The Importance of Identifying Molecular Markers in Non-Small Cell Lung Cancer

To understand the importance of molecular markers in the current and future treatment of lung cancer, one should first understand how lung cancer was classified up until the beginning of this decade. Pathologists would look at a sample of a patient’s lung tumor under a microscope, and then make a judgment of whether the cells represented small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Although that is an oversimplification, for all practical purposes, that is what oncologists cared about when it came to choosing treatment. If the diagnosis was NSCLC, then oncologists treated the patient with platinum doublet chemotherapy using one of many standard regimens that were felt to be equally effective. Unfortunately we knew that these regimens only worked in a certain proportion of patients, but we had no way to predict ahead of time who would benefit and who would not.

At the same time pathologists and molecular biologists have know for some time that NSCLC is not really just one disease, but rather a constellation of many diseases that all share the distinction of starting in the lung. For example, major subtypes such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma were often reported in pathology reports but did not influence treatment choice. Since 2004 we have taken this one step farther, asking pathologists to tell us not just that the lung cancer is non-small cell but also that it is non-squamous cell, for purposes of safety with Avastin (bevacizumab) and efficacy with Alimta (pemetrexed), but that is the topic for another chapter.

As our understanding of the molecular basis of cancer has grown, we have developed a number of new molecularly-targeted agents with promise in the treatment of lung cancer. However, targeted drugs tend to have limited or no effect on cancers that lack the “target” of the drug, creating a need for markers to guide us.

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Introduction to Molecular Markers

A molecular marker is an identifiable molecular characteristic (usually DNA, RNA, or protein) in a patient or a tumor that can be used to provide prognostic or predictive information about the cancer or about a particular treatment. A prognostic marker is one which indicates a better or worse outcome irrespective of treatment. For example, a mutation in the KRAS gene has been widely regarded as a poor prognostic molecular marker (see below), but does not necessarily guide us in selecting therapy for a particular patient. In contrast a predictive marker indicates a better or worse chance of an outcome for a specific treatment. Identifying this type of marker is a major goal of translational research and forms the basis of “personalized medicine”, which is simply saying that you may be able to determine ahead of time which treatment will or will not work in a specific patient.

In this chapter, I will try and describe the most common molecular markers being investigated in lung cancer, including some tests that are already being used in practice today. Read the rest of this entry »

When I was a medical student, the question about lung cancer that was always asked on “the Boards” had to do with the difference between stage IIIA and stage IIIB non-small cell lung cancer (NSCLC).  The reason this question was always asked is because patients with stage IIIA NSCLC might be considered for surgery, whereas patients with stage IIIB NSCLC would not be considered for surgery and instead would be treated with chemotherapy and radiation.  The idea is that young doctors should be able to make that distinction and to direct patients to the appropriate specialist/treatment.  While I guess it makes a good test question, this distinction is too simplistic and doesn’t really give anyone a good understanding of the complexities of managing stage III lung cancer. And, in reality, all patients with suspected stage III lung cancer should be evaluated by a multidisciplinary team that includes thoracic surgeons, radiation oncologists, pulmonologists and medical oncologists.  If the Medical Board would write a test question aimed at getting across this important principle, I’d breathe a big sigh of relief for lung cancer patients.

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This is the second of two parts in the Reference Library by Dr. Gadgeel on small cell lung cancer.

Patients with Limited Stage Small Cell Lung Cancer

As stated in the prior chapter from the reference library on basic principles and workup of small cell lung cancer (SCLC), in patients with limited disease (LD)-SCLC, the cancer is only detected in the lung, or the lung and the lymph nodes. But even if it is only detected in these sites it is known, based on prior studies, we remain concerned that the cancer has spread to other parts of the body but that it has not yet grown in these other sites for it to be seen on the scans.

It is for this reason chemotherapy is always included in the treatment of LD-SCLC . Chemotherapy goes throughout the body and therefore will not only attack the cancer visible in the primary lung tumor and the lymph nodes, but also the SCLC cells in the other parts of the body that may exist but remain invisible on the scans.

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General Introduction to Small Cell Lung Cancer

Lung cancer consists of two major types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Approximately 85% percent of all lung cancer patients have NSCLC,  and the remaining 15% have SCLC.

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In 2010, the American Cancer Society has estimated that approximately 222,000 new cases of lung cancer will be diagnosed, of which 35,000 will have SCLC. Even though both subtypes are lung cancers, they are considered as separate diseases in most ways, and the management of these two cancers is different. It is important to recognize that the treatments applicable for NSCLC, including many newer agents that have been approved and are the subject of increasing research and media attention, are not clearly relevant for patients with SCLC.

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Bronchioloalveolar carcinoma, or BAC,  is a unique subtype of non-small cell lung cancer (NSCLC) that has unique features in terms of the demographics of who gets it, how it appears on scans, how it often behaves, and potentially in how it responds to treatment.  It is a subset of lung cancer for which most of what we know emerged in the last 10 years, with our understanding of this entity, and even the definition of BAC, still evolving.

What is BAC?

BAC was first identified and defined as a separate subtype of lung cancer by Dr. Averill Liebow in 1960.  At that time, he highlighted it as a form of well differentiated adenocarcinoma of the lung that appeared to not be able to invade the surrounding lung scaffolding and spread within the lung(s), presumably aerogenously and/or through lymphatic channels.

