Introduction MET gene copy number gain (CNG) may be a predictive biomarker for MET inhibition in lung cancer, but the most appropriate method and criteria for defining MET positivity are uncertain. Methods MET copy number was assessed by fluorescence in situ hybridization (FISH) in lung adenocarcinoma. Positivity criteria included mean MET/cell ≥5 (low ≥5 – <6, intermediate ≥6 –<7, high ≥7) and MET/CEP7 ratio ≥1.8 (low ≥1.8 – ≤2.2, intermediate >2.2 – < 5, high ≥5). Associated clinical and molecular characteristics were captured. Results 99/686 cases (14%) had mean MET/cell ≥ 5, 52/1164 (4.5%) had MET/CEP7 ≥1.8. Other oncogenic drivers (in EGFR, KRAS, ALK, ERBB2, BRAF, NRAS, ROS1 or RET) were detectable in 56% of the mean MET/cell ≥ 5 group and 47% of the MET/CEP 7 ratio ≥1.8 group, suggesting many MET ‘positive’ cases are not truly MET-addicted. Concomitant drivers in low, indeterminate and high categories of mean MET/cell were 32/52 (62%), 12/19 (63%) and 11/27 (41%) (p=0.2) and in MET/CEP7: 15/29 (52%), 9/18 (50%) and 0/4 (0%) respectively (p=0.04). MET/CEP7 ≥1.8, in the absence of other oncogenes, was associated with a higher rate of adrenal metastases (p=0.03), but not with never smoking status. Conclusions FISH MET/CEP7 ≥ 5 defined a MET ‘positive’ group with no oncogenic overlap. As this method and criteria are also associated with the highest response rate to MET inhibition it represents the clearest definition of a MET CNG-addicted state. However, a MET-associated phenotype may also exist across MET/CEP7 ≥ 1.8 cases when no other oncogene overlap occurs.

No abstract

Half of lung cancers are diagnosed in former smokers, leading to a significant treatment burden in this population. Chemoprevention in former smokers using the prostacyclin analogue iloprost reduces endobronchial dysplasia, a premalignant lung lesion. Iloprost requires the presence of the WNT receptor Frizzled 9 (Fzd9) for inhibition of transformed growth in vitro. To investigate the relationship between iloprost, cigarette smoke, and Fzd9 expression, we used human samples, mouse models, and in vitro studies. Fzd9 expression was low in human lung tumors and in progressive dysplasias. In mouse models and in vitro studies, tobacco smoke carcinogens reduced expression of Fzd9 while prostacyclin maintained or increased expression. Expression of miR-31 repressed Fzd9 expression, which was abrogated by prostacyclin. We propose a model where cigarette smoke exposure increases miR-31 expression, which leads to decreased Fzd9 expression and prevents response to iloprost. When smoke is removed miR-31 is reduced, prostacyclin can increase Fzd9 expression, and progression of dysplasia is inhibited. Fzd9 and miR-31 are candidate biomarkers for precision application of iloprost and monitoring of treatment progress. As we continue to investigate the mechanisms of prostacyclin chemoprevention and identify biomarkers for its use, we will facilitate clinical trials and speed implementation of this valuable prevention approach.

The aim of this study was to compare tumor expression of prognostic biomarkers between interval breast cancers and screen-detected breast cancers overall, and according to age at diagnosis and familial risk. Tissue micro-arrays were constructed from 98 breast cancers (47 interval and 51 screen-detected) diagnosed in women in the Cancer Genetics Network. Arrays were immuno-stained to compare protein expression of six biomarkers including estrogen and progesterone receptor (ER/PR), Her2/neu, EGFR, cytokeratin 5/6, and Ki67. Fisher’s Exact test was used to compare expression between interval and screen-detected cancers. Interval cancers were larger (P = 0.04), higher stage (P < 0.001), and more likely to have lobular histology (P = 0.01) than screen-detected cancers. Overall, interval cancers more often over-expressed EGFR (P = 0.01) and were somewhat more likely to be ER− (55% vs. 43%, P = 0.3), and triple negative (ER−/PR−/Her2−) (21 vs. 12%, P = 0.26). A greater difference in the proportion of interval versus screen-detected tumors that were ER− (53 vs. 35%; P = 0.29), PR− (35 vs. 21%; P = 0.25) and EGFR+ (17 vs. 0%; P = 0.02) was evident among women over 50. There was a trend toward differential expression among women with familial risk for PR− (P = 0.005) and triple negative status (P = 0.02). This study provides new data indicating that EGFR may be important in the etiology of interval cancer and be a possible therapeutic target. Our data also suggest that biological differences between interval and screen-detected cancers are more defined in older women. Future studies to confirm this finding and to elucidate novel markers for characterizing interval cancers may be more beneficial to this subgroup.

Myocardial infarction is a common life-threatening condition. Multiple agents can be used to treat acute coronary syndrome (ACS). These therapeutic agents pose potential life-threatening complications when used outside the realm of the acute coronary syndrome. Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder, occurring in 1 in 500 individuals, which may mimic ACS. The hypertrophy most typically involves the septum in patients with HCM. As many as 25% of Japanese patients with HCM have predominately apical involvement. Apical hypertrophic cardiomyopathy (AHC) occurs in only 1 to 2% of the non-Japanese population. Despite its low incidence, physicians caring for patients with chest pain need to consider AHC in their differential diagnosis. We present the case of a patient with chest pain and electrocardiographic changes suggestive of ACS who was later found to have AHC.