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1.  Mesothelin Overexpression Is a Marker of Tumor Aggressiveness and Is Associated with Reduced Recurrence-free and Overall Survival in Early-Stage Lung Adenocarcinoma 
Purpose
In an effort to identify molecular markers of tumor aggressiveness and therapeutic targets in lung adenocarcinoma (ADC), we investigated the expression of mesothelin (MSLN) in lung ADC, as well as its biological and clinical relevance.
Experimental Design
In a training and validation set of patients with early-stage (I–III) lung ADC (n=1209), a tissue microarray consisting of tumors and normal lung tissue was used to examine the association between MSLN expression and recurrence-free survival (RFS) and overall survival (OS). The influence of MSLN overexpression on lung ADC was investigated in vitro and in vivo by use of clinically relevant orthotopic and metastatic xenogeneic and syngeneic mouse models.
Results
MSLN was expressed in 69% of lung ADC tumors, with one in five patients strongly expressing MSLN and no expression in normal lung tissue. Increased MSLN expression was associated with reduced OS (HR, 1.78 [95% CI, 1.26–2.50]; P<0.01) and RFS (HR, 1.67 [95% CI, 1.21–2.27]; P<0.01) in multivariate analyses, even after adjustment for currently known markers of tumor aggressiveness in lung ADC: male sex, smoking history, increasing stage, morphologic pattern, visceral pleural invasion, lymphatic or vascular invasion, and mutation status. In vitro, lung ADC cells overexpressing MSLN demonstrated increased cell proliferation, migration, and invasion; in vivo, mice with MSLN(+) tumors demonstrated decreased survival (P=0.001).
Conclusions
MSLN expression in patients with early-stage lung ADC is associated with increased risk of recurrence and reduced OS, indicating that MSLN expression is a molecular marker of tumor aggressiveness and a potential target for therapy.
doi:10.1158/1078-0432.CCR-13-1862
PMCID: PMC3944669  PMID: 24334761
Mesothelin; lung adenocarcinoma; prognosis; targeted therapy; non-small cell lung cancer
2.  Esophageal Cancer Recurrence Patterns and Implications for Surveillance 
Introduction
After definitive treatment of esophageal cancer, patients are at high risk for recurrence. Consistent follow-up is important for detection and treatment of recurrence. The optimal surveillance regimen remains undefined. We investigated posttreatment recurrence patterns and methods of detection in survivors of esophageal cancer.
Methods
We retrospectively studied a cohort of patients who had undergone surgical resection for esophageal cancer at our institution between 1996 and 2010. Routine computed tomography (CT) scan and upper endoscopy were performed for surveillance.
Results
In total, 1147 patients with resected esophageal adenocarcinoma or squamous cell carcinoma were included (median follow-up, 46 months). Of these, 723 (63%) had received neoadjuvant therapy before surgery. During follow-up, there were 595 deaths (52%) and 435 recurrences (38%) (distant [55%], locoregional [28%], or both [17%]). Half of recurrences were detected as a result of symptoms (n = 217), 45% by routine chest and abdominal CT scan (n = 194), and 1% by surveillance upper endoscopy (n = 6). The recurrence rate decreased from 27 per 100 person-years in posttreatment year 1 to 4 per 100 person-years in year 6. In the first 2 years, the rate of recurrence was higher among patients who had received neoadjuvant therapy (35 per 100 person-years) than among those who had not (14 per 100 person-years) (p < 0.001).
Conclusions
The incidence of recurrence is high after esophagectomy for cancer. Surveillance endoscopy has limited value for detection of asymptomatic local recurrence. The yield from follow-up scans diminishes significantly after the sixth year; surveillance scans after that point are likely unnecessary.
doi:10.1097/01.JTO.0000437420.38972.fb
PMCID: PMC4066875  PMID: 24389438
Esophageal Cancer; Surveillance; Endoscopy
3.  Phase II trial of neoadjuvant bevacizumab plus chemotherapy and adjuvant bevacizumab in patients with resectable non-squamous non-small cell lung cancers 
Introduction
Bevacizumab improves survival in patients with advanced non-small cell lung cancer (NSCLC). This phase II clinical trial assessed the effects of the addition of bevacizumab to neoadjuvant chemotherapy in resectable non-squamous NSCLC.
Methods
Patients with resectable stage IB-IIIA non-squamous NSCLC were treated with bevacizumab followed by imaging 2 weeks later to assess single agent effect. They then received 2 cycles of bevacizumab with 4 cycles of cisplatin and docetaxel followed by surgical resection. Resected patients were eligible for adjuvant bevacizumab. The primary endpoint was the rate of pathological downstaging (decrease from pretreatment clinical stage to post-treatment pathological stage). Secondary endpoints included overall survival, safety and radiologic response.
Results
Fifty patients were enrolled. Thirty-four (68%) were clinical stage IIIA. All 3 doses of neoadjuvant bevacizumab were delivered to 40/50 patients. Six (12%) patients discontinued due to bevacizumab-related adverse events. The rate of downstaging (38%), response to chemotherapy (45%), and perioperative complications (12%) were comparable to historical data. No partial responses were observed to single-agent bevacizumab but 18% developed new intratumoral cavitation with a trend toward improved pathologic response (57% vs. 21%, p=0.07). A major pathologic response (≥90% treatment effect) was associated with survival at 3 years (100% vs. 49%, p=0.01). No patients with KRAS-mutant NSCLC (0/10) had a pathologic response as compared with 11/31 with wild-type KRAS.
Conclusions
While preoperative bevacizumab plus chemotherapy was feasible, it did not improve downstaging in unselected patients. New cavitation after single-agent bevacizumab is a potential biomarker. Alternative strategies are needed for KRAS-mutant tumors.
doi:10.1097/JTO.0b013e31829923ec
PMCID: PMC4191830  PMID: 23857398
4.  Phase II Study of Docetaxel and Vinorelbine as Adjuvant Chemotherapy for Resected Non-small Cell Lung Cancers 
Cancer chemotherapy and pharmacology  2013;72(4):10.1007/s00280-013-2263-1.
