PIK3CA encodes the p110α subunit of the mitogenic signaling protein phosphatidylinositol 3-kinase (PI3K). PIK3CA mutations in the helical binding domain and the catalytic subunit of the protein have been associated with tumorigenesis and treatment resistance in various malignancies. Characteristics of patients with PIK3CA-mutant lung adenocarcinomas have not been reported.

We examined EGFR, KRAS, BRAF, HER2, PIK3CA, AKT1, NRAS, MEK1, and ALK in patients with adenocarcinoma of the lung to identify driver mutations. Clinical data were obtained from the medical records of individuals with mutations in PIK3CA.

Twenty-three of 1125 (2%, 95% confidence interval (CI) 1–3%) patients had a mutation in PIK3CA, 12 in Exon 9 (10 E545K, 2 E542K) and 11 in Exon 20 (3 H1047L, 8 H1047R). The patients (57% women) had a median age of 66 at diagnosis (range 34–78). Eight patients (35%) were never smokers. Sixteen of 23 (70%, 95% CI 49 – 86%) had coexisting mutations in other oncogenes - 10 KRAS, 1 MEK1, 1 BRAF, 1 ALK rearrangement, and 3 EGFR exon 19 deletions.

We conclude that PIK3CA mutations occur in lung adenocarcinomas, usually concurrently with EGFR, KRAS, and ALK. The impact of PIK3CA mutations on the efficacy of targeted therapies such as erlotinib and crizotinib is unknown. Given the high frequency of overlapping mutations, comprehensive genotyping should be performed on tumor specimens from patients enrolling on clinical trials of PI3K and other targeted therapies.

Background

Mesothelin is overexpressed in several malignancies and is purportedly a specific marker of malignant transformation. In this pilot study, we investigated whether tissue and serum mesothelin are potential markers of neoplastic progression in Barrett’s esophagus (BE) and in esophageal adenocarcinoma (EAC).

Methods

Mesothelin expression was retrospectively evaluated in normal, BE, and EAC tissue from surgically resected esophageal specimens (n = 125). In addition, soluble mesothelin-related peptide (SMRP) levels were measured in serum.

Results

Normal esophageal mucosa did not express mesothelin. BE tissue with high-grade dysplasia specifically expressed mesothelin, whereas BE tissue with low-grade or without dysplasia did not. Fifty-seven (46%) EAC tumors were positive for mesothelin. EAC tumors with BE expressed mesothelin more often than those without BE (58% vs 35%, P = 0.01). SMRP levels were elevated in 70% of EAC patients (mean, 0.89 nM; range, 0.03-3.77 nM), but not in patients with acid reflux and/or BE.

Conclusions

Mesothelin is commonly expressed in BE-associated esophageal adenocarcinoma. Based on this pilot study, a prospective study is under way to evaluate tissue and serum mesothelin are potential markers of neoplastic progression in BE and in EAC (NCT01393483).

Impact

Current surveillance methods in Barrett’s esophagus are invasive and neither cost-effective nor sensitive. This pilot study suggests that serum mesothelin is a marker of neoplastic transformation in BE and may provide a noninvasive method to improve identification of malignant transformation.

Purpose

Paclitaxel is an effective therapy for patients with solid tumors. While the albumin-bound formulation eliminates the hypersensitivity reaction caused by the Cremaphor solvent, significant peripheral neuropathy persists when given over the standard 30-minute infusion time. We sought to determine if the incidence and severity of peripheral neuropathy could be reduced when the infusion time is lengthened to 2-hours.

Methods

This was an open-label, single-arm, phase 2 study of albumin-bound paclitaxel given over 2-hours. Twenty-five patients with advanced non-small cell lung cancer were enrolled to determine whether the longer infusion reduced the severity of neuropathy compared to data from an earlier cohort of 40 similar patients treated over 30-minutes. Patients received 125 mg/m2 of albumin-bound paclitaxel IV over 2-hours without premedication on days 1, 8, and 15 of a 28-day cycle. Radiologic assessment was performed every 8 weeks.

