Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently ...expressed in oncogene-addicted NSCLC.
We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive.
PD-1 positive (+) was significantly associated with current smoking status (P=0.02) and with the presence of KRAS mutations (P=0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology (P=0.005) and with presence of EGFR mutations (P=0.001). In patients treated with EGFR tyrosine kinase inhibitors (N=95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P=0.01) time to progression (TTP: P<0.0001) and survival (OS: P=0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative (P=0.01).
PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.
Current evidence suggest that trabectedin is particularly effective in cells lacking functional homologous recombination repair mechanisms. A prospective phase II trial was designed to evaluate the ...activity of trabectedin in the treatment of recurrent ovarian cancer patients presenting BRCA mutation and/or BRCAness phenotype.
A total of 100 patients with recurrent BRCA-mutated ovarian cancer and/or BRCAness phenotype (≥2 previous responses to platinum) were treated with trabectedin 1.3 mg/mq i.v. q 3 weeks. The activity of the drug with respect to BRCA mutational status and to a series of polymorphisms single-nucleotide polymorphisms (SNPs) involved in DNA gene repair was analyzed.
Ninety-four were evaluable for response; in the whole population, 4 complete and 33 partial responses were registered for an overall response rate (ORR) of 39.4. In the platinum-resistant (PR) and -sensitive (PS) population, an ORR of 31.2% and 47.8%, and an overall clinical benefit of 54.2% and 73.9%, respectively, were registered. In the whole series, the median progression-free survival (PFS) was 18 weeks and the median overall survival (OS) was 72 weeks; PS patients showed a more favorable PFS and OS compared with PR patients. BRCA gene mutational status was available in 69 patients. There was no difference in ORR, PFS and OS according to BRCA 1–2 status nor any association between SNPs of genes involved in DNA repair and NER machinery and response to trabectedin was reported.
Our data prospectively confirmed that the signature of ‘repeated platinum sensitivity’ identifies patients highly responsive to trabectedin. In this setting, the activity of trabectedin seems comparable to what could be obtained using platinum compounds and the drug may represent a valuable alternative option in patients who present contraindication to receive platinum.
2011-001298-17.
Purpose
KRAS
mutation has been associated with enhanced dependency on the folate metabolism in preclinical studies. However, whether
KRAS
mutation correlates to increased sensitivity to pemetrexed in ...patients with advanced NSCLC is unknown.
Methods
Patients with advanced non-squamous NSCLC who had a documented
EGFR
and
ALK
WT genotype with simultaneous
KRAS
mutation assessment were evaluated for clinical outcome to pemetrexed- and non-pemetrexed-based first-line platinum doublet according to
KRAS
mutation status.
Results
Of 356 patients identified, 138 harbored a
KRAS
mutation. Among
KRAS
-mutant NSCLCs, those treated with platinum/pemetrexed (81/138) had significantly lower ORR (30.9% versus 47.4%,
P
= 0.05), DCR (51.8% versus 71.9%,
P
= 0.02) and shorter median progression-free survival mPFS 4.1 versus 7.1 months, HR 1.48 (95% CI 1.03–2.12),
P
= 0.03 and median overall survival mOS 9.7 versus 26.9 months, HR 1.93 (95% CI 1.27–2.94),
P
= 0.002 compared to those who received a non-pemetrexed-based platinum doublet (57/138). No difference in ORR, DCR, mPFS and mOS was observed between
KRAS
WT patients who received a pemetrexed-based (124/218) versus non-pemetrexed base platinum doublets (94/218). After adjusting for performance status, age and the presence of brain metastasis at baseline, treatment with pemetrexed-based platinum doublet was associated with an increased risk of death HR 2.27 (95% CI 1.12–4.63),
P
= 0.02 among
KRAS
-mutant patients in multivariate analysis.
Conclusion
Patients with
KRAS
-mutant lung adenocarcinoma have a poorer outcome on pemetrexed-based first-line chemotherapy. Whether
KRAS
-mutant NSCLCs should be excluded from pemetrexed-containing regimens should be assessed prospectively.