Purpose
For patients with resected stage II-III non-small cell lung cancers (NSCLCs), adjuvant cisplatin-based chemotherapy improves survival over surgery alone. For cisplatin ineligible patients, there is no standard adjuvant option. We evaluated drug delivery and toxicity of docetaxel and vinorelbine in patients who could not receive cisplatin.
Methods
Patients with completely resected stage IB-III NSCLCs were treated with up to 4 cycles of docetaxel and vinorelbine at the recommended phase II dose. The primary endpoint was drug delivery compared to historical delivery of adjuvant cisplatin plus vinorelbine. Secondary endpoints were toxicity and feasibility.
Results
Twenty-five patients were enrolled. Overall, 13/25 (52%, 95% CI 34 – 70%) completed 4 cycles, and 19/25 (76%, 95% CI 60 – 87%) completed ≥ 3 cycles. Twenty of 25 patients (80%) experienced a Grade 3 or 4 adverse event.
Conclusions
Delivery of this dose and schedule of docetaxel and vinorelbine was difficult with a dose delivery comparable to cisplatin plus vinorelbine, and cisplatin plus docetaxel, used in this setting.
doi:10.1007/s00280-013-2263-1
PMCID: PMC3841970  PMID: 23975243
vinorelbine; docetaxel; adjuvant chemotherapy; early-stage non-small cell lung cancer
5.  Airway Basal Cells of Healthy Smokers Express an Embryonic Stem Cell Signature Relevant to Lung Cancer 
Stem cells (Dayton, Ohio)  2013;31(9):1992-2002.
Activation of the human embryonic stem cell (hESC)-signature genes has been observed in various epithelial cancers. In this study, we found that the hESC signature is selectively induced in the airway basal stem/progenitor cell population of healthy smokers (BC-S), with a pattern similar to that activated in all major types of human lung cancer. We further identified a subset of 6 BC-S hESC genes, whose coherent overexpression in lung AdCa was associated with reduced lung function, poorer differentiation grade, more advanced tumor stage, remarkably shorter survival and higher frequency of TP53 mutations. BC-S shared with hESC and a considerable subset of lung carcinomas a common TP53 inactivation molecular pattern which strongly correlated with the BC-S hESC gene expression. These data provide transcriptome-based evidence that smoking-induced reprogramming of airway BC towards the hESC-like phenotype might represent a common early molecular event in the development of aggressive lung carcinomas in humans.
doi:10.1002/stem.1459
PMCID: PMC4051142  PMID: 23857717
Airway epithelium; basal cells; gene expression; lung cancer; stem cells
6.  Impact of Micropapillary Histologic Subtype in Selecting Limited Resection vs Lobectomy for Lung Adenocarcinoma of 2cm or Smaller 
Background
We sought to analyze the prognostic significance of the new International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) lung adenocarcinoma (ADC) classification for patients undergoing resection for small (≤2cm) lung ADC and to investigate whether histologic subtyping can predict recurrence after limited resection (LR) vs lobectomy (LO).
Methods
Comprehensive histologic subtyping was performed according to the IASLC/ATS/ERS classification on all consecutive patients who underwent LR or LO for small lung ADC between 1995 and 2009 at Memorial Sloan-Kettering Cancer Center. Clinical characteristics and pathologic data were retrospectively evaluated for 734 consecutive patients (LR: 258; LO: 476). Cumulative incidence of recurrence (CIR) was calculated using competing risks analysis and compared across groups using Grey’s test. All statistical tests were two-sided.
Results
Application of IASLC/ATS/ERS lung ADC histologic subtyping to predict recurrence demonstrates that, in the LR group but not in the LO group, micropapillary (MIP) component of 5% or greater was associated with an increased risk of recurrence, compared with MIP component of less than 5% (LR: 5-year CIR = 34.2%, 95% confidence interval [CI] = 23.5% to 49.7% vs 5-year CIR = 12.4%, 95% CI = 6.9% to 22.1%, P < .001; LO: 5-year CIR = 19.1%, 95% CI = 12.0% to 30.5% vs 15-year CIR = 12.9%, 95% CI = 7.6% to 21.9%, P = .13). In the LR group, among patients with tumors with an MIP component of 5% or greater, most recurrences (63.4%) were locoregional; MIP component of 5% or greater was statistically significantly associated with increased risk of local recurrence when the surgical margin was less than 1cm (5-year CIR = 32.0%, 95% CI = 18.6% to 46.0% for MIP ≥ 5% vs 5-year CIR = 7.6%, 95% CI = 2.3% to 15.6% for MIP < 5%; P = .007) but not when surgical margin was 1cm or greater (5-year CIR = 13.0%, 95% CI = 4.1% to 22.1% for MIP ≥ 5% vs 5-year CIR = 3.4%, 95% CI = 0% to 7.7% for MIP < 5%; P = .10).
Conclusions
Application of the IASLC/ATS/ERS classification identifies the presence of an MIP component of 5% or greater as independently associated with the risk of recurrence in patients treated with LR.
doi:10.1093/jnci/djt166
PMCID: PMC3748005  PMID: 23926067
7.  A nuclear grading system is a strong predictor of survival in epitheloid diffuse malignant pleural mesothelioma 
Epithelioid mesothelioma is the most prevalent subtype of diffuse malignant pleural mesothelioma in which only staging is prognostic for survival. In this study of epithelioid diffuse malignant pleural mesothelioma, we investigate the prognostic utility of nuclear features. The slides of 232 epithelioid diffuse malignant pleural mesothelioma patients (14 stage I, 54 stage II, 130 stage III, and 34 stage IV) from a single institution were reviewed for the following seven nuclear features: nuclear atypia, nuclear/cytoplasmic ratio, chromatin pattern, intranuclear inclusions, prominence of nucleoli, mitotic count, and atypical mitoses. MIB-1 immunohistochemistry was performed using tissue microarray, and MIB-1 labeling index was recorded as the percentage of positive tumor cells. Median overall survival of all patients was 16 months and correlated with nuclear atypia (P<0.001), chromatin pattern (P=0.031), prominence of nucleoli (P<0.001), mitotic count (P<0.001), and atypical mitoses (P<0.001) by univariate analysis. Multivariate analysis revealed nuclear atypia (P=0.012) and mitotic count (P<0.001) as independent prognostic factors, and these two factors were utilized to create a three-tier nuclear grade score. The resulting nuclear grade stratified patients into three distinct prognostic groups: grade I (n=107, median overall survival = 28 months), grade II (n=91, 14 months), and grade III (n=34, 5 months). Not only was nuclear grade an independent predictor of overall survival (P<0.001), but it was also a stronger discriminator of survival than all currently available factors. Furthermore, nuclear grade was associated with time to recurrence (P=0.004) in patients who underwent complete surgical resection (n=159). MIB-1 labeling index correlated with mitotic count (P<0.001) and nuclear atypia (P=0.037) and stratified overall survival (P<0.001) and time to recurrence (P=0.048), confirming the prognostic value of the nuclear grade. Nuclear grading in epithelioid mesothelioma provides a simple, practical, and cost-effective prognostic tool that better stratifies clinical outcome and time to recurrence than currently available clinicopathologic factors.
