DNA repair protein expression in resected NSCLC: a different predictive value for platinum benefit in adenocarcinoma versus squamous-cell carcinoma?

Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) accounting for >80% of all newly diagnosed cases of lung cancer. For patients with early-stage disease, from clinical stage IA through IIB, surgical resection represents the standard of care. However, ∼50% of those patients undergoing surgical resection will relapse and die of recurrent disease within 5 years [1]. In order to improve survival in patients with early-stage NSCLC, efforts have been focused on the use of chemotherapy before or after surgery with the aim of reducing the risk of relapse. In 1995, the meta-analysis carried out by the NonSmall Cell Lung Cancer Collaborative Group was published; this included data from 14 studies (4357 patients and 2574 deaths) that compared surgery alone with surgery followed by adjuvant chemotherapy [2]. Results from eight studies using cisplatin-based combinations (n = 1394) showed an absolute survival benefit of 5% at 5 years with the use of adjuvant chemotherapy, although these findings were not statistically significant (HR = 0.87, P = 0.08). Results from this metaanalysis prompted additional evaluation of platinum-based regimens in resectable NSCLC, resulting in further prospective randomized phase III trials. The major adjuvant studies conducted in this regard were the International Adjuvant Lung Cancer Trial (IALT) [1], the Adjuvant Lung Project Italy (ALPI) [3], the Big Lung Trial (BLT) [4], the National Cancer Institute of Canada Clinical Trials Group (NCIC-BR10) [5] trial, the Adjuvant Navelbine International Trialist Association (ANITA) [6] study, and the Cancer and Leukemia Group B (CALGB 9633) [7] study. Information from these adjuvant studies conducted after 1995 yielded conflicting results regarding the benefit of adjuvant treatment. For that reason, The Lung Adjuvant Cisplatin Evaluation (LACE) pooled individual data of 4854 patients from five randomized adjuvant trials using adjuvant cisplatin combinations, the ALPI, the ANITA, the BLT, the IALT, and the NCIC-BR10 studies [8]. Adjuvant chemotherapy was associated with an improvement in overall survival with an 11% relative reduction in the risk of death (HR = 0.89, CI 0.82–0.96, P = 0.04). However, the degree of benefit varied depending on stage. In stages II and III, overall survival benefit was 5.3% at 5 years (HR = 0.83, CI 0.73–0.95, and HR = 0.83, CI 0.72–0.94, respectively), whereas a small and not statistically significant benefit was observed in stage IB (HR = 0.93, CI 0.78–1.10) and a detrimental effect in stage IA (HR = 1.40, CI 0.95–2.06). At present, the benefit of adjuvant platinum-based chemotherapy is widely accepted for patients with resected stage II–IIIA [8]. Overall, adjuvant chemotherapy in NSCLC improves survival at 5 years between 4% and 15%. However, adjuvant chemotherapy is associated with a potentially significant toxicity and not all patients treated with adjuvant chemotherapy benefit from it. Furthermore, recovery from thoracic surgery may compromise the administration of adjuvant treatment. A real challenge, therefore, is to find a way to identify which patients are most likely to obtain clinical benefit from a given chemotherapy treatment. In surgically resected patients, identifying prognostic factors that help predict patients at risk of recurrence and defining predictive factors for treatment benefit in this group are essential if we are to successfully optimize treatment. To better define those patients that may benefit from adjuvant platinum-based chemotherapy, the study published by Pierceall et al. [9] analyzed prognostic and predictive markers in tumor samples from patients in the IALT study. In this paper, the authors carried out an immunohistochemistry (IHC) evaluation to determine the prognostic and predictive value of levels of seven key proteins involved in DNA damage response and/or DNA repair pathways [ERCC1, XPF, MSH2, BRCA1, p53, PARP1 (PARP, poly(ADP-ribose) polymerase), ATM (ataxia-telangiectasia mutated)] in 769 samples from patients included in the IALT trial. The findings detailed in the present manuscript are clinically relevant; the IALT trial has been the largest randomized trial in the adjuvant setting comparing cisplatin-based chemotherapy with no treatment and it is one of the most relevant studies that led to adjuvant chemotherapy being considered standard of care. Cisplatin is the backbone of chemotherapy regimens used to treat NSCLC. Therefore, to molecularly define those patients with more possibilities to benefit from this drug would be of great relevance. The main cytotoxic activity of cisplatin is based on the formation of mono-/bifunctional adducts in the DNA, which cause inter-/intrastrand cross-linking. Proposed mechanisms of resistance include decreased intracellular accumulation, increased detoxification through its conjugation with glutathione, and increased tolerance to DNA damage resulting from a highly efficient DNA repair capacity. In this line of research, the study published by Pierceall et al. [9] has a clear relevance, in which the authors carried out an IHC evaluation of seven key proteins (ERCC1, XPF, MSH2, BRCA1, p53, PARP1, ATM) involved in DNA damage response and/or DNA repair pathways among 769 samples from patients included in the IALT trial.