Personalized Medicine in NSCLC

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Personalized Medicine in NSCLC

March 3, 2013 by larryhbern

Personalized Medicine in NSCLC

Reviewer: Larry H Bernstein, MD, FCAP

Introduction

Early in the 21st century, gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor became available for the treatment of non-small cell lung cancer (NSCLC). Over 80% of selected patients

EGFR mutation-positive patients, respond to gefitinib treatment;
most patients develop acquired resistance to gefitinib within a few years.

Recently, many studies have been performed to determine precisely how to select patients who will respond to gefitinib, the best timing for its administration, and how to avoid the development of acquired resistance as well as adverse drug effects.

Lung cancers are classified according to their histological type. Because each variant has different biological and clinical properties, including response to treatment, a precise classification is essential to provide appropriate therapy for individual patients. Lung cancer consists of two broad categories—non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

NSCLC – 20%–40% RR to chemotherapy

adenocarcinoma (AC), 40%–50% ( most common form)
- higher sensitivity to chemotherapy than SCC or LC
squamous cell carcinoma (SCC), ∼30%
large cell carcinoma (LCC). 10%

The majority of patients with SCLC are diagnosed with

advanced cancer with distant metastasis
high sensitivity to chemotherapy.
response rate (RR) for SCLC is reportedly 60%–80%
complete remission is observed in only 15%–20% of patients

The Potential of Personalized Medicine in Advanced NSCLC
Personalized medicine—

matching a patient’s unique molecular profile with an appropriate targeted therapy—
is transforming the diagnosis and treatment of non–small-cell lung cancer (NSCLC).

Through molecular diagnostics, tumor cells may be differentiated based on the presence or absence of

receptor proteins,
driver mutations, or
oncogenic fusion/rearrangements.

The convergence of advancing research in drug development and genetic sequencing has permitted the development of therapies specifically targeted to certain biomarkers, which may offer a differential clinical benefit.

Putting personalized medicine in NSCLC into practice
With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC.1,2
Biomarker Testing in Advanced NSCLC: Evolution in Pathology Clinical Practice
http://www.medscape.com/infosite/letstest/article-3
Multidisciplinary Approaches in the Changing Landscape of Advanced NSCLC
http://www.medscape.com/infosite/letstest/article-4
Oncology Perspectives on Biomarker Testing
http://www.medscape.com/infosite/letstest/article-1

References
1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer. Version 2.2012.
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. August 6, 2012.
2. Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010;29(1):37-48.

Over the last decade, a growing number of biomarkers have been identified in NSCLC.3,4 To date, 2 of these molecular markers have been shown to have both prognostic and predictive value in patients with advanced NSCLC: epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements.5-8 Testing for these biomarkers may provide physicians with more information on which to base treatment decisions, and reflex testing may permit consideration of appropriate therapy from the outset of treatment.2,9,10

References:
Lovly CM, Carbone DP. Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol. 2011;8(2):68-70.
Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380.
Quest Diagnostics. Lung Cancer Mutation Panel (EGFR, KRAS, ALK). Sept 17, 2012
http://questdiagnostics.com/hcp/intguide/jsp/showintguidepage.jsp?fn=Lung/TS_LungCancerMutation_Panel.htm.

Rosell R, Gervais R, Vergnenegre A, et al. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations: interim results of the European Erlotinib Versus Chemotherapy (EURTAC) phase III randomized trial. Presented at: 2011 American Society of Clinical Oncology (ASCO) Annual Meeting, J Clin Oncol. 2011;29(suppl). Abstract 7503. Aug 6, 2012. http://www.asco.org/ASCOv2/Meetings/Abstracts?&vmview=abst_detail_view&confID=102&abstractID=78285.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957.
Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. N Engl J Med. 2010;363(18):1693-1703.
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology™: Non-Small Cell Lung Cancer. Version 2.2012.
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. Aug 6, 2012
College of American Pathologists (CAP)/International Association for the Study of Lung Cancer (IASLC)/Association for Molecular Pathology (AMP) expert panel. Lung cancer biomarkers guideline draft recommendations. http://capstaging.cap.org/apps/docs/membership/transformation/new/lung_public_comment_supporting_materials.pdf. Aug 6, 2012.
Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy. Cancer Metastasis Rev. 2010;29(1):37-48.

