict behavior and response to specific therapies.

The most commonly dysregulated genes in DLBCL are BCL6 (~40%), BCL2(~20%), BCL10 (~15-20%), and MYC (~5-10%).

The presence of a MYC translocation predicts a poor prognosis.

t(14;18)(q32;q21)--identical to that seen in FL--is present in 20% to 30% of DLBCL and is associated with germinal-center-B-cell (GCB) type.  The detection of the translocation does not correlate with bcl2 protein expression.  Some evidence suggests that detection of bcl2 protein expression in the absence of t(14;18) predicts a poorer prognosis.

The gene BCL6 in DLBCL is promiscuous with respect to translocation partners--with at least 20 different partners described.  BCL6 protein expression associated with GCB type and a favorable prognosis.  However, the effect of BCL6 translocation on prognosis depends on the translocation partner.

Gene array data using unsupervised analysis identifies three gene expression subgroups:

1. Germinal center B-cell-like (GCB): expresses genes characteristic of germinal centers.  Detection of t(14;18) is the most specific abnormality in this group.
2. Activated B-cell-like (ABC): expresses genes characteristic of mitogenically-activated peripheral B-cells; associated with activation of the NFκB pathway.
3. Unclassified ("type 3"): neither sets of genes from GCB or ABC are highly expressed.

Although such expression profiling/gene chip array methods are not currently clinically available, this data can be translated into RT-PCR and IHC methods to further characterize DLBCL.

1. Measurement of only 6 genes by quantitative RT-PCR on routinely processed FFPE tissue appears sufficient to predict OS: expression of BCL6, LMD2, and FN1 (GCB genes) are associated with  favorable prognosis, while expression of BCL2, CCND1, and SCYA2 (ABC genes) are associated with an adverse prognosis.
2. Using just three IHC markers--CD10, BCL6, MUM1--can segregate DLBCL into GCB and non-GCB types in about 80% of cases compared with gene expression profiling.  Recently, a 5-marker panel adding GCET1 (Serpin A9) and FOXP1 improves concordance with gene expression profiling to about 93%.
3. There is currently no consensus regarding the optimal IHC panel to distinguish GCB from non=GCB DLBCLs.

Additional insights have been obtained using supervised array analyses.

Expression signatures associated with either curable or refractory disease identified protein kinase C beta (PKCβ) and c-AMP-specific phosphodiesterase (PDE4B) as associated with an adverse outcome and are potential therapeutic targets.

Numerous microRNA signatures have also been described and some of these appear prognostically relevant.

Some of the data appears contradictory and is confusing.

t(14;18) in DLBCL is considered a poor prognostic indicator but is associated with GCB-DLBCL which has a good prognosis.

There is no significant correlation with bcl2 protein expression and OS within the GCB group (which is typically associated with the t(14;18) translocation), while bcl2 protein expression does predict adverse OS in the ABC group (which has a higher frequency of 18q21 amplification--where BCL2 is located).

In addition, there are conflicting and confusing data regarding the use of IHC markers and/or surrogates for prognosis and predictive value in DLBCL.  There are multiple possible reasons for this.  Hence, there is a definite need for standardization and harmonization of these genetic and molecular markers before they can be used clinically to determine therapeutic strategies.

Recent References

Gurbaxani S, Anastasi J, Hyjek E.  Diffuse large B-cell lymphoma--more than a diffuse collection of large B cells.  Arch Pathol Lab Med 2009;133:1121-1134.

Carbone A, Gloghini A, Aiello A, Testi A, Cabras A.  B-cell lymphomas with features intermediate between distinct pathologic entities--from pathogenesis to pathology.  Hum Pathol 2010;41:621-631.

Illinois Society of Pathologists Meeting: Events Affecting Compensation

Back from a relaxing vacation and ready to blog again!

The Illinois Society of Pathologists is hosting a meeting on April 27, 2010 from 6:00-8:30 PM called "Current Events Affecting Pathologists Compensation."  The location is the Sidley & Austin Law Offices, 1 South Dearborn in Chicago.

The meeting will feature health care law attorney Jack Bierig and a round-table discussion with area pathologist leaders concerning recent and on-going litigation related to PC billing, "in-sourcing" of pathology services by clinician groups, and out-of-state competition from non-licensed pathologists.  Our recent newsletter (Spring 2010) has an excellent overview of these issues by the current ISP President, Dr. Pete Candel.  You can sign-up to receive the newsletter at the above link.

The meeting is FREE to ISP members and only $125 for non-members (why not join!).  If you wish to attend in person, please contact Pamela Cramer at [email protected] or phone the ISP office at 847-441-7200.  A Webinar will also be available for non-Chicago members.

