Joseph Seitlinger

Specific KRAS amino acid substitutions and EGFR mutations predict site-specific recurrence and metastasis following non-small-cell lung cancer surgery

Background:We aimed to evaluate whether EGFR mutations (mEGFR) and KRAS amino acid substitutions can predict first site of recurrence or metastasis after non-small-cell lung cancer (NSCLC) surgery.Methods:Data were reviewed from 481 patients who underwent thoracic surgery for NSCLC between 2007 and 2012.Results:Patients with KRAS G12C developed significantly more bone metastases compared with the remainder of the cohort (59% vs 16%, P<0.0001). This was confirmed in multivariate analysis (MA) (odds ratio (OR): 0.113 (95% confidence interval (CI): 0.055–0.231), P<0.0001). Significantly, more patients with mEGFR developed liver and brain metastases compared with the remainder of the cohort (30% vs 10%, P=0.006; 59% vs 1%, P<0.0001, respectively). These were confirmed in MA (OR: 0.333 (95% CI: 0.095–0.998), P=0.05; OR: 0.032 (95% CI: 0.008–0.135), P<0.0001, respectively). Patients with KRAS G12V developed significantly more pleuro-pericardial metastases compared with the remainder of the cohort (94% vs 12%, P<0.0001). This was confirmed in MA (OR: 0.007 (95% CI: 0.001–0.031), P<0.0001). Wild-type patients developed significantly more lung metastases (35% vs 10%, P<0.0001). This was confirmed in MA (OR: 0.383 (95% CI: 0.193–0.762), P=0.006).Conclusion:Epidermal growth factor receptor mutation and KRAS amino acid substitutions seem to predict site-specific recurrence and metastasis after NSCLC surgery.

KRAS exon 2 codon 13 mutation is associated with a better prognosis than codon 12 mutation following lung metastasectomy in colorectal cancer

Introduction The utilization of molecular markers as routinely used biomarkers is steadily increasing. We aimed to evaluate the potential different prognostic values of KRAS exon 2 codons 12 and 13 after lung metastasectomy in colorectal cancer (CRC). Results KRAS codon 12 mutations were observed in 116 patients (77%), whereas codon 13 mutations were observed in 34 patients (23%). KRAS codon 13 mutations were associated with both longer time to pulmonary recurrence (TTPR) (median TTPR: 78 months (95% CI: 50.61–82.56) vs 56 months (95% CI: 68.71–127.51), P = 0.008) and improved overall survival (OS) (median OS: 82 months vs 54 months (95% CI: 48.93–59.07), P = 0.009). Multivariate analysis confirmed that codon 13 mutations were associated with better outcomes (TTPR: HR: 0.40 (95% CI: 0.17–0.93), P = 0.033); OS: HR: 0.39 (95% CI: 0.14–1.07), P = 0.07). Otherwise, no significant difference in OS (P = 0.78) or TTPR (P = 0.72) based on the type of amino-acid substitutions was observed among KRAS codon 12 mutations. Materials and Methods We retrospectively reviewed data from 525 patients who underwent a lung metastasectomy for CRC in two departments of thoracic surgery from 1998 to 2015 and focused on 150 patients that had KRAS exon 2 codon 12/13 mutations. Conclusions KRAS exon 2 codon 13 mutations, compared to codon 12 mutations, seem to be associated with better outcomes following lung metastasectomy in CRC. Prospective multicenter studies are necessary to fully understand the prognostic value of KRAS mutations in the lung metastases of CRC.

Perioperative bevacizumab improves survival following lung metastasectomy for colorectal cancer in patients harbouring v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue exon 2 codon 12 mutations†

OBJECTIVES The role of perioperative chemotherapy (POC) and targeted therapies in lung metastasectomy for colorectal cancer (CRC) is still subject to debate. We aimed to evaluate whether POC and targeted therapies were associated with different outcomes according to the mutational status. METHODS We reviewed data from 223 patients who underwent pulmonary metastasectomy for CRC from 1998 to 2015 and for whom the V-Ki-ras2 Kirsten sarcoma viral oncogene homologue (KRAS) and V-raf Murine sarcoma viral oncogene homologue B1 (BRAF) mutational statuses were known. RESULTS A total of 167 patients (74%) underwent POC: 62 (37%) received neoadjuvant therapy, 59 (35%) were in the adjuvant setting and 46 (28%) were in both the neoadjuvant and adjuvant settings. POC did not significantly influence either the loco-regional recurrence free survival (LRRFS) (P = 0.21) or the overall survival (OS) (P = 0.29). Furthermore, in cases of adjuvant chemotherapy, outcomes were not significantly different in cases of neoadjuvant chemotherapy or both neoadjuvant and adjuvant treatment (P = 0.26 for OS, P = 0.14 for LRRFS). For patients with KRAS mutation, perioperative bevacizumab was associated with a significant improvement in both LRRFS [70 months (41.58–98.42) vs 24 months (1.15–46.86), P = 0.001] and OS [101 vs 55 months (49.77–60.23), P = 0.004]. However, this benefit was only significant in cases of KRAS exon 2 codon 12 mutations [median OS: 101 months (83.97–118.02) vs 60 months (53–66.99), P < 0.001; median LRRFS: 76 months (64.62–87.38) vs 44 months (35.27–52.73), P < 0.001]. CONCLUSION Perioperative bevacizumab appears to be beneficial in patients with exon 2 codon 12 KRAS mutations who have undergone lung metastasectomy for CRC.