Background Studies

In 2002, gefitinib (ZD1839; AstraZeneca) , the first epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, became available as an innovative molecular-targeted drug for the treatment of unresectable NSCLC. Initially, many NSCLC patients were expected to respond to gefitinib because many solid tumors, including NSCLC, are known to overexpress EGFR, which has a role in tumor proliferation and is used as a biomarker to predict poor prognosis. Gefitinib was shown to have a dramatic effect on a limited number of patients; but it was ineffective in 70%–80% of patients with NSCLC. There have been reports of death caused by interstitial pneumonia (IP), one of the critical adverse drug reactions (ADRs) associated with gefitinib use. Therefore, there is a need for predicting the effects of gefitinib, and criteria for selecting patients who could be treated with gefitinib.

In 2004, Lynch et al. and Paez et al. each published, on the same day, sensational reports in the New England Journal of Medicine and Science, identifying somatic mutations in the tyrosine kinase domain of the EGFR gene in patients with gefitinib-sensitive lung cancer, as compared with none of the patients who had no response. Therefore, screening for EGFR mutations in lung cancer showed potential for identifying patients who would respond to gefitinib therapy. It then was found that patients with EGFR mutations in the area of the gene coding for the ATP-binding pocket of the tyrosine kinase domain responded to gefitinib. Consequently, the EGFR genotyping has been used to select patients who will respond to gefitinib. Other genetic mutations have also been reported as indicators of the response or resistance to gefitinib; for example, mutations of the KRAS gene are associated with primary resistance to gefitinib. Thus, screening of EGFR and KRAS is used to

predict the effects of gefitinib and
to select patients who will respond to gefitinib in the clinical setting.

Until now, the effects of gefitinib have been predicted only by genotyping factors, such as EGFR and KRAS mutations. However, Nakamura et al showed a relationship between the blood concentration of gefitinib and its clinical effects. In their study of 23 NSCLC patients with EGFR mutations, the ratio of the gefitinib concentration on day 8 to that on day 3 after the first administration of gefitinib (C8/C3) correlated with the progression-free survival (PFS) period. Patients with a higher C8/C3 ratio had a significantly longer PFS (P = 0.0158, 95% confidence interval [CI]: 0.237–0.862), which suggests the importance of the PK of gefitinib on its clinical outcome. Chmielecki et al. concurrently reported that maintaining a high concentration of erlotinib, another EGFR tyrosine kinase inhibitor (EGFR-TKIs) with the same mechanism of action as gefitinib, could

delay the establishment of drug-resistant tumor cells and
decrease the proliferation rate of drug-resistant cells compared to

treatment using a lower concentration of erlotinib.

Pharmacogenetic profile

Initially, gefitinib was expected to induce a response in patients with tumors that overexpressed EGFR because it exerts its antineoplastic effects by competitively inhibiting the binding of ATP to the ATP-binding site of EGFR. A number of studies contradict this hypothesis:
(1) while approximately 40%–80% of NSCLC overexpress EGFR, only 10%–20% of NSCLC patients respond to gefitinib;5,6 and
(2) while EGFR overexpression is known to be more common in SCC than AC, gefitinib shows a higher antineoplastic effect on AC than on SCC, while other reports indicated no correlation between the expression levels of EGFR and clinical outcomes.

In 2004, somatic mutations were identified in the EGFR tyrosine kinase domain of patients with gefitinib-responsive lung cancer, as compared with no mutations in patients exhibiting no response, and the presence of an EGFR mutation was highly correlated with a good response to gefitinib.The conformational change of the EGFR ATP-binding site caused by genetic mutations constitutively activates the EGFR downstream signaling pathway and increases the malignancy of cancer. Conversely, the conformational change of the ATP-binding site can also increase its affinity for gefitinib; therefore, gefitinib can inhibit the downstream signaling pathway more easily, strongly induces apoptosis, and reduces the proliferation of cancer cells.