Insulin-like growth factor receptor-1 (IGFR-1) represents a novel molecular target in non-small-cell lung cancer (NSCLC). IGFR-1 and epidermal growth factor receptor (EGFR) activation is essential to ...mediate tumor cell survival, proliferation and invasion. We explored the correlation between IGFR-1 and EGFR, their relationship with clinicopathological parameters and their impact on outcome in resected stage I–III NSCLC patients.
Tumors from 125 surgical NSCLC patients were evaluated for IGFR-1 and EGFR expression by immunohistochemistry. Kaplan–Meier estimates of survival and time to recurrence were calculated for clinical variables and biologic markers using the Cox model for multivariate analysis.
IGFR-1 protein overexpression was detected in 36.0% of NSCLC patients and was associated with larger tumor size (P=0.04) but not with other clinical or biological characteristics. EGFR protein overexpression was observed in 55.2% of NSCLC, more frequently in squamous cell carcinoma (SCC) than non-SCC (63.7% versus 36.3%, χ2 = 9.8, P=0.001). IGFR-1 protein expression was associated with EGFR protein expression (P=0.03). At the multivariate analysis, high coexpression of both IGFR-1 and EGFR was a significant prognostic factor of worse disease-free survival (DFS) (hazard ratio 2.51, P=0.01).
A statistically significant association was observed between high coexpression of both IGFR-1 and EGFR and worse DFS in early NSCLC patients.
Background
We present a comprehensive analysis of
KRAS
,
PIK3CA
,
MET,
and non-sensitizing
EGFR
mutations in advanced non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase ...inhibitors (TKIs), with the aim of clarifying the relative contribution of these molecular alterations to resistance.
Patients and methods
One hundred and sixty-six patients with advanced NSCLC treated with EGFR-TKIs with available archival tissue specimens were included.
EGFR
(exons 18–21),
KRAS
(exons 2, 3),
PIK3CA
(exons 9, 20), and
MET
(exons 14, 15) mutations were analyzed using PCR-based sequencing. Among all the mutations evaluated, only
KRAS
,
PIK3CA
,
MET,
and non-sensitizing
EGFR
mutations, defined as “TKI non-sensitizing mutations” were used for response, time to progression (TTP), and overall survival (OS) analysis.
Results
TKI non-sensitizing mutations were associated with disease progression (
p
= 0.001), shorter TTP (
p
< 0.0001), and worse OS (
p
= 0.03). Cox’s multivariate analysis including histology and performance status showed that TKI non-sensitizing mutations were independent factors for shorter TTP (
p
< 0.0001) and worse OS (
p
= 0.01).
Conclusions
When
KRAS
,
PIK3CA
,
MET,
and non-sensitizing
EGFR
mutations are concomitant, up to 96.0% of NSCLC patients unlikely to respond to TKIs can be identified, and they represented independent negative prognostic factors. Comprehensive molecular dissection of EGFR signaling pathways should be considered to select advanced NSCLC patients for TKIs therapies.
Background: We explored the correlation between serum human epidermal growth factor receptor-2 (HER2) extracellular domain (ECD) and tissue HER2 status, their relationship with clinicopathological ...parameters and their impact on disease-free survival (DFS) and overall survival in early breast cancer patients. Patients and methods: This prospective trial included patients with stage I–III breast cancer. Serum HER2 ECD levels were measured by two enzyme-linked immunosorbent assays before surgical treatment. Tissue HER2 status was analyzed by immunohistochemistry (IHC) in all tumors; FISH assay was utilized in HER2 2+ tumors by IHC. Results: From May 2000 to July 2005, 256 consecutive stage I–III breast cancer patients were included in this study. High serum HER2 ECD levels (≥15 ng/ml) were reported in 23 patients (9.0%) and HER2-positive status in tumor tissue was observed in 42 patients (16.4%) with a concordance of 87.1%. High HER2 ECD levels were significantly associated with high histological grade (P = 0.003), stage III (P = 0.008), lymph node involvment (P = 0.035) and negativity of both estrogen (P = 0.016) and progesterone (P = 0.007) receptors. At multivariate analysis, high serum HER2 ECD levels were a significant independent prognostic factor of worse DFS (P = 0.009). Conclusions: A statistically significant association was observed between high serum HER2 ECD levels and worse DFS in early breast cancer patients.