Bronchial complications after lung transplantation are associated with primary lung graft dysfunction and surgical technique

BACKGROUND After lung transplantation, bronchial complications are one of the major concerns for surgeons and physicians. In the era of evolving immunosuppressive regimens and surgical approaches, we have reassessed risk factors for bronchial complications after lung transplantation. METHODS We undertook a retrospective study of all consecutive lung transplantations performed at a single center from 2004 to 2014. We monitored the incidence of symptomatic bronchial complications. Demographic data of donors and recipients were also studied. Our objective was to evaluate the impact of 3 subsequent immunosuppressive regimens (including the use of induction therapy), and of a technical modification of bronchial anastomosis on the incidence of airway complications. RESULTS We performed 270 consecutive lung transplantations during the study period. On multivariate analysis, bronchial complications were not directly associated with the different immunosuppressive regimens. In subgroup analysis, when comparing different immunosuppressive regimens, primary graft dysfunction within 72 hours (odds ratio [OR] = 2.55; p = 0.08), lung infection within the first month (OR = 2.96; p = 0.039), diabetes before transplantation (OR = 2.66; p = 0.11) and chronic obstructive pulmonary disease (OR = 2.20; p = 0.04) appeared as major risk factors (c-index = 0.77 on multivariate analysis). The use of a modified bronchial suture technique was associated with fewer bronchial complications (OR = 0.47; p = 0.059) (c-index = 0.71 on multivariate analysis). CONCLUSIONS The mode of immunosuppression had no influence on airway complications. We were able to reproduce the beneficial effect of a modified suture technique.

KRAS-specific amino acid substitutions are associated with different responses to chemotherapy in advanced non-small cell lung cancer

&NA; Emerging evidence is highlighting different behaviors of non–small‐cell lung cancer according to KRAS amino acid substitutions (AAS). We have shown that, in a large sample of 1190 patients, response to chemotherapy differs according to KRAS AAS in non–small‐cell lung cancer. This supports the use of different chemotherapy regimens according to KRAS AAS. Background: Emerging data highlight different clinical behaviors according to KRAS amino acid substitutions (AASs) in patients with non–small‐cell lung cancer (NSCLC). We aimed to evaluate whether different KRAS AASs were associated with different responses to chemotherapy. Patients and Methods: We retrospectively reviewed data from 1190 patients with KRAS mutations who underwent first‐line platinum‐based chemotherapy for stage IV NSCLC. The response to different chemotherapy regimens was evaluated using the Response Evaluation Criteria In Solid Tumors criteria (v 1.1). Overall survival and time to progression (TTP) were secondary endpoints. Results: Taxane was associated with the best response in the entire cohort (odds ratio, 2.52; 95% confidence interval [CI], 1.82‐3.48; P < .001), especially in G12V patients (odds ratio, 2.15; 95% CI, 1.05‐4.41; P = .036). Taxane was associated with improved TTP in the entire cohort (hazard ratio [HR], 0.31; 95% CI, 0.26‐0.38; P < .001), especially in G13D patients (HR, 0.47; 95% CI, 0.22‐1.01; P = .054). Pemetrexed was associated with the worst TTP in the entire cohort, particularly in G12V patients, who had the worst response rates (HR, 0.55; 95% CI, 0.30‐0.99; P = .049). No impact on overall survival was observed according to different chemotherapy regimens and AASs. Conclusion: KRAS‐specific AAS appears to induce different responses to chemotherapy regimens after first‐line platinum‐based chemotherapy in advanced NSCLC.

Clamshell Closure With Absorbable Sternal Pins in Lung Transplant Recipients

Clamshell (bilateral anterolateral thoracotomy combined to transverse sternotomy) is an invasive surgical approach that is helpful in particular situations, especially bilateral lung transplantation. The closure technique remains challenging because clamshell incision can end with override, separation, or sternal pseudarthrosis complications. We describe the use of new absorbable sternal pins to stabilize the sternal closure and to help avoid additional sternal complications.

MicroRNAs: a new tool in the complex biology of KRAS mutated non-small cell lung cancer?

Despite several advances in the last decades in both medical and surgical management, with a 5-year overall survival (OS) not exceeding 15%, non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide (1). The past few years have seen an increased understanding in the molecular alterations of several cancers, helping clinicians to guide medical treatment and offer more accurate prognosis to patients. NSCLC was not left behind (2). Indeed, the recent discovery of oncogenic drivers such as activating mutations in the tyrosine kinase domain of the Epidermal Growth Factor Receptor (EGFR) has led to a dramatic increase in survival of patients harboring these mutations (3). Meanwhile, the prognostic and predictive values of EGFR mutations seem to be largely established in metastatic NSCLC (4), only a fleeting glimpse of clinical implications of many other mutations has been offered so far by the published literature, and might need further researches. One of the most promising molecular markers seems to rely in the mutations of the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) gene. KRAS encodes for RAS proteins which are small GTPases bounding between inactive guanosine diphosphate (GDP) and active guanosine triphosphate (GTP) forms. RAS proteins are central mediators downstream of growth factor receptor signaling and therefore are critical for cell proliferation, survival, and differentiation. Approximately 15% to 25% of NSCLC adenocarcinomas exhibit KRAS mutations (5). In the very large majority of the cases, these mutations are missense mutations introducing an amino-acid substitution at codon 12, 13 or 61 of the exon 2 of the gene (6). This confers a constitutive activation of KRAS signaling pathways, including the PI3K-AKT-mTOR pathway, involved in cell survival, and the RAS-RAF-MEK-ERK pathway, involved in cell proliferation. The complexity of KRAS mutations is reflected by the difficulty to develop effective therapies for patients with NSCLC harboring such mutations, and so far KRAS mutations are related to a poor prognosis in both locally and advanced NSCLC patients (7,8).