Mutations in exons 18–21 of EGFR are predictive factors for the clinical efficacy of gefitinib;

deletions in exon 19 and missense mutations in exon 21 account for ∼90% of these mutations.

The detection of EGFR mutations in exons 19 and 21 is considered to be essential to predict the clinical efficacy of gefitinib.
Acquired resistance
All responders eventually develop resistance to gefitinib but in 2005, an EGFR mutation in exon 20, which substitutes methionine for threonine at amino acid position 790 (T790M), was reported to be one of the main causes of acquired resistance to gefitinib. The EGFR T790M variant

changes the structural conformation of the ATP-binding site, thereby
increasing the affinity of ATP to EGFR, while
the affinity of gefitinib to ATP is unchanged.

Screening methods for EGFR and KRAS mutations
The detection of EGFR and KRAS mutations has been usually achieved by sequencing DNA amplified from tumor tissues; however, sequencing techniques are too complex, time-consuming, and expensive. The selection of an appropriate method to detect EGFR and KRAS mutations is essential to make an exact prediction of the efficacy of gefitinib in individual patients. Advances in diagnostics and treatments for NSCLC have led to better outcomes and higher standards of what outcomes are expected. These new understandings and treatments have raised multiple new questions and issues with regard to the decisions on the appropriate treatment of NSCLC patients.

Biomarkers are increasingly recognized and applied for guidance in diagnosis, prognosis and treatment decisions and evaluation.
Biologics and newer cancer treatments are enabling the possibility for new combined treatment modalities in earlier stage disease
Maintenance therapy has been shown to be useful, but optimal therapy choices before and after maintenance therapy need clarification
The importance of performance status on treatment decisions
Comparative effectiveness is becoming an expectation across all treatments and diseases, and will prove difficult to accomplish within the complexity of cancer diseases

NCCN Molecular Testing White Paper: Effectiveness, Efficiency, and Reimbursement

PF Engstrom, MG Bloom,GD Demetri, PG Febbo, et al.
Personalized medicine in oncology is maturing and evolving rapidly, and the use of molecular biomarkers in clinical decisionmaking is growing. This raises important issues regarding the safe, effective, and efficient deployment of molecular tests to guide appropriate care, specifically regarding laboratory-developed tests and companion diagnostics. In May 2011, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations to identify challenges and provide guidance regarding molecular testing in oncology and its corresponding utility. The NCCN Molecular Testing Work Group identified

challenges surrounding molecular testing, including health care provider knowledge, determining clinical utility, coding and billing for molecular tests, maintaining clinical and analytic validity of molecular tests, efficient use of specimens, and building clinical evidence. (JNCCN 2011;9[Suppl 6]:S1–S16)

Executive Summary

The FDA recently announced plans for oversight of laboratory-developed tests (LDTs) and released draft guidance regarding the development of companion diagnostics concurrently with therapeutics, both areas over which the FDA has regulatory authority. As recognized by the FDA, these types of diagnostic tests are used increasingly to directly inform treatment decisions, and this especially impacts patients with cancer and their oncologists. However, because of the increasing complexity of some LDTs and increasing commercial interest in oncology-related LDTs in general, the FDA is considering whether its policy of exercising “enforcement discretion”

for LDTs is still appropriate. To provide guidance regarding challenges of molecular testing to health care providers and other stakeholders, NCCN assembled a work group composed of thought leaders from NCCN Member Institutions and other organizations external to NCCN. The NCCN Molecular Testing Work Group agreed to define molecular testing in oncology as

procedures designed to detect somatic or germline mutations in DNA and
changes in gene or protein expression that could impact the
- diagnosis,
- prognosis,
- prediction, and
- evaluation of therapy of patients with cancer.

