V. Ludovini

High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients

BACKGROUND 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. PATIENTS AND METHODS 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. RESULTS 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%, chi(2) = 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). CONCLUSION A statistically significant association was observed between high coexpression of both IGFR-1 and EGFR and worse DFS in early NSCLC patients.

EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry : correlation with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab

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.

Unique case of sporadic multiple gastro intestinal stromal tumour

Introduction Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and they derived from transformed neoplastic precursors of Cajal’s interstitial cell (ICC). Presentation of the case We are presenting a sporadic and exemplary case of 42 multiple GISTs in a young female patient. Our patient showed anemia for the gastric GIST bleeding and only after other tumors were instrumentally and intra-surgery discovered. The patient showed genetic mutation V559A/1676 T > C of the juxtamembrane domain of the exon 11 causing the replacement of Valine with Alanine in the 559 codon. Discussion GISTS estimated annual incidence is 12–14 per million. Multiple GISTs associated with familiarity or hereditary syndromes are described only in few case reports and sporadic mGISTs have not been studied yet. Literature review has been done. Conclusion We are presenting a sporadic and exemplary case of 42 multiple GISTs in a young female patient localized trough out all the gastrointestinal tract. This is the only case of sporadic multiple GISTs reported in literature.

Long-term survival with erlotinib in advanced lung adenocarcinoma harboring synchronous EGFR G719S and KRAS G12C mutations

Although epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) mutations were thought to be mutually exclusive in patients with non-small cell lung cancer (NSCLC), the development of high sensitive large-scale mutation analysis, has increasingly shown that activating EGFR mutations occasionally coexist with other dominant genetic alterations. Herein, we discuss the case of a patient with advanced NSCLC harboring both the uncommon EGFR G719S and the KRAS G12C mutations, who was treated for 9 years with erlotinib achieving a long-term survival. In light of their rarity, multiple mutations are very challenging for the decision of tyrosine kinase inhibitors (TKIs) treatment, especially when EGFR mutations occur together with mutations known to provide resistance to EGFR TKIs, such as KRAS.

1255PCLINICAL FEATURES AND OUTCOME IN NEVER-SMOKER (NS) NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS (PTS): A SINGLE-INSTITUTION OBSERVATIONAL ANALYSIS

ABSTRACT Aim: NSCLC in NS often harbors proto-oncogene aberrations, showing enrichment for targetable alterations compared to unselected populations. Objectives of this study were to define the proportions of the driver gene alterations and to examine survival in genotype-specific subsets of NS NSCLC. Methods: We identified 243 NS NSCLC pts treated at our Institution from October 2003 to January 2014. Pts with tissue available for biological analysis were as follows: 207 pts (85.1%) assessable for EGFR/KRAS mutation, 77 (31.6%) for ALK rearrangement, 37 (15.2%) for ROS1 rearrangement, 33 (13.5%) and 32 (13.1%) for RET fusion and HER2 mutation. The cohort comprised 58% women, median age 62, 86% advanced adenocarcinomas (10% brain metastases at diagnosis). Results: Out of 207 tumors, frequency of EGFR and KRAS mutation was 42.5% (88 pts) and 7.7% (16), respectively. Among pts screened for ALK, ROS1, RET, HER2, the proportion of individual testing, were 25.9% (20), 13.5% (5), 9% (3), 0%. 228 pts were evaluable for treatment and outcomes.158 pts (69%) received at least one line of an EGFR tyrosine kinase inhibitor (TKI), of which 42 (27%) as first line. 16 pts (7%) received an ALK/ROS1 inhibitor, and 8 pts (4%) had both treatments, 50 pts (21%) received exclusively chemotherapy. Median progression-free survival (PFS) after treatment with first line EGFR TKI was 13.2 months (mo) vs 5.3 mo for chemotherapy (p Conclusions: The study confirmed the clinical and outcome features which make lung cancer in NS a distinct disease. Of particular note is the marked increase in OS with EGFR TKI therapy when evaluating this subset in contrast to previous studies not specifically focusing on NS. Disclosure: All authors have declared no conflicts of interest.

Clinical outcome of KRAS-mutated advanced non-small cell lung cancer (NSCLC) patients (pts): A mono-institutional analysis.

