Meeting Report: AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer

Lung cancer is the most common cause of cancer-related death, accounting for one-third of all cancer deaths.  Lung cancer is also the second most common cancer in men (after prostate cancer) and women (after breast cancer).  Over 200,000 people are diagnosed with and about 150,000 people die from lung cancer every year in the United States [a, b].  While surgery, chemotherapy and radiotherapy are routine treatment choices, in the recent years, patients have benefited from the introduction of targeted therapies based on the discovery of mutations in the EGFR and KRAS genes, and EML/ALK translocations.   EGFR mutations are more commonly found in non-small cell lung cancer (NSCLC) tumors in Asian population (30-40%) than Caucasians (10-15%).   About 4% of the patients carry EML/ALK translocation.


The ongoing 2012 AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy and Personalized Medicine in San Diego highlights some of the recent advances in lung cancer biology, diagnosis and treatment (see below)

Available targeted therapies for lung cancer include,

• Bevacizumab (Avastin; Genentech/Roche) which is used in combination with chemotherapy for NSCLC [cancer.gov]
• Crizotinib (Xalkori; Pfizer) for NSCLC with EML/ALK traslocations (ALK gene over-expression)
• Erlotinib (Tarceva; Genentech/Roche and OSI Pharma.) for advanced or recurrent NSCLC with EGFR over-expression
• Gefitinib (Iressa; AstraZeneca and Teva) as first-line therapy for advanced NSCLC with EGFR mutations [cancer.gov]  

Since Crizotinib benefits only a small percent of lung cancer patients and tumors in others can develop resistance to EGFR block, additional targets and drugs are needed for durable personalized medicine approach to lung cancer.

Highlights from the AACR-IASLC joint conference on lung cancer

The second AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer: Biology, Therapy and Personalized Medicine is being held this week (Jan. 8-11, 2012) at the San Diego Marriott Marina & Hotel, Calif.  Some of the presentations/posters that are of interest to lung cancer drug development and care are summarized below.  Most of this information is compiled from AACR press releases, AACR blog or News outlets, as well as the press conference this afternoon.

"Conference leaders have [...] designated the following research as newsworthy:"

1. Estrogen-Targeting Drug Combo May Help Prevent Lung Cancer.
2. Researchers Map Potential Genetic Origins, Pathways of Lung Cancer in Never-Smokers
3. Ganetespib Showed Activity in KRAS-Mutant NSCLC as Monotherapy and in Combinations
4. Precancer Markers Identified in Airway Epithelium Cells of Healthy Smokers
5. Sorafenib Effective in Patients With Non-Small Cell Lung Cancer, but Low Survival Rates Reported
6. Sensitive Detection Method Analyzes Circulating Tumor Cells in Patients With Lung Cancer
7. Genetic Composition of Multicentric Lung Tumors Appears to be Similar

* Treatments and trials

1. Aromatase inhibitor and antiestrogen combination  (preclinical data)


Jill Siegfried and her colleagues at the University of Pittsburgh Cancer Institute presented data suggesting that combination of aromatase inhibitor anastrozole and antiestrogen fulvestrant prevents development of tumors in a tobacco-carcinogen-induced lung cancer as well as decreases pre-existing tumors in a preclinical model.[aacr]  Seigfried's group exposed two groups of mice with tobacco carcinogens to induce lung cancer--one group was treated with drugs during carcinogen exposure (prevention trial) while the other group was exposed after small tumors had formed (treatment trial.)


Most tobacco-induced lung cancers are estrogen receptor (ER)-positive and express estrogen-producing enzyme aromatase.  Therefore,  aromatase inhibitor and antiestrogen combination could be a good option for some NSCLC patients.

2. Sorafenib (Nexavar; Bayer and Onyx Pharmaceuticals) for non-small cell lung cancer patients



Wouter W. Mellema, M.D., from the VU University Medical Center in Amsterdam presented data from an ongoing sorafenib phase II trial in patients (n=57) with KRAS mutation-positive NSCLC who were treated with 400 mg of sorafenib twice daily.  Sorafenib decreased the progression rate in half, but the median PFS (survival rate) was modest.   

"At six weeks, Mellema and colleagues reported a rate of no progression of 52.6 percent. Fifteen patients stopped treatment before six weeks — 10 of whom stopped due to clinical progression. Median progression-free survival was 2.3 months, and median overall survival was 5.3 months. The researchers reported that 14 patients are still alive." [aacr]

Poster: A phase II study of sorafenib in patients with stage IV non-small cell lung cancer (NSCLC) with a K-Ras mutation. Anne-Marie C. Dingemans, Wouter W. Mellema, Harry J.M. Groen, Atie van Wijk, Sjaak Burgers, Peter W.A. Kunst5, Frederik B. Thunnissen, Daniëlle A.M. Heideman, Egbert F. Smit. Maastricht University Medical Center, Maastricht, The Netherlands, VU University Medical Center, Amsterdam, The Netherlands, University Medical Center Groningen, Groningen, The Netherlands, Netherlands Cancer Institute, Amsterdam, The Netherlands, 5Academic Medical Center, Amsterdam, The Netherlands.

* Diagnostic biomarkers and tools

1. Cancer genomes of never-smokers

Scientists from the Translational Genomics Research Institute (TGen) in Phoenix, Ariz., discovered that lung adenocarcinoma cancers from never-smokers do not carry common genetic signatures, such as, EGFR and KRAS mutations and EML-ALK gene fusions.  Currently never-smokers account for nearly 10% of all lung cancer patients.  Never-smoker is someone who has smoked less than 100 cigarettes in his/her lifetime.  TGen results are based on a very small dataset (n=3) and thus, conclusions should be considered very preliminary.  The researchers used whole genome sequencing (WGS) and whole transcriptome sequencing (WTS), and compared genomes of one never-smoker female patient with early-stage disease and one one never-smoker female patient with late-stage disease with one smoker female with early-stage disease. [aacr, tgen]

2.  Multicentric tumors have same genetic makeup


Do multiple tumors occurring simultaneously in the lung of a lung-cancer patient have same molecular diver(s) or do they originate independently?  This is an important question because, if they have same mutations, one targeted drug may be effective, but if they are different, then one drug will not get rid of all the nodules.