Therefore, the discussion focused on molecular tests that predict outcomes for therapy.
Realizing the importance of personalized medicine in advanced NSCLC

E Topol, B Buehler, GS Ginsburg. Medscape Molec Medicine

With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC
http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf/

Lung Cancer in the Never Smoker Population: An Expert Interview With Dr. Nasser Hanna

Lung cancer in the never smoker population is a distinct disease entity with specific molecular changes, offering the potential for targeted therapy.
Experts And Viewpoint, Medscape Hematology-Oncology, December 2007

An Update on New and Emerging Therapies for NSCLC

Simon L. Ekman, MD, PhD; Fred R. Hirsch, MD, PhD

On completion of these readings participants will be thoroughly familiar with these issues:

The influence of histologic types and genetic and molecular markers on choosing and personalizing therapy in patients with advanced NSCLC
The role of the pathologist in properly classifying subtypes of NSCLC and reporting the presence of molecular markers in tumor samples
Familiarize themselves with effective methods of obtaining adequate tissue samples from patients and recognize the importance of accurate pathologic assessment of NSCLC

The rapid developments in molecular biology have opened up new possibilities for individualized treatment of non-small cell lung cancer (NSCLC), and, in recent years, has mainly focused on the epidermal growth factor receptor (EGFR). A greater understanding of the molecular mechanisms behind

tumorigenesis and
the identification of new therapeutic targets
- have sparked the development of novel agents

- intended to improve the standard chemotherapy regimens for NSCLC.

Along with the advent of targeted therapy, identifying biomarkers to predict the subset of patients more likely to benefit from a specific targeted intervention has become increasingly important.

EGFR TYROSINE KINASE INHIBITORS

tumor-associated mutations in the tyrosine kinase domain of EGFR have been associated with response to EGFR TKIs

The most common EGFR-sensitizing mutations encompass deletions in exon 19 and a point mutation at L858R in exon 21; together,

they account for approximately 85% of EGFR mutations in NSCLC.
Other EGFR mutations have been detected, particularly in exon 20.
- mutations identified in exon 20 have been linked to resistance to EGFR TKIsNon-Small Cell Lung Cancer: Biologic and Therapeutic Considerations for Personalized Management
  Taofeek K. Owonikoko, MD, PhD

What is the role and application of molecular profiling in the management of NSCLC?

It is essential to:

Identify advances in the understanding of molecular biology and histologic profiling in the treatment of NSCLC
Summarize clinical data supporting the use of tumor biomarkers as predictors of therapeutic efficacy of targeted agents in NSCLC
Devise an individualized treatment plan for patients with advanced NSCLC based on a tumor’s molecular profile
Identify methods for overcoming barriers to effective incorporation of molecular profiling for the management of NSCLC into clinical practice

Non-small cell lung cancer (NSCLC),the most common type of lung cancer, usually grows and spreads more slowly than small cell lung cancer.

The three common forms of NSCLC are:

Adenocarcinomas are often found in an outer area of the lung.
Squamous cell carcinomas are usually found in the center of the lung next to an air tube (bronchus).
Large cell carcinomas occur in any part of the lung and tend to grow and spread faster than the other two types

Smoking causes most cases of lung cancer. The risk depends on the number of cigarettes you smoke every day and for how long you have smoked. Some people who do not smoke and have never smoked develop lung cancer.

Working with or near the following cancer-causing chemicals or materials can also increase your risk:

Asbestos
Chemicals such as uranium, beryllium, vinyl chloride, nickel chromates, coal products, mustard gas, chloromethyl ethers, gasoline, and diesel exhaust
Certain alloys, paints, pigments, and preservatives
Products using chloride and formaldehyde

Non-small cell lung c

ancer

(NSCLC) accounts for

approximately 85% of all lung cancers.

Lung cancer may produce no symptoms until the disease is well advanced, so early recognition of symptoms may be beneficial to outcome.