Results

There was a significant 0.45 grade decrease in average peripheral neuropathy experienced by patients in the 2-hour group versus the 30-minute group (90% CI 0.03–0.87). There was, in addition, a significant decrease in grade ≥ 2 peripheral neuropathy in patients treated over 2-hours versus 30-minutes (28% vs. 55%, 2-sided P = .04). A decrease in grade ≥ 2 neutropenia (20% vs. 48%, 2-sided P = .07) was also observed. The median survival, 11 months, was the same for both groups.

Conclusion

Increasing the infusion time of albumin-bound paclitaxel from 30-minutes to 2-hours resulted in a significant reduction in both average and grade ≥ 2 peripheral neuropathy without affecting survival.

Purpose

Given the unprecedented efficacy of EGFR tyrosine kinase inhibitors (TKI) in advanced EGFR-mutant lung cancer, adjuvant TKI therapy is an appealing strategy. However, there are conflicting findings regarding the potential benefit of adjuvant EGFR-TKI in patients with lung cancer harboring EGFR mutations. To better understand these results, we studied the natural history of lung cancers which recurred despite adjuvant TKI.

Experimental design

Patients with recurrent EGFR-mutant lung cancer following adjuvant TKI were identified using an IRB approved mechanism. Recurrent cancer specimens were tested for resistance mutations. Sensitivity to re-treatment with EGFR-TKI was evaluated.

Results

Twenty-two patients with cancers harboring an EGFR sensitizing mutation received adjuvant erlotinib or gefitinib for a median of 17 months (range 1–37 months). T790M was more common in cancers which recurred while receiving TKI than in those which recurred after stopping TKI (67% vs. 0%, p=0.011). Fourteen patients who developed recurrence after stopping EGFR-TKI were re-treated, with a median time to progression of 10 months and radiographic response seen in 8 of 11 patients with evaluable disease (73%).

Conclusions

Recurrence of EGFR-mutant lung cancer after stopping adjuvant TKI should not preclude a trial of TKI re-treatment; a phase II trial of erlotinib in this setting is underway. Studies of adjuvant EGFR-TKI will underestimate the potential survival benefit of adjuvant TKI for patients with EGFR-mutant lung cancers if re-treatment at recurrence is not given.

Purpose

We use changes in tumor measurements to assess response and progression, both in routine care and as the primary objective of clinical trials. However, the variability of computed tomography (CT) –based tumor measurement has not been comprehensively evaluated. In this study, we assess the variability of lung tumor measurement using repeat CT scans performed within 15 minutes of each other and discuss the implications of this variability in a clinical context.

Patients and Methods

Patients with non–small-cell lung cancer and a target lung lesion ≥ 1 cm consented to undergo two CT scans within a period of minutes. Three experienced radiologists measured the diameter of the target lesion on the two scans in a side-by-side fashion, and differences were compared.

Results

Fifty-seven percent of changes exceeded 1 mm in magnitude, and 33% of changes exceeded 2 mm. Median increase and decrease in tumor measurements were +4.3% and −4.2%, respectively, and ranged from 23% shrinkage to 31% growth. Measurement changes were within ± 10% for 84% of measurements, whereas 3% met criteria for progression according to Response Evaluation Criteria in Solid Tumors (RECIST; ≥ 20% increase). Smaller lesions had greater variability of percent measurement change (P = .005).

Conclusion

Apparent changes in tumor diameter exceeding 1 to 2 mm are common on immediate reimaging. Increases and decreases less than 10% can be a result of the inherent variability of reimaging. Caution should be exercised in interpreting the significance of small changes in lesion size in the care of individual patients and in the interpretation of clinical trial results.

Background

Inflammation, as measured by the circulating inflammatory marker high sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data regarding CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial demonstrated that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined if serum hsCRP modified these results.

Methods

We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive three years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at Year 1 and 3.

Results

Among 1,680 patients, the estimated three-year cumulative incidence of adenoma was 42% for patients with hsCRP <1mg/L, compared with 43% (RR=1.02; 95% confidence interval (CI)=0.85–1.22) for hsCRP 1–3mg/L, and 41% (RR=1.1; CI=0.90–1.34) for hsCRP >3mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3mg/L) compared with low (≦3mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95%CI=0.72–7.14) for those randomized to celecoxib 200-mg-bid and 3.28 (CI=1.09–9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (CI=0.53–1.83) and 1.11 (CI=0.61–2.02).