Kenji Sugio, M.D., and colleagues from the National Kyushu Cancer Center in Fukuoka, Japan, compared the presence of common biomarkers, EGFR, KRAS and EML4-ALK, in multiple tumors (or nodules) in the lung of an adenocarcinoma patient.  They found that these multicentric tumors, in fact, have same genetic change.  This suggests that, host lung environment (patient's genetic makeup) determines the effect of potential environmental carcinogens.[aacr]  This finding also suggest that EGFR, KRAS and EML4-ALK profile can help molecularly define subsets of lung adenocarcinoma.  Clinically, this simplifies the treatment decisions and choice of targeted drugs.


3. CT scan diagnostics have serious issues


(see below under "press conference.")

4. Genetic profiling of circulating tumor cells (diagnostic tool)

Heidi S. Erickson's group at the MD Anderson Cancer Center has developed a method to interrogate 13 genes and 135 commonly found lung cancer mutations in the DNA isolated from NSCLC circulating tumor cell (CTCs) specimens.Erickson H. Abstract #A12. [hemonctoday.com]  The non-invasive nature of this method requiring simple blood collection is a big advantage over other methods, such as biopsy (which is invasive) or spiral CT scan (which is prone to false negatives.)

5. Breath test for lung cancer diagnosis (biomarkers and diagnostic tool)

Investigators from the Sheba Medical Center, Tel Aviv, Israel, showed that exhaled volatile organic compounds (VOCs) profiling can help distinguish benign from malignant and small cell from non-small cell lung cancer by 80-90% accuracy.  Nir Peled, M.D., of Sheba Medical Center presenting at the meeting showed that the levels of  decanal (P=0.0011), octene (P<0.0001), ethylbenzene (P=0.046) and benzene 1-ethyl[3-methyl] (P=0.0512) were different in the breath samples of malignant and benign nodules containing patients. [read more at medpage.com]

Also, heard at the media event at the conference 

Press conference event entitled “Lung Cancer Diagnosis: Pitfalls, Challenges and the Path Ahead,” was held in the Atlanta/Chicago room of the San Diego Marriott Marquis & Marina on Tuesday, Jan. 10 at 1:00 p.m. PST.  

Moderators:  Roy Herbst, M.D., Ph.D., chief of medical oncology and associate director for translational research at the Yale Cancer Center; David P. Carbone, M.D., Ph.D., Harold L. Moses chair in cancer research, director of the Specialized Program of Research Excellence in Lung Cancer and co-leader of the Thoracic/Head and Neck Research Program at the Vanderbilt-Ingram Cancer Center; and Paul A. Bunn, M.D., professor and James Dudley chair in cancer research at the University of Colorado School of Medicine.

Statistics, Epidemiology

• Lung cancer is #1 cause of death in US, but is not #1 diagnosed cancer.  Because, of relatively poor screening effort compared to prostate or breast cancers.  
• Lung cancer is no longer a disease of smokers only.  More than 80% of patients are/were smokers, but a new type of lung cancer in people who have never smoked is increasing--biology is not well understood. 
• Asian smokers have lower risk of lung cancer compared to North  American smokers.  On the other hand, Asian non-smokers have higher risk compared to the North American non-smokers.  Are there environmental factors involved or genetics is the answer: GWAS studies are being done in Japan to study this dichotomy.
• 15% survival rate for lung cancer patients has not improved over the years.  Although targeted interventions have started to make a difference.
• Smoking among people decreased awhile ago to 20% but is no longer dropping.  This is #1 public health issue.

The risk of over-diagnosis using Spiral CT scan; other diagnostic tests

• Dr. Paul Bunn said that Spiral CT-scans are much safer diagnostic tools but there are major issues:  Using this technique, nodules are discovered in almost a quarter of patients; however, 96% of them are benign.  There are risks associated with "unnecessary surgery," and expense.  We need other complementary diagnostic tests!  
• He mentioned three new developments (posters) from the meeting:  Scientists from the Vanderbilt University are working on an immunostaining assay to assess mutagenic proteins in the nodule; Erickson's group at MD Anderson Cancer Center is studying CTCs as diagnostic tool (see above); and, there was a poster on analysis of breath samples for volatile organic compounds.  Interestingly, the scientists were able to subtype and stage lung cancers by volatile organic compounds' profiling.  
• The non-invasive and cost-effective blood and breath-based analytical tools could complement spiral CT scan, and help in decisions around benign vs malignant disease.

Guidelines for CT scan and if they are likely to change

• There are no new guidelines yet.  New recommendations will come out after European NELSON trial and other ongoing trials in US.  In the United States, NCCN has published guidelines which recommend annual spiral CT scan for smokers who smoke 20 or more packs and are between ages 55-74 years.

Former smokers and risk of lung cancer

• How can people who stopped smoking, have pre-cancerous lesions in lungs, can decrease the risk of full-blown disease.  This areas of research is called chemoprevention.  Paul Bunn mentioned that, yes, it is possible to improve bronchial histology and decrease lung cancer risk in such patients.  Besides lifestyle changes, some common drugs can help reduce atypical cells in the bronchus.
• A quick search of literature points to other common drugs, such as, Cele­brex or Cele­coxib [here].

***

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The Four Percent Lung Cancer Solution. June 8, 2011.
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Updated: January 10, 2012. 10:12 PM PST.