At initial diagnosis,

20% of patients have localized disease,
25% of patients have regional metastasis, and
55% of patients have distant spread of disease.

Revisiting Doublet Maintenance Chemo in Advanced NSCLC

H. Jack West, MD

Pemetrexed Versus Pemetrexed and Carboplatin as Second-Line Chemotherapy In Advanced Non-Small-Cell Lung Cancer

Ardizzoni A, Tiseo M, Boni L, et al

J Clin Oncol. 2102;30:4501-4507

Historically, our second-line therapy has evolved into a strategy of pursuing single-agent therapies for patients with advanced non-small cell lung cancer (NSCLC) who have received prior chemotherapy. This approach was developed on the basis of benefits conferred by such established treatments as docetaxel, pemetrexed, and erlotinib — each well-tested as single agents — and evidence indicating a survival benefit in previously treated patients.

A study out of Italy by Ardizzoni and colleagues published in the Journal of Clinical Oncology directly compares carboplatin/pemetrexed with pemetrexed alone, and

it provides more evidence that our current approach of sequential singlet therapy remains appropriate.

This randomized phase 2 trial enrolled 239 patients with advanced NSCLC, initially of any histology, then later amended (September 2008) to enroll

only patients with non-squamous NSCLC because of mounting evidence that pemetrexed is not active in patients with the squamous subtype of advanced NSCLC.

Patients must have received prior chemotherapy (without restriction on regimen except that it could not include pemetrexed). Participants were randomly assigned 1:1 to receive pemetrexed at the standard dose of 500 mg/m2 IV every 21 days or the same chemotherapy with carboplatin at an area under the curve of 5, also IV every 21 days.
The primary endpoint for the trial was progression-free survival (PFS), and the trial was intended to have results pooled with a nearly identically designed trial that was done in The Netherlands. The Dutch trial compared pemetrexed with carboplatin/pemetrexed at the same dose and schedule. The vast majority of patients (97.5%) had a performance status of 0 or 1, and the median age was 64 years.

The Italian study found no evidence to support a benefit in efficacy from the more aggressive doublet regimen. Specifically,

median PFS was 3.6 months with pemetrexed alone vs 3.5 months with carboplatin/pemetrexed.
Response rate (RR) and median overall survival (OS) were also no better with the doublet regimen

Moreover, pooling the data from the Italian trial with the Dutch trial demonstrated no significant differences between the 2 strategies. Subgroup analysis showed that

the patients with squamous NSCLC had a superior median PFS of 3.2 months with the carboplatin doublet vs 2.0 months with pemetrexed alone.

Unfortunately, this only confirms that adding a second agent is beneficial for patients receiving an agent previously shown to be ineffective in that population.

Viewpoint

Putting it in the context of previous data, these results only provide further confirmation that more is not better.

combinations are associated with more toxicity than single-agent therapy, and
this is likely to be especially relevant in previously treated patients whose ability to tolerate ongoing therapy over time may be reduced.

It is critical to balance efficacy with tolerability to enable us to deliver the treatment over a prolonged period. We need to recognize the importance of pacing ourselves if our goal is to administer treatments in a palliative setting for an increasingly longer duration.

http://www.medscape.com/viewarticle/777367

Epidermal growth factor receptor (EGFR) signaling pathway. (Photo credit: Wikipedia)

EGFR structure (Photo credit: Wikipedia)

ATP synthase (Photo credit: Ethan Hein)

Non-small cell carcinoma – FNA (Photo credit: Pulmonary Pathology)

