IASLC 2011 Report – Defining the unmet needs in non-small cell lung cancer

by Dr Sunil Upadhyay – The way we have defined cancer has not changed over centuries. Most of the lung cancers are associated with smoking. There is plenty of evidence to suggest that lung cancers in never smokers are a distinct pathology in terms of carcinogenesis, clinical characteristics, anatomical distribution, biology and prognosis. With rapid scientific progress and availability of modern technologies, lung cancer from being a single disease has become multiple diseases. Based on the histology, it used to be broadly divided in to two main groups i.e. squamous cell carcinoma and non-squamous cell carcinoma. This was simply brought about by emerging differences in their systemic treatment selection by oncologists. The most commonly used marker for the squamous cell carcinoma is p63 and CK 5/6 although desmocollin-3 (DSC3) is probably the most specific marker. Similarly, TTF-1, CK7 are frequently used for adenocarcinoma though Napsin A and mucin stains are most specific but lack sensitivity. The histo-pathological distinction was essential for judicious use of tissue and chemotherapy regimen selection. However, over the last decade, the canvas has changed. This has been brought forward mainly following the most exciting discovery of molecular profiling of cancer. Who could have predicted that lung cancer would be the front runner in the race for gene profiling and molecular targeted therapy even as late as 15 years ago? Discovery of EGFR mutation led to the development and successful treatment of TKI therapy.

Potential molecular targets

Lung cancer is known to harbour multiple genetic mutations particularly adenocarcinoma like KRAS, EGFR, BRAF, ALK, c-Met, HER2, PI3KCA and many others. Similarly, adenocarcinoma in never smokers, particularly Asian females is more frequently associated with EGFR, EML4-ALK and less frequently with KRAS and c-MET mutation. Though KRAS remains the most difficult mutation to understand, most of the other genes are already being targeted with promising outcome. Many of these agents are already in routine clinical use and others are showing promising results in Phase II and III trials. The role of gefitinib as first-line systemic treatment in exon 19 & 21 EGFR mutation positive tumours was confirmed in the iPASS trial. E4599 trial data showed unprecedented extra overall survival benefit of 3.9 months in bevacizumab treated group (HR=0.69). The latest excitement has been the results of crizotinib, an ALK-MET kinase inhibitor in ALK positive tumours.

Table: Prevalence of genetic mutation

	Squamous cell carcinoma	Adenocarcinoma
KRAS mutation	5%	10-30%
BRAF mutation	3%	2%
EGFR Mutation TK Amplification Mutation variant III	2-5% 30% 5%	10-40% 15% Rare
HER2 Mutation TK Amplification	Rare 2%	2-4% 6%
ALK (fusion)	Rare	7%
MET Mutation Amplification	5% <10%	5% <10%
P53 mutation	60-70%	50-70%
LKB1 mutation	10-20%	3-40%
PIK3CA Mutation Amplification	2% 33%	2% 6%

Jean-Charles Soria WCLC 2011

 

The genetics of squamous cell carcinoma have not remained untouched.  Some of the significant genetic alterations already detected like c-MET, p53 mutation, FGFR1 and DDR2 are potential therapeutic targets. Peter Hammerman presented a detailed genomic analysis of squamous cell carcinoma of lung tumours (n=118) at the Presidential Symposium (PRS.1).  Several other genes likely to be important in the pathogenesis and management of lung cancer are CMYC, PDGFRA, EGFR, HER2, CCNV1 and PTEN. Agents targeting the FGFR, PI3KCA and DDR family are already undergoing clinical testing. The role of thymidylate synthase (TS), ERCC1 and RRM1 for selection of the platinum or non-platinum doublets is getting stronger.

Therefore, clinical and histological characteristics alone should not be used for treatment selection. One must define the tumours based on genetic mutation, deletion, amplification and loss of heterozygosity. This welcoming knowledge has pushed us away from histology to molecular biology and personalised therapy. Unfortunately, this histological and molecular profiling has to be based on small cytology and small biopsy samples. Frequently these small samples contain only a few undifferentiated cells and so tumour subtype prediction becomes difficult. Therefore, EGFR mutation testing in plasma has been attempted and the sensitivity reported has been variable and proper validation of these techniques is essential. We need to know the number, group and “drivers” of genes critical for making the treatment decision. How to account for the differences between prognostic and predictive markers? The precise target for some of the targeted agents like bevacizumab and cetuximab remains hazy. Better understanding is essential to be able to translate these advances from clinical trials into daily practice