doi:10.1038/modpathol.2011.146
PMCID: PMC4080411  PMID: 21983936
epithelioid mesothelioma; MIB-1; mitosis; nuclear atypia; nuclear grade; survival
8.  FDG-PET SUVmax Combined with IASLC/ATS/ERS Histologic Classification Improves the Prognostic Stratification of Patients with Stage I Lung Adenocarcinoma 
Annals of surgical oncology  2012;19(11):3598-3605.
Background
We investigated the association between the newly proposed International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification and 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET), and whether the combination of these radiologic and pathologic factors can further prognostically stratify patients with stage I lung adenocarcinoma.
Methods
We retrospectively evaluated 222 patients with pathologic stage I lung adenocarcinoma who underwent FDG-PET scanning before undergoing surgical resection between 1999 and 2005. Patients were classified by histologic grade according to the IASLC/ATS/ERS classification (low, intermediate, or high grade) and by maximum standard uptake value (SUVmax) (low <3.0, high ≥3.0). The cumulative incidence of recurrence (CIR) was used to estimate recurrence probabilities.
Results
Patients with high-grade histology had higher risk of recurrence (5-year CIR, 29 % [n = 25]) than those with intermediate-grade (13 % [n = 181]) or low-grade (11 % [n = 16]) histology (p = 0.046). High SUVmax was associated with high-grade histology (p < 0.001) and with increased risk of recurrence compared to low SUVmax (5-year CIR, 21 % [n = 113] vs. 8 % [n = 109]; p = 0.013). Among patients with intermediate-grade histology, those with high SUVmax had higher risk of recurrence than those with low SUVmax (5-year CIR, 19 % [n = 87] vs. 7 % [n = 94]; p = 0.033). SUVmax was associated with recurrence even after adjusting for pathologic stage (p = 0.037).
Conclusions
SUVmax on FDG-PET correlates with the IASLC/ATS/ERS classification and can be used to stratify patients with intermediate-grade histology, the predominant histologic subtype, into two prognostic subsets.
doi:10.1245/s10434-012-2414-3
PMCID: PMC4049004  PMID: 22644511
9.  Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR TKI therapy in 155 patients with EGFR mutant Lung Cancers 
Purpose
All patients with EGFR mutant lung cancers eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Smaller series have identified various mechanisms of resistance, but systematic evaluation of a large number of patients to definitively establish the frequency of various mechanisms has not been performed.
Experimental Design
Patients with lung adenocarcinomas and acquired resistance to erlotinib or gefitinib enrolled onto a prospective biopsy protocol and underwent a re-biopsy after the development of acquired resistance. Histology was reviewed. Samples underwent genotyping for mutations in EGFR, AKT1, BRAF, ERBB2, KRAS, MEK1, NRAS and PIK3CA, and FISH for MET and HER2.
Results
Adequate tumor samples for molecular analysis were obtained in 155 patients. Ninety-eight had second-site EGFR T790M mutations (63%, 95% CI 55-70%) and four had small cell transformation (3%, 95% CI 0-6%). MET amplification was seen in 4/75 (5%, 95% CI 1-13%). HER2 amplification was seen in 3/24 (13%, 95% CI 3-32%). We did not detect any acquired mutations in PIK3CA, AKT1, BRAF, ERBB2, KRAS, MEK1, or NRAS. (0/88, 0%, 95% CI 0-4%). Overlap among mechanisms of acquired resistance was seen in 4%.
Conclusions
This is the largest series reporting mechanisms of acquired resistance to EGFR TKI therapy. We identified EGFR T790M as the most common mechanism of acquired resistance, while MET amplification, HER2 amplification, and small cell histologic transformation occur less frequently. More comprehensive methods to characterize molecular alterations in this setting are needed to improve our understanding of acquired resistance to EGFR TKIs.
doi:10.1158/1078-0432.CCR-12-2246
PMCID: PMC3630270  PMID: 23470965
EGFR mutant lung cancer; lung adenocarcinoma; targeted therapy; acquired resistance; tyrosine kinase inhibitor therapy
10.  A Phase 1 Study of Everolimus Plus Docetaxel Plus Cisplatin as Induction Chemotherapy for Patients With Locally and/or Regionally Advanced Head and Neck Cancer 
Cancer  2013;119(10):1823-1831.
BACKGROUND
Activation of the phosphatidylinositol-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is common in head and neck cancers, and it has been demonstrated that inhibition of mTOR complex 1 sensitizes cell lines to platinum and taxane chemotherapy. The authors conducted a phase 1 study to evaluate the addition of oral everolimus to cisplatin and docetaxel as induction chemotherapy for head and neck cancer.
METHODS
In this single-institution phase 1 study, 3 doses of daily everolimus were explored: 5 mg daily, 7.5 mg daily (administered as 5 mg daily alternating with 10 mg daily), and 10 mg daily of each 21-day cycle. Cisplatin and docetaxel doses were fixed (both were 75 mg/m2 on day 1 of 21-day cycle) at each dose level with pegfilgrastim support. A standard 3 + 3 dose-escalation plan was used. After induction, patients were removed from protocol.
