E. Fabre

Different prognostic impact of STK11 mutations in non-squamous non-small-cell lung cancer.

STK11 is commonly mutated in lung cancer. In light of recent experimental data showing that specific STK11 mutants could acquire oncogenic activities due to the synthesis of a short STK11 isoform, we investigated whether this new classification of STK11 mutants could help refine its role as a prognostic marker. We conducted a retrospective high-throughput genotyping study in 567 resected non-squamous non-small-cell lung cancer (NSCLC) patients. STK11 exons 1 or 2 mutations (STK11ex1-2) with potential oncogenic activity were analyzed separately from exons 3 to 9 (STK11ex3-9). STK11ex1-2 and STK11ex3-9 mutations occurred in 5% and 14% of NSCLC. STK11 mutated patients were younger (P = .01) and smokers (P< .0001). STK11 mutations were significantly associated with KRAS and inversely with EGFR mutations. After a median follow-up of 7.2 years (95%CI 6.8-.4), patients with STK11ex1-2 mutation had a median OS of 24 months (95%CI 15-57) as compared to 69 months (95%CI 56-93) for wild-type (log-rank, P = .005) and to 91 months (95%CI 57-unreached) for STK11ex3-9 mutations (P = .003). In multivariate analysis, STK11ex1-2 mutations remained associated with a poor prognosis (P = .002). Results were validated in two public datasets. Western blots showed that STK11ex1-2 mutatedtumors expressed short STK11 isoforms. Finally using mRNAseq data from the TCGA cohort, we showed that a stroma-derived poor prognosis signature was enriched in STK11ex1-2 mutated tumors. All together our results show that STK11ex1-2 mutations delineate an aggressive subtype of lung cancer for which a targeted treatment through STK11 inhibition might offer new opportunities.

Composite biomarkers defined by multiparametric immunofluorescence analysis identify ALK-positive adenocarcinoma as a potential target for immunotherapy

ABSTRACT Anaplastic lymphoma kinase (ALK) inhibitors have been successfully developed for non-small cell lung carcinoma (NSCLC) displaying chromosomal rearrangements of the ALK gene, but unfortunately resistance invariably occurs. Blockade of the PD-1-PD-L1/2 inhibitory pathway constitutes a breakthrough for the treatment of NSCLC. Some predictive biomarkers of clinical response to this therapy are starting to emerge, such as PD-L1 expression by tumor/stromal cells and infiltration by CD8+ T cells expressing PD-1. To more effectively integrate all of these potential biomarkers of clinical response to immunotherapy, we have developed a multiparametric immunofluorescence technique with automated immune cell counting to comprehensively analyze the tumor microenvironment of ALK-positive adenocarcinoma (ADC). When analyzed as either a continuous or a dichotomous variable, the mean number of tumor cells expressing PD-L1 (p = 0.012) and the percentage of tumor cells expressing PD-L1 were higher in ALK-positive ADC than in EGFR-mutated ADC or WT (non-EGFR-mutated and non-KRAS-mutated) NSCLC. A very strong correlation between PD-L1 expression on tumor cells and intratumoral infiltration by CD8+ T cells was observed, suggesting that an adaptive mechanism may partly regulate this expression. A higher frequency of tumors combining positive PD-L1 expression and infiltration by intratumoral CD8+ T cells or PD-1+CD8+ T cells was also observed in ALK-positive lung cancer patients compared with EGFR-mutated (p = 0.03) or WT patients (p = 0.012). These results strongly suggest that a subgroup of ALK-positive lung cancer patients may constitute good candidates for anti-PD-1/-PD-L1 therapies.

Facteurs pronostiques cliniques et paracliniques dans la chirurgie du cancer du poumon non à petites cellules

INTRODUCTION Lung cancer prognosis is mainly based on the TNM, histology and molecular biology. Our aim was to analyze the prognostic value of certain clinical and paraclinical variables. PATIENTS AND METHODS We studied among 6105 patients operated on, divided during 3 time-periods (1979 to 2010), the following prognostic factors: type of surgery, pTNM, histology, age, sex, smoking history, clinical presentation, and paraclinical variables. RESULTS Postoperative mortality was 4% (243/6105), rate of complications was 23.3% (1424/6105). The 5-year overall survival was 43.2% and 10-year was 27%. Best survival was observed after complete resection (R0) (P<10(-6)), lobectomy (P<10(-6)), lymph node dissection (P=0.0006), early pTNM stages (P<10(-6)), absence of a solid component in adenocarcinoma. Other pejorative factors were: male gender (P=10(-5)), age (P=0.0000002), comorbidity (P=0.016), history of cancer (P<10(-5)), postoperative complications (P=0.0018), FEV lower than 80% (P=0.0000025), time-periods (P<10(-6)). All these factors were confirmed by multivariate analysis, except gender. Smoking was not poor prognostic factor in univariate analysis (P=0.09) but became significant in the multivariate one (P=0.013). CONCLUSION Medical and human factors, and the general physiological state, play an important role in prognosis after surgery. We do not know their exact meaning and, like studies on chemotherapy, they justify special research.

