Customized chemotherapy in metastatic non-small cell lung cancer (NSCLC)

Abstract

Metastatic non-small cell lung cancer (NSCLC) unfortunately remains a lethal disease, despite recent genetic characterization of subclasses of NSCLC, mainly adenocarcinoma, which has led to the development of targeted therapies that improve progression-free survival (PFS). Ultimately, however, patients fatally relapse. In this review we will focus on the search to improve survival for NSCLC patients deemed to be pan-negative for the common driver alterations susceptible to targeted therapy, above all those with EGFR mutations or ALK, ROS or RET translocations. Other uncommon driver mutations such as HER2 and BRAF mutations should be tested in order to rule out targeted treatment before assigning patients to chemotherapy. Chemotherapy yields short lived response with median survival still less than one year. Customized chemotherapy represents one way to attempt to prolong survival, although to date no prospective randomized customized studies have reported sufficient evidence to support this. In one attempt to demonstrate the role of tailoring chemotherapy, the Spanish Lung Cancer Group (SLCG) phase II customized chemotherapy trial (NCT00883480) showed that RAP80, a component of the BRCA1-A complex, influenced outcome in patients with low BRCA1 expression treated with cisplatin/gemcitabine, and in patients with intermediate/high BRCA1 levels receiving cisplatin/docetaxel or docetaxel alone. We are currently performing a prospective, randomized phase III trial comparing non-customized cisplatin/docetaxel with customized therapy in metastatic NSCLC patients (NCT00617656/GECP-BREC) and a parallel phase II study (ChiCTR-TRC-12001860) is being carried out in China (BREC-China) under the auspices of the SLCG.

Keywords: BRCA1; BRCA1 and RAP80 expression customized (BREC); Non-small cell lung cancer; RAP80; RING finger protein 8 (RNF8); customized chemotherapy.

Figure 1

BREC trial design.

Figure 2

Ubiquitin modification activity of BRCA1 in homologous recombination repair. Reprinted from FEBS Letters 585, Ohta T, Sato K, Wu W. “The BRCA1 ubiquitin ligase and homologous recombination repair”, pg 2836-44, Copyright 2011, with permission from Elsevier.

Figure 3

BRCA1-BRCT interacting complexes in DNA damage response. From Wang et al. “Abraxas and RAP80 form a BRCA1 protein complex required for the DNA damage response”. Science 2007;316:1194, Adapted with permission from AAAS.

Figure 4

The ubiquitin chain, RAD51, BRCA1 and 53BP1 do not assemble at sites of double-strand breaks in RNF8/BRCA1-depleted cells or RNF8/BRCA1/53BP1-depleted cells. Adapted by permission from the American Association for Cancer Research: Nakada S. et al. “RNF8 regulates assembly of RAD51 at DNA double strand breaks in the absence of BRCA1 and 53BP1”, Cancer Research 2012;72:4974-83.