RESULTS
Eighteen patients were enrolled (15 men, 3 women), and their median Karnofsky performance status was 90. The most common toxicities were hyperglycemia, low hemoglobin, fatigue, and thrombocytopenia. Dose-limiting toxicities (DLTs) were neutropenic fever (1 event at dose level 2, 2 events at dose level 3), and all patients recovered fully from these DLTs. The maximum tolerated dose was exceeded at dose level 3. The progression-free survival rate at 1 year was 87.5% (95% confidence interval, 56.8%–96.7%); and, at 2 years, it was 76.6% (95% confidence interval, 41.2%–92.3%). Activating PI3K catalytic subunit α (PIK3CA) gene mutations were identified in 2 human papillomavirus-associated oropharyngeal cancers.
CONCLUSIONS
The phase 2 recommended dose was 7.5 mg daily for everolimus plus cisplatin and docetaxel (both at 75 mg/m2 on day 1 of a 21-day cycle) given with pegfilgrastim support.
doi:10.1002/cncr.27986
PMCID: PMC3969235  PMID: 23408298
phase 1; everolimus; induction; neck; squamous
11.  Association of KRAS and EGFR Mutations with Survival in Patients with Advanced Lung Adenocarcinomas 
Cancer  2012;119(2):356-362.
Background
Lung adenocarcinomas can be distinguished by identifying mutated driver oncogenes including EGFR and KRAS. Mutations in EGFR are associated with both an improved survival as well as response to treatment with erlotinib and gefitinib. However, the prognostic significance of KRAS has not been evaluated in large numbers of patients and remains controversial. We examined the association of EGFR and KRAS mutations with survival among patients with advanced lung adenocarcinomas.
Methods
We analyzed data from patients with advanced lung adenocarcinomas and known EGFR and KRAS mutation status evaluated between 2002 and 2009. We collected clinical variables including age, gender, Karnofsky Performance Status, smoking history, and treatment history. Overall survival from diagnosis of advanced disease was analyzed using Kaplan-Meier and Cox proportional hazard methods.
Results
We evaluated 1036 patients, including 610 women (59%) and 344 never-smokers (33%). Patients had a median age of 65 (range, 25–92) and the majority (81%) had a KPS ≥80%. In multivariate analysis, EGFR mutations were associated with a longer overall survival (HR= 0.6, p<0.001) and KRAS mutations with a shorter survival (HR=1.21, p=0.048).
Conclusions
KRAS mutations predict shorter survival for patients with advanced lung adenocarcinomas. The presence of EGFR and KRAS mutations define distinct subsets of patients with lung adenocarcinomas, and should be determined in patients upon diagnosis of advanced disease. Clinical trial reports should include EGFR and KRAS mutation status along with other prognostic factors.
doi:10.1002/cncr.27730
PMCID: PMC3966555  PMID: 22810899
non-small cell lung cancer; adenocarcinomas; EGFR; KRAS; survival; prognostic factors
12.  Thyroid Transcription Factor–1 Expression Is an Independent Predictor of Recurrence and Correlates with the IASLC/ATS/ERS Histologic Classification in Patients with Stage I Lung Adenocarcinoma 
Cancer  2012;119(5):931-938.
BACKGROUND
We investigated whether thyroid transcription factor–1 (TTF-1) expression correlates with the IASLC/ATS/ERS classification and whether it stratifies patients with stage I lung adenocarcinoma with respect to recurrence.
METHODS
Patients with stage I lung adenocarcinoma were classified according to the IASLC/ATS/ERS classification. We constructed tissue microarrays and performed immunostaining for TTF-1; 452 cases were available for analysis. Tumors were dichotomized by intensity of nuclear TTF-1 expression: negative (score 0) or positive (score 1–3). Cumulative incidence of recurrence (CIR) was used to estimate recurrence probabilities.
RESULTS
TTF-1 expression was identified in 92% of all patients, including 100% of patients with minimally invasive or lepidic-predominant adenocarcinoma, 94% of acinar-predominant, 98% of papillary-predominant, 93% of micropapillary-predominant, 86% of solid-predominant, 67% of colloid-predominant, and 47% of invasive-mucinous. The CIR for patients with negative TTF-1 expression (n = 34; 5-year CIR, 40%) was significantly higher than that for patients with positive TTF-1 (n = 418; 5-year CIR, 15%; p < 0.001). Among the intermediate-grade tumors, the CIR for patients with negative TTF-1 expression (n = 16; 5-year CIR, 45%) was significantly higher than that for patients with positive TTF-1 (n = 313, 5-year CIR, 14%; p < 0.001). In multivariate analysis, negative TTF-1 expression significantly correlated with increased risk of recurrence (hazard ratio, 2.55; p = 0.009).
CONCLUSIONS
TTF-1 expression is an independent predictor of recurrence, stratifying intermediate-grade tumors into 2 prognostic subsets, and it correlates with the IASLC/ATS/ERS classification.
doi:10.1002/cncr.27863
PMCID: PMC3691693  PMID: 23096929
lung adenocarcinoma; thyroid transcription factor–1; histologic subtype; recurrence
13.  Clinical Impact of Immune Microenvironment in Stage I Lung Adenocarcinoma: Tumor Interleukin-12 Receptor β2 (IL-12Rβ2), IL-7R, and Stromal FoxP3/CD3 Ratio Are Independent Predictors of Recurrence 
Journal of Clinical Oncology  2012;31(4):490-498.
Purpose
Mounting evidence suggests that tumor-infiltrating immune cells have prognostic value for patients with solid organ malignancies. Our aim was to investigate the prognostic significance of the immune microenvironment in patients with stage I lung adenocarcinoma (ADC).
Patients and Methods
Using tissue microarray and immunohistochemistry, we investigated eight types of tumor-infiltrating immune cells in the tumor nest and tumor-associated stroma as well as tumor expression of five cytokines in a uniform cohort of 956 patients with stage I lung ADC (478 each in training and validation cohorts).
Results
Although a high density of stromal forkhead box P3 (FoxP3) –positive cells was associated with shorter recurrence-free probability (RFP; P = .043), the relative proportion of stromal FoxP3 to CD3 was a stronger predictor of recurrence (5-year RFP, 85% for high v 77% for low ratio; P = .004). High expression of tumor interleukin-12 receptor β2 (IL-12Rβ2) was associated with better outcome (5-year RFP, 90% for high v 80% for low expression; P = .026), whereas high expression of tumor IL-7R was associated with worse outcome (5-year RFP, 76% for high v 86% for low expression; P = .001). In multivariate analysis, these immune markers were independently associated with recurrence. Although IL-7R remained significant for poor overall survival, all the markers remained prognostic for recurrence in patients with stages IA and IB disease as well as for patients with tumors ≤ 2 cm.