Background: In an attempt to identify markers of resistance to trastuzumab, we evaluated both the profiling of human epidermal growth factor receptor 2 (HER2)-positive tumor cells measuring the ...relative levels of EGFR, pMAPK, pAkt and PTEN and their correlations with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab. Patients and methods: Tumor tissues for this retrospective analysis were available from 45 out of 76 patients with metastatic breast cancer treated from April 1999 to March 2006 with trastuzumab-based therapy at our Institution. Evaluations of EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry (IHC) were carried out on all 45 tissue samples and their correlations with response to trastuzumab, incidence of central nervous system (CNS) metastases, time to progression (TTP), overall survival from diagnosis of breast cancer (OS1), from diagnosis of metastatic disease (OS2) and from the start of trastuzumab (OS3) were analyzed. Results: We observed that TTP (P = 0.001) and median OS2 and OS3 were significantly longer in patients responsive to trastuzumab-based regimen compared with nonresponsive patients. EGFR, pMAPK, pAkt and PTEN status by IHC were not significantly associated with response to trastuzumab, TTP, overall survival (OS1, OS2, OS3) and CNS metastases incidence. A trend for shorter OS3 was observed for pMAPK-positive patients compared with pMAPK-negative patients (22.8 versus 31.2 months; P = 0.076). Median OS1 resulted shorter in 22 pAkt-positive patients (69.8 months) compared with 23 pAkt-negative patients (108.2 months); P = 0.091. It is likely that high expression of pMAPK (pMAPK-positive status) or pAkt (pAkt-positive status) could identify a subgroup of HER2-positive tumors with high activity of proliferation and survival pathways and with resistance to trastuzumab. Conclusions: In HER2-positive metastatic breast cancers, EGFR, pMAPK, pAkt and PTEN status evaluated by IHC was not significantly associated with response to trastuzumab, TTP, OS and CNS metastases incidence. However, HER2 status determined by IHC and/or FISH assays may not be sufficient to predict response to trastuzumab-based therapy.
High levels of serum and/or plasma circulating DNA (cDNA) have been described in patients with systemic autoimmune diseases (SADs). However, the role of this molecule has not been clarified. Our aim ...was to evaluate plasma cDNA levels in 48 systemic lupus erythematosus (SLE) and 44 primary Sjögren’s syndrome (SS) patients, as compared with healthy and rheumatoid arthritis (RA) subjects, and to analyse their correlation with disease activity, disease damage and clinical manifestations. Plasma DNA was extracted using Qiagen columns and quantified by real-time quantitative PCR. Disease activity and damage were evaluated in both diseases by analysis of clinical and laboratory findings. Our results showed that plasma cDNA levels were significantly higher in patients with SS (mean ± SE: 32.0 ± 7.3 ng/ml) and with SLE (35.0 ± 9.0 ng/ml) than in controls (5.1 ± 1.1 ng/ml) (p < 0.0001 for both). Disease activity index correlated with cDNA levels in SS (p = 0.02), but not in SLE, and SS subjects with active disease displayed significantly higher cDNA levels with respect to inactive patients (p < 0.05). No correlation was found between plasma cDNA levels and disease damage indexes in either SLE or SS. These results indicate that increased plasma cDNA levels can been demonstrated in SLE and in SS patients with respect to healthy subjects. Interestingly, although cDNA levels did not correlate with indexes of disease damage in these disorders, a significant correlation between cDNA concentrations and disease activity was observed in SS, but not in SLE, suggesting a possible role of cDNA as non-invasive marker of disease activity. The different results obtained in these SADs may be explained by distinct disease pathogenesis or the influence of immunosuppressive and corticosteroid therapy that, unlike in SS, is usually employed in SLE.
PDF