Articles on NSCLC in Pharmaceutical Intelligence:

http://pharmaceuticalintelligence.com/2012/11/08/lung-cancer-nsclc-drug-administration-and-nanotechnology/

http://pharmaceuticalintelligence.com/2012/09/18/personalized-rx-decisions-in-nsclc-treatments-symposium-in-thoracic-oncology/

http://pharmaceuticalintelligence.com/2013/01/23/state-of-the-art-in-oncologic-imaging-of-lungs/

http://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

http://pharmaceuticalintelligence.com/2012/12/19/nanotechnology-detecting-and-treating-metastatic-cancer-in-the-lymph-node/

http://pharmaceuticalintelligence.com/2012/11/06/non-small-cell-lung-cancer-drugs-where-does-the-future-lie/

http://pharmaceuticalintelligence.com/2012/11/02/cancer-innovations-from-across-the-web/

http://pharmaceuticalintelligence.com/2012/10/22/advances-in-separations-technology-for-the-omics-and-clarification-of-therapeutic-targets/

Key Sources:

Realizing the importance of personalized medicine in advanced NSCLC
E Topol, B Buehler, GS Ginsburg.
Medscape Molec Medicine The Potential of Personalized Medicine in Advanced NSCLC

With the data on the prognostic and predictive biomarkers EGFR and ALK, biomarker testing is increasingly important in therapy decisions in NSCLC

http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf/
Revisiting Doublet Maintenance Chemo in Advanced NSCLC
H. Jack West, MD http://www.medscape.com/viewarticle/777367
Pemetrexed Versus Pemetrexed and Carboplatin as Second-Line Chemotherapy In Advanced Non-Small-Cell Lung Cancer
Ardizzoni A, Tiseo M, Boni L, et al
J Clin Oncol. 2102;30:4501-4507
Lung Cancer in the Never Smoker Population: An Expert Interview With Dr. Nasser Hanna
Experts And Viewpoint, Medscape Hematology-Oncology, December 2007
Non-Small Cell Lung Cancer: Biologic and Therapeutic Considerations for Personalized Management
Taofeek K. Owonikoko, MD, PhD August 24, 2011. Medscape
An Update on New and Emerging Therapies for NSCLC
Simon L. Ekman, MD, PhD; Fred R. Hirsch, MD, PhD Medscape
Lovly CM, Carbone DP. Lung cancer in 2010: one size does not fit all. Nat Rev Clin Oncol. 2011;8(2):68-70.
Dacic S. Molecular diagnostics of lung carcinomas. Arch Pathol Lab Med. 2011;135(5):622-629.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359(13):1367-1380.
Gazdar AF. Epidermal growth factor receptor inhibition in lung cancer: the evolving role of individualized therapy.

Cancer Metastasis Rev. 2010;29:37-48.
NCCN Oncology Insights Report on Non-Small Cell Lung Cancer 1.2010
Review of the Treatment of Non-Small Cell Lung Cancer with Gefitinib
T Araki, H Yashima, K Shimizu, T Aomori
Clinical Medicine Insights: Oncology 2012:6 407–421 http://dx.doi.org/10.4137/CMO.S7340

Posted in Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Genetics, Computational Biology/Systems and Bioinformatics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Health Law & Patient Safety, Imaging-based Cancer Patient Management, International Global Work in Pharmaceutical, Molecular Genetics & Pharmaceutical, Nanotechnology for Drug Delivery, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Industry Competitive Intelligence, Pharmacogenomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical | Tagged American Society of Clinical Oncology, AstraZeneca, EGFR, Epidermal growth factor receptor, Gefitinib, KRAS, Lung cancer, National Comprehensive Cancer Network, Non-small-cell lung carcinoma, NSCLC, progression-free survival, The New England Journal of Medicine | 2 Comments

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on May 13, 2013 at 10:23 AM | Reply Late Onset of Alzheimer’s Disease and One-carbon Metabolism | Pharmaceutical Intelligence

I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
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on May 27, 2013 at 9:24 PM | Reply Personalized medicine-based diagnostic test for NSCLC | Pharmaceutical Intelligence

I actually consider this amazing blog , âSAME SCIENTIFIC IMPACT: Scientific Publishing –
Open Journals vs. Subscription-based « Pharmaceutical Intelligenceâ, very compelling plus the blog post ended up being a good read.
Many thanks,Annette

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