Conclusion
Our investigation confirms the biologic and prognostic significance of the tumor immune microenvironment for patients with stage I lung ADC and provides support for its use to stratify clinical outcome and immunotherapeutic interventions.
doi:10.1200/JCO.2012.45.2052
PMCID: PMC3731922  PMID: 23269987
14.  Sun Exposure, Vitamin D Receptor Genetic Variants, and Risk of Breast Cancer in the Agricultural Health Study 
Environmental Health Perspectives  2013;122(2):165-171.
Background: Epidemiologic evidence suggests a negative relation between sunlight exposure and breast cancer risk. The hypothesized mechanism is sunlight-induced cutaneous synthesis of vitamin D.
Objectives: Our goal was to examine sun exposure and its interaction with vitamin D receptor (VDR) gene variants on breast cancer risk.
Methods: We examined sun exposure and breast cancer incidence among 31,021 private pesticide applicators’ wives, including 578 cases, enrolled in the prospective Agricultural Health Study cohort and followed 8.6 years on average. We estimated interactions between sun exposure, VDR variants, and breast cancer in a nested case–control study comprising 293 cases and 586 matched controls. Information on sun exposure was obtained by questionnaire at cohort enrollment. Relative risks were estimated using Cox proportional hazards regression for the cohort data and conditional logistic regression for the nested case–control data.
Results: We observed a small decrease in breast cancer risk in association with usual sun exposure of ≥ 1 hr/day (versus < 1 hr/day) 10 years before the start of follow-up among all participants [hazard ratio (HR) = 0.8; 95% CI: 0.6, 1.0]. The association appeared to be slightly stronger in relation to estrogen receptor–positive tumors (HR = 0.7; 95% CI: 0.5, 0.9) than estrogen receptor–negative tumors (HR = 1.1; 95% CI: 0.6, 2.1). The HR for joint exposure ≥ 1 hr/day of sunlight and one VDR haplotype was less than expected given negative HRs for each individual exposure (interaction p-value = 0.07).
Conclusion: Our results suggest that sun exposure may be associated with reduced risk of breast cancer, but we did not find clear evidence of modification by VDR variants. Larger studies are warranted, particularly among populations in whom low levels of usual sun exposure can be more precisely characterized.
Citation: Engel LS, Satagopan J, Sima CS, Orlow I, Mujumdar U, Coble J, Roy P, Yoo S, Sandler DP, Alavanja MC. 2014. Sun exposure, vitamin D receptor genetic variants, and risk of breast cancer in the Agricultural Health Study. Environ Health Perspect 122:165–171; http://dx.doi.org/10.1289/ehp.1206274
doi:10.1289/ehp.1206274
PMCID: PMC3915256  PMID: 24252436
15.  Lungs don’t forget: Comparison of the KRAS and EGFR mutation profile and survival of “collegiate smokers” and never smokers with advanced lung cancers 
HYPOTHESIS
We hypothesize that among patients with lung cancers the KRAS/EGFR mutation profile and overall survival of “collegiate smokers” (former smokers who smoked between 101 lifetime cigarettes and 5 pack years) are distinct from those of never smokers and former smokers with ≥ 15 pack years.
METHODS
We collected age, sex, stage, survival, and smoking history for patients evaluated from 2004 to 2009 with advanced stage lung cancers and known KRAS/EGFR status. Mutation profile and overall survival were compared using Fisher’s exact test and log-rank test, respectively.
RESULTS
Data were available for 852 patients with advanced stage lung cancers with known KRAS/EGFR status. 6% were “collegiate smokers”, 36% were never smokers, and 30% were former smokers with ≥ 15 pack years. The mutation profile of “collegiate smokers” (15% KRAS mutations, 27% EGFR mutations) was distinct from those of never smokers (p < .001) and former smokers with ≥ 15 pack years (p < .001)and not significantly different from those of former smokers with 5 to 15 pack years (p = 0.9). Median overall survival for “collegiate smokers” was 25 months, compared to 32 months for never smokers (p = 0.4), 33 months for former smokers with 5–15 pack years (p = 0.48),and 21 months for former smokers with ≥ 15 pack years (p = 0.63).
CONCLUSIONS
“Collegiate smokers” with advanced stage lung cancers represent a distinct subgroup of patients with a higher frequency of KRAS mutations and lower frequency of EGFR mutations compared to never smokers. These observations reinforce the recommendation for routine mutation testing for all patients with lung cancers and that no degree of tobacco exposure is safe.
doi:10.1097/JTO.0b013e31827914ea
PMCID: PMC3534987  PMID: 23242442
Collegiate Smokers; non-small cell lung cancers; epidermal growth factor receptor mutation; KRAS mutation
16.  Toxicity of initial chemotherapy in older patients with lung cancers 
Journal of geriatric oncology  2012;4(1):64-70.
Objectives
Despite the growing number of elderly patients with lung cancers, we lack adequate information about how best to treat them. A phase III trial demonstrated a survival benefit of doublet chemotherapy in elderly patients with lung cancers compared to single agents at the cost of increased toxicity. We undertook this study to identify and describe chemotherapy-associated toxicity patterns among elderly patients treated for lung cancers.
Materials and methods
We reviewed records of patients age 70 or older with metastatic lung cancers who received initial chemotherapy at the Memorial Sloan-Kettering Cancer Center during 2008 and 2009.
Results
We identified 70 patients: 28 (40%) completed at least 4 cycles of chemotherapy without dose reduction but 31 (44%) required hospitalization for toxicity. Baseline albumin <3.5 g/dL and anemia were associated with grade 3–5 chemotherapy-associated toxicity. Also, an increase in platelets from cycle 1 to cycle 2 was associated with chemotherapy-associated toxicity. No other statistically significant associations between chemotherapy-associated toxicity and putative biologic and functional risk factors, including age and performance status, were identified.