7580 Background: In the present analysis we evaluated the clinical outcome of KRAS mutated advanced non-small cell lung cancer (NSCLC) patients (pts) treated at a single Institution from April 2007 to December 2010. METHODS KRAS mutational status was assessed on tumor tissue collected at the time of first diagnosis (either primary or metastatic). KRAS (exons 2 and 3) gene was amplified by nested PCR and sequenced in both sense and antisense direction using 3500 Genetic Analyzer. Retrospective chart review was approved by the local Ethics Committee. RESULTS 64 pts with an identified KRAS mutation were evaluable for the analysis. The majority of them (87.5%) had a good performance status (ECOG 0), while 82.5% were former or current smokers. All pts except for one who was treated with single-agent gemcitabine, received a platinum-based doublet mainly including either gemcitabine (56,5%) or pemetrexed (25%). Overall, 82% of pts received at least two lines of chemotherapy. Three types of KRAS mutations were identified, the most common being codon 12 (78.1%) mutation, followed by codon 13 (12.5%) and codon 61 (9.4%) mutations, respectively. Of the 52 (81,2%) who were evaluable for response 2 complete responses (3,8%), 21 partial responses (40,4%), 13 disease stabilizations (25%) and 16 progressive diseases (30,8%) were observed. Median overall survival (OS) from the beginning of treatment was 39 months, with no statistically significant differences according to the type of K-RAS mutation (p< 0,2). Median OS and first-line PFS were significantly higher in responders versus non-responders (55.4 months versus 24.8 months for OS and 11.2 months versus 4.8 months for first-line PFS, p<0.009). CONCLUSIONS KRAS mutated NSCLC pts do not represent a population with homogeneous clinical characteristics. Response to treatment seems to predict benefit from first-line chemotherapy in terms of OS and first-line PFS. The excellent OS rate observed in the whole group might be the result of a population highly selected for good clinical prognostic factors. Prospective studies of KRAS mutations and sensitivity to chemotherapy are warranted.

Insulin-like growth factor receptor-1 (IGF1R) and epidermal growth factor receptor (EGFR) amplification and expression in surgically resected NSCLC.

10519 Background: IGF1R represents a novel molecular target in non-small cell lung cancer (NSCLC). IGF1R and EGFR activation is essential to mediate tumor cell survival, proliferation and invasion. This study investigates the prognostic role of IGF1R and EGFR copy number gain (CNG) by fluorescence in situ hybridization (FISH) and protein overexpression by immunohistochemistry (IHC) in surgically resected NSCLC. METHODS 114 NSCLC patients were evaluated; median age was 66y (range 40-84), Male/Female:96/18; squamous (SCC)/adeno/BAC/other:59/34/9/12; smoker/never smoker:105/9, and stage I/II/III:71/18/25. IGF1R and EGFR FISH were tested by customized and commercial probes, respectively; positive specimens showed gene amplification or polysomy (≥4 copies in ≥10% of tumor cells). IGF1R and EGFR protein expression were evaluated using mouse antibodies (clones 24-31 and 3147, respectively); overexpression was defined by ≥10% positive cells. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical and biologic variables using Cox model for multivariate analysis. RESULTS 46 tumors (40%) were IGF1R FISH+ and 76 (77%) were EGFR FISH+. IGF1R FISH+ was associated with EGFR FISH+ (p=0.03) and co-amplification was observed in 34 cases (30%). IGF1R and EGFR FISH+ were associated with SCC (p=0.01 and p=0.05, respectively). IGF1R and EGFR overexpression was detected in 36% and 55% of NSCLC patients and co-expression was detected in 25%. Co-amplification and co-expression of both receptors were significantly associated (p=0.045). IGF1R and EGFR co-amplification and co-expression associated with shorter disease free survival (DFS; p=0.05, p=0.05 respectively), also at multivariate analysis adjusting for stage (p=0.0002). CONCLUSIONS IGF1R and EGFR are frequently co-amplified in NSCLC and CNG correlates with protein overexpression. Both co-amplification and co-expression of IGF1R and EGFR predicts shorter DFS. These results provide a strong rational for targeting simultaneously EGFR and IGF1R in clinical trials for NSCLC. We thank the Italian Association for Cancer Research (AIRC) for supporting the study (AF Fellowship).

Biological prognostic factors for early stage completely resected non-small cell lung cancer

BACKGROUND AND OBJECTIVES The different and unpredictable outcomes in early-stage non-small cell lung cancer patients requires urgent research concerning the biological pathway of this neoplasm. Our study investigated the frequency of expression and the clinicopathologic and prognostic significance of a series of biological markers in stage I and II resected non-small cell lung cancer. METHODS A total of 99 cases of pathologic stage I and II were analyzed. The mean follow-up of surviving patients was 41 months. The expressions of the following biological markers were tested: bcl-2, p53, Ki-67, angiogenesis, and tumor vessel invasion. Kaplan-Meier estimates of survival and time to recurrence were calculated for clinical variables and biological markers using Coxs model for multivariate analysis. RESULTS Tumoral vessel invasion was present in 22 (22%) pathologic samples, the angiogenesis mean value was 37 +/- 13, and median was 35; 13 (13%) patients showed positive immunostaining for bcl-2 oncoprotein. P53 oncoprotein expression was present in 48 patients (48.5%). All samples presented Ki-67 expression (mean value = 25.3 +/- 19.3, median = 20). The pathologic staging of the tumor was the most important independent prognostic factor for survival (P = 0.037) and for recurrence of disease (P = 0.040). Tumoral vessel invasion was the only marker with an independent predictive factor for survival and recurrence of disease in the group of patients without lymph node involvement (P = 0.02). CONCLUSION Our data do not support a relevant prognostic role for p53, bcl-2, or Ki-67 immunohistochemical markers in non-small cell cancer. Tumor vessel invasion was an independent predictive factor of poor outcome in the group of patients without lymph node involvement. Pathological stage was confirmed as the most important independent prognostic factor.