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What is mesothelioma?

Mesothelioma is a unique cancer that starts from the mesothelium, the membrane lining that contains the body cavities.  Mesothelioma can arise from the pleura (lining of the lungs), pericardium (sac around the heart), peritoneum (abdominal lining), and tunica vaginalis testis (lining of the male reproductive organs).    The majority of mesothelioma cases originate from the pleura.

Epidemiology and Cause of Mesothelioma

Mesothelioma occurs everywhere in the world.  In the United States, it is estimated that ~3000 new cases of mesothelioma occur each year.  Western Europe has over 5000 new cases/year and China estimates 4000 new cases/year.

The main cause of mesothelioma is environmental and well-established; patients have often been exposed to asbestos fibers in their work or living area.  Asbestos is a long thin silicate mineral and has been linked not only to mesothelioma but also to pneumoconiosis and lung cancer.  Asbestos was a popular material used in insulation and construction because it had desirable properties of heat/fire and chemical resistance.  The fibers are hazardous when they become airborne and are inhaled or swallowed.  There are 2 main classes of asbestos: serpentine and amphibole.  Serpentine minerals (chrysotile) account for 95% of the asbestos in buildings in the United States.   The amphibole group consists of 5 types of asbestos - amosite, crocidolite, anthophyllite, tremolite, and actinolite.  Amosite is called the brown asbestos and is found in building materials.  The types of asbestos that are most carcinogenic are amosite and crocidolite.  However, chrysolite also is hazardous and is linked to development of mesothelioma in people.

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Introduction to Adjuvant Therapy: Why More than Just Surgery?

For patients with early-stage non-small-cell lung cancer (NSCLC) (stages I, II and some III), surgical resection (removal by surgery) is the standard treatment. Unfortunately, the rates of recurrence (cancer returning) after resection can be high, and additional therapy (chemotherapy) can improve the odds that the cancer won’t return for some patients. This article goes through the data we have that demonstrate the benefit of chemotherapy after surgery for early stage lung cancer, information about chemotherapy before surgery, new treatments being studied for lung cancer patients after surgery and ongoing studies to help better determine which patients might benefit the most from particular treatments.  We have learned about the importance of chemotherapy and other treatment after surgery from patients who were willing to go on clinical trials.  Patients on the trials either received new treatments or were randomized (assigned by chance) to either get chemotherapy or not after surgery.  The information below comes from the analyses that have been done of the patients who were willing to participate in clinical trials.

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The medical literature tells us that one of the most stressful times of a patients’ cancer course is the time between discovering that they may have cancer and beginning their treatment.  So much is new and unknown.  For many patients, this is their first exposure to the health care system.  The patient often requires multiple tests and need to consult with different physician specialties, sometimes in different hospitals before treatment can begin.

It can be a time where well meaning family and friends provide advice and anecdotes from their experiences with cancer.  Such advice can be helpful but sometimes can lead to further confusion.  Add to that the explosion of information on the internet with the gravity of finding out you may have cancer, and it is no wonder that patients find themselves scared, anxious, and confused.

To help organize and simplify the process leading up to the treatment of the patients disease, it may be good to think in terms of a 3 step pathway; diagnosis (what is it?), stage (where is it?), and treatment options (what can I do about it?).  Each of these steps is critically important, because the treatment options you will be provided with vary considerably by the type and location of lung cancer and the general health of the patient.  If the diagnosis and stage are not adequate, the patient may receive the wrong treatment, and that could adversely effect survival. Read the rest of this entry »

Introduction to Locally Advanced NSCLC

About the only thing that lung cancer experts agree on in the management of stage IIIA NSCLC with N2 nodes involved is that this setting is the most controversial one in the field of lung cancer.  First, it’s worth backing up to clarify what we mean when we talk about stage III, also referred to as locally advanced, NSCLC.  As outlined in another summary chapter, staging is based on the 3 components of Tumor (the primary cancer from which everything originated), Nodal status (which lymph node areas has the cancer spread to), and Metastases (has it gone through the bloodstream to develop new lesions in more distant locations, most common the liver, adrenal glands, bones, other parts of the lungs, or the brain).   Below are schematic drawings from a not quite current staging system after a new revision in 2010, but this is the staging upon which eligibility for our prior studies are based.   Nodes on the same (ipsilateral, in medical jargon) side of the mid-chest (mediastinum, between the lungs), are called N2 nodes, which are considered more advanced than N1 nodes inside the same lung lobe as the main cancer.  Nodes on the opposite side (contralateral) of the mediastinum, or above the collarbone/clavicle (supraclavicular nodes) are termed N3 nodes, which are associated with a higher stage and less favorable prognosis than N2 or N1 nodes. The other potential determinant of locally advanced NSCLC is a higher tumor stage: a tumor that involves chest wall or is close to the carina, which is the split of the main airway (trachea) into right and left main bronchi, can be resected but is complicated and designated T3.  A tumor that involves classically unresectable structures (though potentially with exceptions, depending on circumstances and the surgeon) that are shown below are called T4.  The division between N2 and N3, and between T3 and T4, separates stages IIIA and IIIB, as shown below:

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