Conclusion
Patients deemed eligible for chemotherapy by their physicians were just as likely to have severe chemotherapy-associated toxicity requiring hospitalization as to finish an initial course of therapy without any serious problems. An increase in platelet count from cycle 1 to cycle 2 was associated with increased toxicity. Additional research, such as exploration of inflammatory cytokines (PDGF, IL6, and IGF-1) to identify the mechanisms of chemotherapy tolerance and prospective evaluation and validation of existing metrics, is needed so that all patients can be appropriately risk stratified.
doi:10.1016/j.jgo.2012.09.003
PMCID: PMC3601754  PMID: 23525607
Elderly; Chemotherapy toxicity; Lung cancers; Geriatric assessment
17.  Exploratory Analysis of Serum CA-125 Response to Surgery and the Risk of Relapse in Patients with FIGO Stage IIIC Ovarian Cancer 
Gynecologic oncology  2009;115(2):10.1016/j.ygyno.2009.06.038.
Objective
To analyze whether serum CA-125 response to cytoreductive surgery before initiation of postoperative chemotherapy is associated with progression-free survival (PFS) in patients with stage IIIC ovarian carcinoma.
Methods
We included consecutive patients with paired pre- and postoperative CA-125 measurements who underwent primary cytoreductive surgery followed by platinum-based chemotherapy between 1989 and 2006. The association of perioperative CA-125 changes with PFS was investigated using a time-to-event analysis. A Cox proportional hazards model was fit using clinical, surgical, and postoperative treatment characteristics.
Results
The study included 307 evaluable patients. Overall, perioperative serum CA-125 changes were associated with PFS. The risk of disease progression increased incrementally as the magnitude of the serum CA-125 response to surgery decreased (trend test; P=0.003). This association was pronounced in optimally but not observed in suboptimally debulked patients. After optimal cytoreduction, a perioperative increase of serum CA-125 levels was strongly associated with an increased risk of relapse compared to patients who experienced a decline of 80% or more (adjusted HR=4.2; 95%CI: 2.04-8.66; P=0.0001).
Conclusion
Perioperative serum CA-125 changes are strongly associated with the risk of relapse in patients with optimally resected stage IIIC disease. The results of this study provide meaningful support for additional translational research correlating perioperative serum CA-125 responses of patients with molecular tumor characteristics. This may be useful for patient counseling and risk stratification during subsequent clinical trials as well as for the development of novel prognostic models.
doi:10.1016/j.ygyno.2009.06.038
PMCID: PMC3870341  PMID: 19664812
Perioperative serum CA-125 changes; CA-125; advanced epithelial ovarian cancer; ovarian cancer; surgery
18.  Driver Mutations Determine Survival in Smokers and Never Smokers with Stage IIIB/IV Lung Adenocarcinomas 
Cancer  2012;118(23):5840-5847.
Background
We previously demonstrated that stage IIIB/IV non-small cell lung cancer (NSCLC) never smokers lived 50% longer than former/current smokers. This observation persisted after adjusting for age, performance status, and gender. We hypothesized that smoking-dependent differences in the distribution of driver mutations might explain differences in prognosis between these subgroups.
Methods
We reviewed 293 never smokers and 382 former/current smokers with lung adenocarcinoma who underwent testing for EGFR and KRAS mutations and rearrangements in ALK between 2009 and 2010. Clinical outcomes and patient characteristics were collected. Survival probabilities were estimated using the Kaplan-Meier method. Group comparison was performed with log-rank tests and Cox proportional hazards methods.
Results
While the overall incidence of these mutations was nearly identical (55% never smokers vs. 57% current/former smokers, p=0.48), there were significant differences in the distribution of mutations between these groups: EGFR mutations- 37% never smokers vs. 14% former/current smokers (p<0.0001); KRAS mutations- 4% never smokers vs. 43% former/current smokers (p<0.0001); ALK rearrangements- 12% never smokers vs. 2% former/current smokers (p<0.0001). Among never smokers and former/current smokers, prognosis differed significantly by genotype. Patients harboring KRAS mutations demonstrated the poorest survival. Smoking status, however, had no influence on survival within each genotype.
Conclusion
Never smokers and former/current smokers with lung adenocarcinomas are not homogeneous subgroups. Each is made up of individuals whose tumors have a unique distribution of driver mutations which are associated with different prognoses, irrespective of smoking history.
doi:10.1002/cncr.27637
PMCID: PMC3424296  PMID: 22605530
non-small cell lung cancer; adenocarcinoma; EGFR; KRAS; ALK; never smoker
19.  Vitamin D receptor gene haplotypes and polymorphisms and risk of breast cancer: a nested case-control study 
Background
Observational and experimental studies suggest that vitamin D may influence breast cancer etiology. Most known effects of vitamin D are mediated via the vitamin D receptor (VDR). Few polymorphisms in the VDR gene have been well studied in relation to breast cancer risk and results have been inconsistent.
Methods
We investigated VDR polymorphisms and haplotypes in relation to breast cancer risk by genotyping 26 single nucleotide polymorphisms (SNPs) that i) had known/suspected impact on VDR function, ii) were tagging SNPs for the three VDR haplotype blocks among whites, or iii) were previously associated with breast cancer risk. We estimated odds ratios (OR) and 95% confidence intervals (CI) in relation to breast cancer risk among 270 incident cases and 554 matched controls within the Agricultural Health Study cohort.
Results
In individual SNP analyses, homozygous carriers of the minor allele for rs2544038 had significantly increased breast cancer risk (OR=1.5; 95% CI: 1.0, 2.5) and homozygous carriers of the minor allele for rs11168287 had significantly decreased risk (OR=0.6; 95% CI: 0.4, 1.0). Carriers of the minor allele for rs2239181 exhibited marginally significant association with risk (OR=1.4; 95% CI: 0.9, 2.0). Haplotype analyses revealed three haplotype groups (blocks “A”, “B”, and “C”). Haplotype GTCATTTCCTA in block B was significantly associated with reduced risk (OR=0.5; 95% CI: 0.3, 0.9).
Conclusions
These results suggest that variation in VDR may be associated with breast cancer risk.
