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Molecular Profiling of Lung Cancer (article)

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http://www.mycancergenome.org/content/d ... ung-cancer

Molecular Profiling of Lung Cancer

Lung cancer is the leading cause of cancer related mortality in the United States, with an estimated 224,210 new cases and 159,260 deaths anticipated in 2014 (ACS 2014​). Classically, treatment decisions have been empiric and based upon histology of the tumor. Platinum based chemotherapy remains the cornerstone of treatment. However, survival rates remain low. Novel therapies and treatment strategies are needed.

Lung cancer is comprised of two main histologic subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Over the past decade, it has become evident that subsets of NSCLC can be further defined at the molecular level by recurrent 'driver' mutations that occur in multiple oncogenes, including AKT1, ALK, BRAF, EGFR, HER2, KRAS, MEK1, MET, NRAS, PIK3CA, RET, and ROS1 (Table 1). Another altered kinase gene involves MET. 'Driver' mutations lead to constitutive activation of mutant signaling proteins that induce and sustain tumorigenesis. These mutations are rarely found concurrently in the same tumor. Mutations can be found in all NSCLC histologies (including adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma) and in current, former, and never smokers (defined by individuals who smoked less than 100 cigarettes in a lifetime). Never smokers with adenocarcinoma have the highest incidence of EGFR, HER2, ALK, RET, and ROS1 mutations. Importantly, targeted small molecule inhibitors are currently available or being developed for specific molecularly defined subsets of lung cancer patients.

Historically, efforts at characterizing the molecular underpinnings of SCC of the lung have lagged behind those of adenocarcinoma of the lung. Many of the 'driver' mutations found in lung adenocarcinoma are only rarely found in lung SCC. Moreover, newer agents, such as bevacizumab (Avastin) and pemetrexed (Alimta) are not approved for or exhibit diminished efficacy in SCC (Sandler et al. 2006; Scagliotti et al. 2008). Thus, patients with metastatic SCC have fewer treatment options than those with non-squamous NSCLC. Despite these caveats, however, 'driver' mutations that may be linked to outcomes with targeted therapies in SCC are emerging. Altered genes include FGFR1 and DDR2 as well as PIK3CA. In addition, results from a recent large genomic study in lung SCC have added a variety of potential therapeutic targets that await validation in prospective clinical trials (Hammerman et al. 2012).

The following text is meant to provide a broad overview of several of the oncogenes known to be important for lung cancer pathogenesis. Where possible, the presence of a specific mutation is correlated to clinical parameters as well as response to both conventional chemotherapy and targeted agents. At present, only data for treatment of advanced (stage IIIB/IV) disease is presented.

Table 1. Frequency of Mutations and Availability of Targeted Therapies in NSCLC.

Gene Alteration Frequency in NSCLC

AKT1 Mutation 1%

ALK Rearrangement 3–7%

BRAF Mutation 1–3%

DDR2 Mutation ~4%

EGFR Mutation 10–35%

FGFR1 Amplification 20%

HER2 Mutation 2–4%

KRAS Mutation 15–25%

MEK1 Mutation 1%

METa Amplification 2–4%

NRAS Mutation 1%

PIK3CA Mutation 1–3%

PTEN Mutation 4–8%

RET Rearrangement 1%

ROS1​a Rearrangement 1%

Key:

Drugs approved in NSCLC.

Drugs approved in NSCLC but for other molecular subtype.

Drugs approved in other cancer.

Drugs in clinical development.

Note: a Crizotinib is a dual ALK/MET tyrosine kinase inhibitor which is currently only FDA approved for ALK positive NSCLC. However, there is a case report of a patient with NSCLC harboring MET amplification who responded to this agent (Ou et al. 2011). In addition, one patient with NSCLC harboring a ROS1 gene rearrangement had a partial response to crizotinib, which has ‘off-target’ anti-ROS1 activity (Bergethon et al. 2012).

​​​​

Contributors: Christine Lovly, M.D., Ph.D., Leora Horn, M.D., M.Sc., William Pao, M.D., Ph.D.

Last Updated: February 20, 2014

Disclaimer: The information presented at MyCancerGenome.org is compiled from sources believed to be reliable. Extensive efforts have been made to make this information as accurate and as up-to-date as possible. However, the accuracy and completeness of this information cannot be guaranteed. Despite our best efforts, this information may contain typographical errors and omissions. The contents are to be used only as a guide, and health care providers should employ sound clinical judgment in interpreting this information for individual patient care.

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I am stage 2A adenocarcinoma, surgery and chemo afterwards....local reoccurrence in chest nodes. Radiation/ chemo done..my  question is my Dr never did any testing for mutations that I am aware of...do they usually do the if the stage is higher or no surgery was done ??? I read about others syncing this done..but never heard from Dr that I did...not real sure what it's for.?  Thanks for any response..Merilee

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Merilee, welcome here.

Your question is a good one.  You should indeed ask your doctor, perhaps through the practice administrator, if your biopsy was tested for adenocarcinoma mutations.  If not, you should ask if the original sample is sufficient to have molecular profiling performed, and if it is, I'd ask that it be done.

Having this information in hand is useful if you need additional treatment and may indeed dictate the type of treatment you receive.  So I'd be asking.

Stay the course.

Tom 

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I have adeno carcinoma with mixed subtypes (acinar and  micropapillary) Have different approaches been developed to address these subtypes? BTW-I tested negative on the Alk lung fish, ros1 fish, and Egfr mutation analysis not detected.

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I'm not aware of different treatment approaches to the sub-types.  

As for those with a mutation- around 20% or less of the lung cancer patient population have them, but know that researchers ARE searching for more identifiable/treatable biomarkers 

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Hi,

I'm going to have a meeting with my mom's oncologist (pneumologist) in a couple of hours. 

My mother is stage IIa, T2a N0vsN1 M0 and she had surgery yesterday.

My father asked her already in relation to the mutations testing and her answer was "is to early, we have to wait to see if she is an n0 or an n1" and "of course we keep the resected tissue to be tested at any time" and "if she has a recurrence the new tumor could be different"

My question is: in case they prescribe some rounds of chemio, is this usually done immidiatly with targeted therapy based on the patient possible mutation? Or the first rounds of chemio after surgery are normally "generic"?

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Stokedsurfer,

In my experience, the answer your dad received was unusual.  Or perhaps you dad misunderstood the doctor.  Or perhaps the medical community in Portugal has a different approach to treatment than the US.  If your mom has adenocarcinoma, then there is no reason why the pathologist shouldn't determine if her tumor displays mutations.  The answer about keeping resected tissue to be tested at a future time is standard in the US.  The different new tumor on recurrence is confusing.  Normally, generally and usually, a recurrence after treatment that yields no evidence of disease (NED) is considered to be the same type of cancer, at least in the states.  True, it could be different but in my experience, the medical community here presumes it is not.

Normally adjuvant chemotherapy (post surgical) is administered in conformance to the first line (first treatment) "standard of care" in the US.  A standard of care treatment is one to have shown by actual trial to have the best clinical outcome for arresting disease.  While some targeted therapies have achieved first line status, I've not heard of use as adjuvant therapy after surgery.  I'm not a doctor and because I've not heard about it doesn't mean it is not done.

If by generic you mean infused platinum-based or similar conventional chemotherapy, then yes. 

Stay the course.

Tom

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