Intérêt de la chirurgie dans le cancer bronchique à petites cellules

Surgery is the most effective treatment of lung cancer provided that there is complete resection. Even though the results in the early stages of small cell lung cancers (SCLC) are encouraging, many oncologists still consider SCLC a contra-indication. The authors report their experience. They retrospectively reviewed the clinical and pathological characteristics and long-term results of 104 patients (mean age: 58.6, male: N=82 and female: N=22) who underwent lung resection with mediastinal lymphadenectomy (lobectomy: N=51 and pneumonectomy: N=53) for small cell lung cancer between 1984 and 2006. The diagnosis was established before the operation in 49 patients (47.1%) of whom 61.2% (N=30) received neoadjuvant therapy. The survival (5-year survival rate 21.7%, median=18 months), postoperative mortality (deaths: N=6) included, depended on the stage: stage I: N=39, 5-year, 34.3%, median=29; stage II: N=23, 5-year, 26.1%, median=12; stage III: N=37, 5-year, 2.7%, median=12 (p=0.000067). There were no 5-year survivors among the N2 patients. The survival did not depend on the diagnostic aspect of the resection, the non-small cell lung cancer histological patterns or perioperative neoadjuvant and adjuvant therapy. The pneumonectomies were more frequent in case of neoadjuvant treatment (23/30 versus 30/47, p=0.00084). The results and the review of the literature indicate that surgery for small cell lung cancer may provide a cure in stages I and II and should not to be ruled out. The only contra-indication is proven pN2. A multicentre, randomised study on surgery versus medical treatment in the early stages should confirm this conclusion.

Tim-3 - Biomarqueur et cible thérapeutique en cancérologie

T cells harboring multiple co-inhibitory molecules lose their anti-tumoral functionality. PD-1 is a clinically approved target in cancer therapy, but its expression alone does not mean dysfunctionality. The expression of Tim-3 on numerous cell types (T cell, Treg, dendritic cell, myeloid cells) favors tumor escape to immune cells. Within many tumors, PD-1/Tim-3 coexpressing CD8-T cells lose their ability to secrete cytokines (IFNγ, IL-2, TNFα) and their intratumoral infiltration correlates with a bad prognosis. Tim-3 recently appeared as a potential biomarker of anti-PD-1 resistance. Combined blockade of PD-1 and Tim-3 axis demonstrated potent clinical efficacy in preclinical models and reinforced the rationale of using an anti-Tim-3 to override tumor resistance.

Chirurgie du cancer bronchique sur poumon unique

INTRODUCTION The diagnosis of a second lung cancer in a patient with a previous medical history of lung cancer is no longer a rarity. Also, it is possible to observe a new location in a patient who underwent pneumonectomy in the past. Surgery remains the best treatment. Our objective was to overview this subject. PATIENTS AND METHODS Among 5611 patients operated in our institution, 186 (3.3%) had metachronous cancer and 17 had previous pneumonectomy (0.7% of pneumonectomies and 0.2% of NSCLC treated in our department). The procedure was diagnostic and therapeutic in 88% of cases (n=15). RESULTS There were 16 males and 1 female, mean age was 62.5-years. All were smokers (11 were former smokers) and 6 had other medical history. Mean FEV was 52% (range 35-95%). Types of resection were 2 lobectomies, 4 segmentectomies, and 11 wedge resections. There were no postoperative deaths, but two complications. Histological subtype of the first and second cancer was the same in 11 patients. All patients were pN0 after second surgery. The long-term survival (median 33 months) was 35.3% at 5-years and 14.1% at 10-years. Two patients treated with pneumonectomy for their first cancer were pN2. Patients who underwent upper right lobectomy for treatment of their second cancer survived longer than 5-years. CONCLUSION Surgical resection for lung cancer on single-lung is associated with acceptable morbidity and mortality. Prolonged survival can be achieved in selected patients.

Cancer épidermoïde de la trachée : imagerie de l’atteinte ganglionnaire

The anatomy of the trachea lymphatics is poorly understood and the only researches date back to more than one century. Tracheal tumors are very rare, miscellaneous and variously lymphophilic. The cancers of the trachea have no TNM and their lymph node metastases are little studied despite their poor prognosis. We observed 2 cases of squamous cell carcinoma, one in the cervical and the other in the intrathoracic trachea. TDM-3D reformats demonstrated metastatic lymph nodes of the right para-tracheal lymph node chain (2R and 4R) in both patients and in the cervical lymph nodes (right recurrent nerve lymph node chain) in the patient with cervical tumor. Right location of the mediastinal metastases may be explained by the anatomy of the lymph node chain drainage of the lung segments, the right para-tracheal chain being the only one to regularly possess lymph nodes at that level. The right recurrent nerve lymph node metastases of the cervical tumor are explained by common lymph drainage of the cervical trachea towards larynx lymph centres. Besides lymph node metastases, cancers prognosis may also depends on its location in the trachea. Thus, the tracheal tumors are complex and constitute quite as many orphan tumors. Multicentric studies are mandatory to better understand their behavior. Means provided by new imaging techniques might permit establishing a veritable TNM lymph node mapping of these tumors.