Impact
Our findings may help guide future research needed to define the role of vitamin D in breast cancer prevention.
doi:10.1158/1055-9965.EPI-12-0551
PMCID: PMC3483029  PMID: 22892281
vitamin D receptor; VDR; haplotype; genotype; breast cancer; nested case-control study
20.  Distinct profile of driver mutations and clinical features in immunomarker-defined subsets of pulmonary large cell carcinoma 
Pulmonary large cell carcinoma - a diagnostically and clinically controversial entity - is defined as a non-small cell carcinoma lacking morphologic differentiation as either adenocarcinoma or squamous cell carcinoma, but suspected to represent an end-stage of poor differentiation of these tumor types. Given the recent advances in immunohistochemistry to distinguish adenocarcinoma and squamous cell carcinoma, and the recent insights that several therapeutically-relevant genetic alterations are distributed differentially in these tumors, we hypothesized that immunophenotyping may stratify large cell carcinomas into subsets with distinct profiles of targetable driver mutations. We therefore analyzed 102 large cell carcinomas by immunohistochemistry for TTF-1 and ΔNp63/p40 as classifiers for adenocarcinoma and squamous cell carcinoma, respectively, and correlated the resulting subtypes with 9 therapeutically-relevant genetic alterations characteristic of adenocarcinoma (EGFR, KRAS, BRAF, MAP2K1/MEK1, NRAS, ERBB2/HER2 mutations and ALK rearrangements) or more common in squamous cell carcinoma (PIK3CA and AKT1 mutations). The immunomarkers classified large cell carcinomas as variants of adenocarcinoma (n=62; 60%), squamous cell carcinoma (n=20; 20%), or marker-null (n=20; 20%). Genetic alterations were found in 38 cases (37%), including EGFR (n=1), KRAS (n=30), BRAF (n=2), MAP2K1 (n=1), ALK (n=3) and PIK3CA (n=1). All molecular alterations characteristic of adenocarcinoma occurred in tumors with immunoprofiles of adenocarcinoma or marker-null, but not in tumors with squamous immunoprofiles (combined mutation rate 50% vs 30% vs 0%, respectively; P<0.001), whereas the sole PIK3CA mutation occurred in a tumor with squamous profile (5%). Furthermore, marker-null large cell carcinomas were associated with significantly inferior disease-free (P<0.001) and overall (P=0.001) survival. In conclusion, the majority (80%) of large cell carcinomas can be classified by immunomarkers as variants of adenocarcinoma or squamous cell carcinoma, which stratifies these tumors into subsets with a distinct distribution of driver mutations and distinct prognoses. These findings have practical implications for diagnosis, predictive molecular testing and therapy selection.
doi:10.1038/modpathol.2012.195
PMCID: PMC3594043  PMID: 23196793
large cell carcinoma; TTF-1; ΔNp63/p40; EGFR; KRAS; ALK
21.  Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients 
Purpose
Mesothelin (MSLN) is a tumor-associated antigen, being investigated as a biomarker and therapeutic target in malignant pleural mesothelioma (MPM). The biological function of MSLN overexpression in MPM is unknown. We hypothesized that MSLN may promote tumor invasion in MPM, a tumor characterized primarily by regional aggressiveness and rare distant metastases.
Experimental Design
Human and murine MPM cells with MSLN forced expression and shRNA knockdown were examined for proliferation, invasion, and matrix metalloproteinase (MMP) secretion. The influence of MSLN overexpression on MPM cell invasion was assessed in an orthotopic mouse model and in patient samples.
Results
MSLN expression promotes MPM cell invasion and MMP secretion in both human and murine MPM cells. In an orthotopic MPM mouse model characterized by our laboratory, MPM cells with MSLN overexpression preferentially localized to the tumor invading edge, co-localized with MMP-9 expression, and promoted decreased survival without an increase in tumor burden progression. In a tissue microarray from epithelioid MPM patients (n=139, 729 cores), MSLN overexpression correlated with higher MMP-9 expression at individual core level. Among stage III MPM patients (n=72), high MSLN expression was observed in 26% of T2 tumors and 51% of T3 tumors.
Conclusions
Our data provide evidence elucidating a biological role for MSLN as a factor promoting tumor invasion and MMP-9 expression in MSLN-expressing MPM. As regional invasion is the characteristic feature in MSLN-expressing solid cancers (MPM, pancreas, and ovarian), our observations add rationale to studies investigating MSLN as a therapeutic target.
doi:10.1158/1078-0432.CCR-11-2614
PMCID: PMC3759995  PMID: 22371455
Mesothelin; mesothelioma; matrix metalloproteinase; tumor invasion; locoregional aggressiveness
22.  Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib – implications for clinical trial design 
Purpose:
Treatment of patients with oncogene-addicted cancers with tyrosine kinase inhibitors (TKI) is biologically and clinically different than with cytotoxic chemotherapy. We have observed that some patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib (RECIST progression after initial benefit) have accelerated progression of disease after discontinuation of TKI. To examine this observation and define the course of patients following TKI discontinuation, we systematically evaluated patients enrolled on clinical trials of agents to treat acquired resistance to erlotinib or gefitinib.
Methods:
We evaluated patients with EGFR-mutant lung cancer who participated in trials for patients with acquired resistance which mandated TKI discontinuation prior to administration of study therapy. Disease flare was defined as hospitalization or death attributable to disease progression during the “washout” period.
Results:
Fourteen of 61 patients (23%; 95% CI 14-35%) experienced a disease flare. The median time to disease flare after TKI discontinuation was 8 days (range 3-21). Factors associated with disease flare included shorter time to progression on initial TKI (p=0.002) and the presence of pleural (p=0.03) or CNS disease (p=0.01). There was no association between disease flare and the presence of T790M at the time of acquired resistance.
Conclusion:
In patients with EGFR-mutant lung cancer and acquired resistance to EGFR TKIs, discontinuation of erlotinib or gefitinib prior to initiation of study treatment is associated with a clinically significant risk of accelerated disease progression. Clinical trials in this patient population must minimize protocol mandated washout periods.
doi:10.1158/1078-0432.CCR-11-1468
PMCID: PMC3756539  PMID: 21856766
EGFR; adenocarcinoma of lung; drug resistance
23.  Cancer Screening Among Patients With Advanced Cancer 
Context
Cancer screening has been integrated into routine primary care but does not benefit patients with limited life expectancy.