Molecular markers for targeted therapy in lung cancer: USCAP 2010

I attended the Special Course at USCAP 2010, "Basic Principles and Practice of Molecular Pathology in Cancer."  One of the talks was given by Dr. Marc Ladanyi from MSKCC and one of the leaders in the field of molecular pathology of lung cancer.  The title of his presentation was "Molecular Predictive Markers for Targeted Therapies in Lung Cancer."  Here's my "take-home" points from the talk:

• Term: "lung adenocarcinoma oncogenome"--(I like this) and he presented a pie chart illustrating the different (and (generally) mutually exclusive) mutations found so far in lung ACa
• •  KRAS
  • EGFR
  • BRAF
  • ERBB2 (HER2)
  • ALK fusions (especially, ALK-EML4)
  • MEK1
  • NF1
  • but still about one-third of lung ACa have an unknown mutation
• Although there are morphologic and clinical features associated with EGFR mutations, their predictive value are insufficient to exclude EGFR mutation testing.  Thus, every adenocarcinoma should be tested for EGFR mutation (with the exception of mucinous ACa/BAC which are always KRAS mutants).  Although uncommon or even rare, one does find EGFR-mutant ACa in former and current smokers and in men who could benefit from targeted therapy.  This is important for testing algorithms (see below).
• EGFR mutation versus EGFR amplication is difficult to tease out because they frequently occur together but--
• • The response rate to EGFR-TKIs is high in EGFR-mutated cases regardless of the EGFR copy number.
  • EGFR amplified cases lacking one of the mutations have a very low response rate to EGFR-TKIs.
• Why are some patients with EGFR-mutant tumors non-responders to EGFR-TKIs?
• •  Not all EGFR mutations confer sensitivity (dependent on type of mutation detection method, i.e., direct sequencing versus targeted approach to known sensitive mutations)
  • There may be concurrent "downstream" mutations, e.g. BRAF, PTEN loss, PIK3CA, etc.)
  • Not a well-studied group.
• Why do some patients with EGFR-wild type tumors respond to EGFR-TKIs?
• • Undetected sensitive mutations due to targeted detection method.
  • Poor sensitivity of direct sequencing methods
  • Not a well-studied group.
• KRAS mutations function better as a negative predictor of response to EGFR-TKIs than EGFR mutations do as a positive predictor.
• Dr. Ladanyi presented data from a MSKCC study of patients with EGFR-mutant tumors who initially responded to EGFR-TKI therapy but relapsed while on therapy and underwent re-biopsy.  Two-thirds of these patients developed acquired resistance due to the development of the EGFR T790M mutation; some also were shown to have MET amplification.
• BRAF mutations (most commonly exon 15 V600E) is also a negative predictor of response to EGFR-TKIs but does predict benefit from MEK-selective inhibition: PLX-4032, an experimental agent from Plexxikon which targets mutated BRAF (currently in trials for melanoma in which >50% of tumors show the V600E mutation).
• Very helpful point in discerning which type of EGFR/KRAS mutation detection testing will be serve your patients: Dr. Ladanyi distinguished between "diagnostic sensitivity" and "technical sensitivity."
• • Diagnostic sensitivity (the "comprehensiveness" of an assay): the percentage of all mutations that will be found with a given assay
  • Technical sensitivity: the percentage of tumor cells that need to be present in the specimen in order for a mutation being tested for to be identified
  • There is a trade-off between low technical sensitivity and the risk of false negatives and increasing comprehensiveness or high diagnostic sensitivity and the risk of false positives due to detection of rare mutations of unknown or no clinical significance.
• There are mutation-specific rabbit MoAbs that are commercially available for the detection of mutant EGFR in lung ACa and these could facilitate detection in an algorithm and perhaps eliminate the need for mutation detection testing in certain situations: Antibody 3197 against EGFR exon 21 L858R mutation and Antibody 2085 against the EGFR exon 19 E746-A750del--both from Cell Signaling Technologies.
• Dr. Ladanyi showed 95% sensitivity and 99% specificity for EGFR L858R Ab and 85% sensitivity and 99% specificity for EGFR exon 19 del Ab. (paper in press)
• EML4-ALK detection issues: RT-PCR requires multiple assays because of multiple possible isoforms, other ALK and other kinase fusion partners have been reported, new IHC antibody clone to detect ALK fusion (rabbit mAb #3633 D5F3, Cell Signaling Technologies) may be useful in screening for EML4-ALK detection.
• Dr. Ladanyi presented the testing algorithm used at MSKCC and contrasted with one published recently in J Clin Oncol 2009;27:4232-4235.
• A future post will include my merged algorithm, combining these and incorporating new IHC.

