Prognostic value of LIPC in non-small cell lung carcinoma.

Lung carcinoma is the primary cause of death by cancer. In the last decades, together with improvements in anesthetic and surgical techniques, several new drugs for chemotherapy or biotherapy have been made available. Thus, while metastatic patients are treated by chemotherapy and/or biologically targeted therapies, in initial stages of disease (I−II), surgery remains the cornerstone of treatment. Locally advanced disease is generally treated in the setting of multimodal combinations, including chemotherapy, radiotherapy and surgery, whose respective indications have been refined in the last years. However, these developments provided only limited increase in survival, and a large room for improvement persists.

If clinical stage of non-small cell lung cancer (NSCLC) is the major determinant of treatment strategy, pathologic stage is currently considered the most important determinant of prognosis in resected patients and is the most important parameter determining the choice of adjuvant treatments. However, within the same stage of disease, large prognostic variability obviously exists and sensitivity to adjuvant treatments is heterogeneous. Furthermore, at present there is no consensus regarding the usefulness of post-operative follow-up. Repeated chest X-ray, CT scan, fiberoptic bronchoscopy or PET scans have been proposed, with enormous variations in medical resource utilization and costs. The identification of patients with poor prognosis within a determined stage would be useful for individual tailoring follow-up procedures.

The identification of prognostic factors is of major importance to develop adequate management strategies. For instance, subgroups of patients who benefit more from peri-operative chemotherapy still need to be identified more precisely, to define those for whom the benefit/risk ratio of neo-adjuvant or adjuvant treatments is the most favorable. This issue is of particular importance in early stages, especially stage IB, in which no strict guidelines are available and which represent the majority of stage I-II resected lung cancer. Several prognostic markers have been proposed in the last years, including characteristics of tumoral immune microenvironment, growth factors and their receptors, markers of systemic inflammation, peptides/proteins/enzymes produced by tumor cells with impact on cell cycle, metabolism and sensitivity to chemotherapy, suggesting the paramount importance of this topic.-

The study by Galluzzi et al. reports evidence that intratumoral levels of hepatic lipase LIPC, as assessed by immunohistochemistry, positively correlate with disease outcome in two independent series of non-metastatic NSCLC patients treated by surgery, possibly in a multimodality setting. Furthermore, the authors found that in one of two series, patients with tumors expressing low levels of LIPC had better survival when receiving adjuvant cis-platinum-based chemotherapy, whereas patients with tumors expressing high levels of LIPC had survival unaffected by post-operative chemotherapy. Although validation by specifically designed prospective clinical trials is mandatory to draw definitive conclusion on possible clinical applications, LIPC seems an extremely interesting marker in resected NSCLC from both a prognostic and a predictive point of view.

The same team previously identified LIPC as a cisplatinum response modifier by a genome-wide siRNA-based screen in human NSCLC A549 cells. Together with LIPC, 84 other functional cisplatinum response modifiers were identified, including several proteins known to regulate platinum-induced cell death (e.g., the pro-apoptotic cytoplasmic adaptor APAF-1 and the anti-apoptotic Bcl-2 family member BCL-XL) as well as factors with no obvious links with platinum-elicited signaling pathways, including another enzyme (pyrixodal kynase) and the hepatic lipase LIPC. Thus the mechanisms responsible for the impact of LIPC on the effect of platinum-based chemotherapy remain to be elucidated.

Although discovered as a platinum-response modifier with possible impact on survival in patients receiving platinum-based chemotherapy, LIPC was shown to have a strong prognostic impact also in patients who did not undergo chemotherapy. Thus, the mechanisms explaining the impact on prognosis of LIPC are even more obscure and probably intriguing. Response to therapy and survival in cancer patients probably depends not only on the ability of treatments in removing or killing proliferating tumor cells, but on a complex interaction between disease, treatments and respective impacts on host reaction, whose determinants are not completely elucidated. Identification of mechanisms responsible for LIPC impact on response to chemotherapy as well as on survival in chemotherapy naïve patients could provide interesting insights in the general knowledge of mechanisms of survival in cancer patients.