Objective
To evaluate the extent to which patients with advanced cancer continue to be screened for new cancers.
Design, Setting, and Participants
Utilization of cancer screening procedures (mammography, Papanicolaou test, prostate-specific antigen [PSA], and lower gastrointestinal [GI] endoscopy) was assessed in 87 736 fee-for-service Medicare enrollees aged 65 years or older diagnosed with advanced lung, colorectal, pancreatic, gastroesophageal, or breast cancer between 1998 and 2005, and reported to one of the Surveillance, Epidemiology, and End Results (SEER) tumor registries. Participants were followed up until death or December 31, 2007, whichever came first. A group of 87 307 Medicare enrollees without cancer were individually matched by age, sex, race, and SEER registry to patients with cancer and observed over the same period to evaluate screening rates in context. Demographic and clinical characteristics associated with screening were also investigated.
Main Outcome Measure
For each cancer screening test, utilization rates were defined as the percentage of patients who were screened following the diagnosis of an incurable cancer.
Results
Among women following advanced cancer diagnosis compared with controls, at least 1 screening mammogram was received by 8.9% (95% confidence interval [CI], 8.6%-9.1%) vs 22.0% (95% CI, 21.7%-22.5%); Papanicolaou test screening was received by 5.8% (95% CI, 5.6%-6.1%) vs 12.5% (95% CI, 12.2%-12.8%). Among men following advanced cancer diagnosis compared with controls, PSA test was received by 15.0% (95% CI, 14.7%-15.3%) vs 27.2% (95% CI, 26.8%-27.6%). For all patients following advanced diagnosis compared with controls, lower GI endoscopy was received by 1.7% (95% CI, 1.6%-1.8%) vs 4.7% (95% CI, 4.6%-4.9%). Screening was more frequent among patients with a recent history of screening (16.2% [95% CI, 15.4%-16.9%] of these patients had mammography, 14.7% [95% CI, 13.7%-15.6%] had a Papanicolaou test, 23.3% [95% CI, 22.6%-24.0%] had a PSA test, and 6.1% [95% CI, 5.2%-7.0%] had lower GI endoscopy).
Conclusion
A sizeable proportion of patients with advanced cancer continue to undergo cancer screening tests that do not have a meaningful likelihood of providing benefit.
doi:10.1001/jama.2010.1449
PMCID: PMC3728828  PMID: 20940384
24.  High-SUVmax on FDG-PET indicates pleomorphic subtype in epithelioid malignant pleural mesothelioma: Supportive evidence to reclassify pleomorphic as non-epithelioid histology 
Background
We have recently proposed to reclassify the pleomorphic subtype of epithelioid malignant pleural mesothelioma (MPM) as non-epithelioid (biphasic/sarcomatoid) histology due to its similarly poor prognosis. We sought to investigate whether preoperative maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) correlates with histologic subtype in MPM.
Methods
Clinical data was collected for 78 patients with MPM who underwent preoperative FDG-PET. We retrospectively classified the epithelioid tumors into five subtypes: trabecular, tubulopapillary, micropapillary, solid and pleomorphic. Tumors were categorized by SUVmax into two groups: low (<10.0) and high (≥10.0).
Results
The median overall survival of epithelioid tumors with high-SUVmax (n=12) was significantly shorter (7.1 months) than that of epithelioid tumors with low-SUVmax (n=54, 18.9 months, p<0.001) and comparable to non-epithelioid tumors (n=12, 7.2 months). Epithelioid tumors with pleomorphic subtype (n=9) had marginally higher SUVmax (mean±SD: 10.6±5.9) than epithelioid non-pleomorphic subtype (n=57, 6.5±3.2, p=0.050), and were comparable to that of non-epithelioid tumors (n=12, 9.1±4.8). Among the epithelioid tumors with high-SUVmax (n=12), 50% (n=6) showed pleomorphic subtype. In contrast, among epithelioid tumors with low-SUVmax (n=54), 6% (n=3) showed epithelioid pleomorphic subtypes (p=0.001). A positive correlation between mitotic count and SUVmax was observed (r=0.30, p=0.010).
Conclusions
Pleomorphic subtype of epithelioid MPM showed higher SUVmax than epithelioid non-pleomorphic subtype and was similar to non-epithelioid histology. Preoperative SUVmax on FDG-PET in epithelioid MPM can indicate patients with pleomorphic subtype with poor prognosis, supporting their reclassification as non-epithelioid.
doi:10.1097/JTO.0b013e3182519d96
PMCID: PMC3691682  PMID: 22617244
Mesothelioma; Pleural neoplasm; Positron emission tomography; Pleomorphic
25.  Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors 
Background
Development of acquired resistance limits the utility of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) for the treatment of EGFR mutant lung cancers. There are no accepted, targeted therapies for use after acquired resistance develops. Metastasectomy is used in other cancers to manage oligometastatic disease. We hypothesized that local therapy is associated with improved outcomes in patients EGFR mutant lung cancers with acquired resistance to EGFR TKI.
Methods
Patients who received non-CNS local therapy were identified by a review of data from a prospective biopsy protocol for patients with EGFR-mutant lung cancers with acquired resistance to EGFR TKI therapy and other institutional biospecimen registry protocols.
Results
Eighteen patients were identified that received elective local therapy (surgical resection, radiofrequency ablation or radiation). Local therapy was well-tolerated, with 85% of patients restarting TKI therapy within one month of local therapy. The median time to progression after local therapy was 10 months (95% Confidence interval [CI]: 2 to 27 months). The median time until a subsequent change in systemic therapy was 22 months (95% CI: 6 to 30 months). The median overall survival from local therapy was 41 months (95% CI: 26 to not reached).
Conclusions
EGFR- mutant lung cancers with acquired resistance to EGFR TKI therapy are amenable to local therapy to treat oligometastatic disease when used in conjunction with continued EGFR inhibition. Local therapy followed by continued treatment with an EGFR TKI is well tolerated, and associated with long PFS and OS. Further study in selected individuals in the context of other systemic options is required.
doi:10.1097/JTO.0b013e31827e1f83
PMCID: PMC3673295  PMID: 23407558

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