Personalizing medicine – strategies for implementing the evaluation of ALK rearrangement in non-small-cell lung cancer in Portugal
Personalizando a medicina – estratégias para implementar a avaliação do rearranjo do ALK no carcinoma do pulmão de não pequenas células em Portugal
A. Araújoa,??, , A. Coelhob, R. de Melloa, I. Azevedoa, M. Soaresa, H. Queirogac, E. Teixeirad, B. Parentee, F. Barataf
a Serviço de Oncologia Médica, Instituto Português de Oncologia Francisco Gentil, Centro do Porto, Porto, Portugal
b Unidade de Oncologia Molecular, Instituto Português de Oncologia Francisco Gentil, Centro do Porto, Porto, Portugal
c Serviço de Pneumologia, Hospital de S. João, Porto, Portugal
d Serviço de Pneumologia, Centro Hospitalar de Lisboa Norte, Lisboa, Portugal
e Serviço de Pneumologia, Centro Hospitalar de Vila Nova de Gaia / Espinho, Vila Nova de Gaia, Portugal
f Serviço de Pneumologia, Centro Hospitalar de Coimbra, Coimbra, Portugal
Recebido 29 Dezembro 2011, Aceitaram 05 Abril 2012

In 2008, in Portugal there were about 3300 new cases of lung cancer and almost the same number of deaths for this pathology.1

Improvement in NSCLC survival has been modest in the past 2 decades. From the early 1990s, there have been changes in the treatment of advanced NSCLC, including the introduction of new chemotherapy (CT) agents and regimens,2 increasing use of salvage CT,3,4 and the development of molecularly targeted therapies, specially the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).5 Tailoring treatment for every NSCLC patient has become the goal in terms of balancing clinical benefit against toxicity ratio.

We are still a long way from understanding the puzzle of genetic driver alterations in NSCLC. There are questions about the molecular characterization of lung cancer leading to the identification of different molecular alterations, such as EGFR mutations or anaplastic lymphoma kinase (ALK) translocations, and to subsets of lung cancer disease with a distinct natural history and response to treatment, together with the growing number of treatment options. How can we match the right patient population to the best treatment option? How much is society able to pay for the implementation of methods for molecular characterization of lung cancer disease? How can we improve the cost-effectiveness of these methods? Is society able to shoulder the burden of these new molecular diagnostic methods and new therapeutic drugs, even if they are at some level cost-effective? Will there ever be sufficient evidence to meet the challenge of cost containment?

Testing patients with advanced or metastatic NSCLC for EGFR mutation status may help doctors to determine those who are most likely to respond to EGFR TK inhibitors, tailoring therapy at diagnosis. In Portugal, we conducted a retrospective analysis of three major centers of the north of the country (Centro Hospitalar de V. N. Gaia, Instituto Português de Oncologia – Centro do Porto, Hospital de S. João), from July 2006 to January 2011 [personal data]. We studied 621 patients, with a mean age of 65 years (20–89 years-old), 30% of whom were female. The tumours were 64% adenocarcinoma and 21% squamous cell carcinoma. In the NSCLC population there was an EGFR mutation in 14.3% (17.5% with adenocarcinoma and 9.5% with squamous cell carcinoma), of which there was 6.3% in exon 19 (43.8% of mutated patients, mp), 5.3% in exon 21 (37.1% of mp), 1.7% in exon 20 (12.4% of mp) and 1.0% in exon 18 (6.7% of mp).

The work began 5 years ago in two major centers with the selection of some patients based on clinical characteristics. After perceived the notion of the role of the EGFR TK inhibitors in first-line treatment for advanced or metastatic NSCLC, these centers and a posteriori the third one began the analysis of all possible newly diagnosed patients. Meanwhile, there were discussions in national scientific forums, involving key opinion leaders and some cooperative groups such as the Portuguese Lung Cancer Study Group, about the need for EGFR mutation analysis. These meetings played a vital role in making everyone think about the following: how much lung cancer tissue is needed, how to optimize the circuit from harvesting of tissue to mutation analysis, how long should (could) we wait from harvest to analysis, what pathologists and geneticists need to give to those who treat patients.