USCAP 2010 TV Highlights!

If you are not able to attend the USCAP meeting, check out the USCAP TV news highlights.  Okay, it is a bit like Revenge of the Nerds, but whatever.  Just check it out.

I'm going to follow with some posts summarizing the highlights of the sessions I attended, posters I liked, and cool stuff at the exhibits.  But first I want to congratulate and thank USCAP for a terrific meeting (at least for the days that I attended!).  It was very well-organized and the content was generally excellent.  The venue (Marriott Wardman Park Hotel) was a little confusing to get around but there was plenty of helpful staff.  I didn't like the way the exhibits and posters were chopped up into different rooms, but I guess I'm somewhat spoiled being in Chicago and used to McCormick Place and its huge exhibit spaces (looking forward to 2010 ASCO Annual Meeting back in Chicago!).  This was the first USCAP meeting I've attended in years, so I'm definitely planning on attending next year's Centennial Meeting in San Antonio (February 26-March 4, 2011).

Chicago to host ASCO meeting for next 10 years

Great news (for me) that Chicago will host the ASCO Annual Meeting for the next 10 years.  I have really been fortunate to take advantage of this the last couple of years and could not get to this year's meeting in Orlando.  It's nice to go home after a day of attending the conference.  From ASCO News:

"ASCO has signed a long-term contract to hold the Annual Meeting at Chicago's McCormick Place for the next 10 years. The contract begins with next year's Annual Meeting in 2010, and runs through 2019 (with the exception of 2016, should Chicago be named the host city of the Summer Olympics). ASCO's Annual Meeting attracts approximately 30,000 attendees each year, and ASCO has been working hard to establish a long-term relationship with the most appropriate host city. Chicago is not only capable of accommodating ASCO's meeting-one of the world's largest medical association meetings; it also provides the convenience and atmosphere that ASCO attendees desire."

Upcoming Audioconference: Integrated Breast Cancer Diagnostics

The Dark Report is presenting an audioconference on August 19, 2009 titled "Pathology and Radiology's Combined Future is Now at KU: How Integrated Breast Cancer Diagnostics are Improving Patient Care."

I am sponsoring this audioconference at my hospital.  The radiologists and I started a radiology-pathology monthly correlation conference last December as part of the radiology quality assurance process which has evolved into a monthly breast conference as part of our weekly Tumor Board Conference that now also attracts oncologists, surgeons, internists, nurses and others.  As I’m sure you are aware, the Dark Report, Dr. Bruce Friedman in LabSoftNews blog has written extensively on this for quite some time and, honestly, I thought it was so “out-there” that I was skeptical and dismissive.  My experience just with this conference and the fruitful, engaging, and instructive interaction with my colleagues opened my mind to the possibilites of integrating diagnostics, especially for breast and lung cancer diagnostics.

I'll be happy to share my summary and response to the audioconference.  Meanwhile, I encourage you pathologists to initiate a conversation with your radiology colleagues regarding integrated diagnostics.  We have much more in common that you might think--and this collaboration can really benefit our patients!

Upcoming Conference on Breast DCIS

The National Institutes of Health (NIH) has organized a free state-of-the-art conference on the Diagnosis and Management of Ductal Carcinoma in Situ from September 22-24, 2009 in Bethesda, Maryland.

The cool things are that 1) it's free (hey, you can't stay home for that!) and 2) if you can't make it, you can register for the live Webcast (like I have).

It looks like this conference will address some practical issues, such as, the role of MRI, as well as frame some of the research questions that remain pertinent for DCIS.  Based on some of my hospital's recent Tumor Board conferences, I hope that follow-up of columnar cell lesions will receive some discussion.  I also hope that there will be some mention of how integrated pathology-radiology diagnostics might impact diagnosis and management of DCIS in the future.

Thoughts on the CAP Futurescape 2009 Digital imaging workshop

Thanks to CAP for putting together this workshop in conjunction with digital pathology company leaders Bioimagene and Aperio!  It was money and time well-spent and I encourage readers to consider attending next year's conference.

I thought that the Aperio exhibit/demonstration was more in the spirit of a workshop and felt that it provided a better appreciation of how one might use their scanning hardware and Spectrum software system in daily practice.

In contrast, the Bioimagene "workshop" was not really a workshop in the sense of a practical demonstration of their system, VIrtuoso.  Although I didn't find it as helpful in directly comparing the two systems,I think their target audience were pathologists new to the applications of digital pathology and not yet at the level of actually using digital pathology in practice.  Nevertheless, the individual presentations were very good (especially my colleague's, Dr. Shriram Jakate!).

I'm definitely considering attending the "Pathology Visions" conference in September.