ALK rearrangement (ALK+) was identified in NSCLC as an inversion in chromosome 2p with or without interstitial deletion, inv(2)(p21p23), resulting in the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion product.6 This fusion oncogene, which represents one of the newest molecular targets in NSCLC, has a role as the key driver of lung tumorigenesis in a subset of patients6,7 and can be effectively blocked by small-molecule inhibitors that target ALK. EML4-ALK is uncommon, occurring in 2–7% of all NSCLC.8,9 It is more prevalent in patients who have never smoked or who have a history of light smoking and in patients with adenocarcinomas.7,10,11 In the selected populations, the prevalence could be about 20–30% of patients with EML4-ALK mutations.12 Nevertheless, sex, age and smoking status were not solid variables related with ALK-rearranged NSCLC.13

At present there is no standard method for detecting EML4-ALK mutations and various molecular techniques can be used. Fluorescent in situ hybridization (FISH) is the most common method currently used and also for enrolment in a clinical trial, although it is expensive and not routinely available. The standardization of all preanalytical variables, including tissue handling, fixation and processing, and the choice of anti-ALK antibodies are essential when using FISH.14

Crizotinib (PF-02341066, Pfizer) is an oral ATP competitive selective inhibitor of the ALK and MET TKs inhibiting tyrosine phosphorylation of activated ALK at nanomolar concentrations.15,16 The first phase I trial published, evaluated 82 patients with ALK-rearranged advanced NSCLC who had received multiple previous therapies.8 At a mean treatment duration of 6.4 months, the overall response rate was an impressive 57% with a rate of stable disease of 33%. The estimated probability of 6-month progression-free survival was 72%, with no median for the study reach. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects.

In an unselected NSCLC population, only around 4% have ALK rearrangements, and this small proportion of ALK+ lung cancer patients is a major limitation for access to the related drug, crizotinib. How we can identify this group of patients and which ALK testing method should be employed is a major issue for discussion and research.

It is possible to define three groups of tumors which do not harbor ALK rearrangements at all and could be excluded from ALK screening: those tumors with activating EGFR mutations, those in patients that showed an objective response to previous EGFR TK inhibitors treatments, and eventually tumors without TTF-1 expression.17 But this strategy will only select patients after knowing the result of the EGFR mutation test or the evaluation of a response to the EGFR TK inhibitors, in this way losing at least 5–7 working days (for the first hypothesis) or 1–3 months (for the second group). In relation to TTF-1 expression, this marker is only negative in a minority of cases, and so its relevance to selection of ALK+ patients is marginal.

For Portugal, the initial step will be to involve some of the major centers, for instance in a selected population (stage IV adenocarcinoma NSCLC who never smoked or were light smokers). The goals will be to evaluate and optimize the circuits needed from harvest to the implementation of the test and how the clinicians obtain the result. At the same time, some national meetings will be necessary to discuss the importance of ALK, the test of its mutation and the value of crizotinib for ALK+ patients. After these initial stages, probably two or three major centers will decide to do the ALK mutation test on all new NSCLC patients, to learn more about the real incidence of the ALK mutation in the Portuguese NSCLC population. These phases will also allow us to request crizotinib for patients with ALK+ and so acquire experience with this drug.

At the end of the day, every clinician who treats NSCLC will need to characterize the tumor histologically and, particularly at the level of some molecular targets. These characteristics will influence the choice of the drugs, taking into account the drug related adverse events and of course survival rates. This is personalizing medicine.

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Please cite this article as: Personalizando a medicina – estratégias para implementar a avaliação do re-arranjo do ALK no carcinoma do pulmão de não pequenas células em Portugal. Rev Port Pneumol. 2012.

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