Conclusions

HsCRP may predict risk of celecoxib-associated cardiovascular toxicity, but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention.

Purpose

BRAF mutations occur in non–small-cell lung cancer. Therapies targeting BRAF mutant tumors have recently been identified. We undertook this study to determine the clinical characteristics of patients with lung adenocarcinomas harboring BRAF mutations.

Patients and Methods

We reviewed data from consecutive patients with lung adenocarcinoma whose tumors underwent BRAF, EGFR, and KRAS mutation testing as well as fluorescence in situ hybridization for ALK rearrangements. Patient characteristics including age, sex, race, performance status, smoking history, stage, treatment history, and overall survival were collected.

Results

Among 697 patients with lung adenocarcinoma, BRAF mutations were present in 18 patients (3%; 95% CI, 2% to 4%). The BRAF mutations identified were V600E (50%), G469A (39%), and D594G (11%). Mutations in EGFR were present in 24%, KRAS in 25%, and ALK translocations in 6%. In contrast to patients with EGFR mutations and ALK rearrangements who were mostly never smokers, all patients with BRAF mutations were current or former smokers (P < .001). The median overall survival of advanced-stage patients with BRAF mutations was not reached. In comparison, the median overall survival of patients with EGFR mutations was 37 months (P = .73), with KRAS mutations was 18 months (P = .12), and with ALK rearrangements was not reached (P = .64).

Conclusion

BRAF mutations occur in 3% of patients with lung adenocarcinoma and occur more commonly in current and former smokers. The incidence of BRAF mutations other than V600E is significantly higher in lung cancer than in melanoma.

Purpose

EGFR mutations underlie the sensitivity of lung cancers to erlotinib and gefitinib and can occur in any patient with this illness. Here we examine the frequency of EGFR mutations in smokers and men.

Methods

We determined the frequency of EGFR mutations and characterized their association with cigarette smoking status and male sex.

Results

We tested 2,142 lung adenocarcinoma specimens for the presence of EGFR exon 19 deletions and L858R. EGFR mutations were found in 15% of tumors from former smokers (181 of 1,218; 95% CI, 13% to 17%), 6% from current smokers (20 of 344; 95% CI, 4% to 9%), and 52% from never smokers (302 of 580; 95% CI, 48% to 56%; P < .001 for ever v never smokers). EGFR mutations in former or current smokers represented 40% of all those detected (201 of 503; 95% CI, 36% to 44%). EGFR mutations were found in 19% (157 of 827; 95% CI, 16% to 22%) of tumors from men and 26% (346 of 1,315; 95% CI, 24% to 29%) of tumors from women (P < .001). EGFR mutations in men represented 31% (157 of 503; 95% CI, 27% to 35%) of all those detected.

Conclusion

A large number of EGFR mutations are found in adenocarcinoma tumor specimens from men and people who smoked cigarettes. If only women who were never smokers were tested, 57% of all EGFR mutations would be missed. Testing for EGFR mutations should be considered for all patients with adenocarcinoma of the lung at diagnosis, regardless of clinical characteristics. This strategy can extend the use of EGFR tyrosine kinase inhibitors to the greatest number individuals with the potential for substantial benefit.

Structured Abstract

Introduction

The detection of mutations in the epidermal growth factor receptor (EGFR) gene, which predict sensitivity to treatment with EGFR tyrosine kinase inhibitors (TKIs), represents a major advance in the treatment of lung adenocarcinoma. KRAS mutations confer resistance to EGFR -TKIs. The prevalence of these mutations in African-American patients has not been thoroughly investigated.

Methods

We collected formalin-fixed, paraffin-embedded material from resected lung adenocarcinomas from African-American patients at three institutions for DNA extraction. The frequencies of EGFR exon 19 deletions, exon 21 L858R substitutions and KRAS mutations in tumor specimens from African-American patients were compared to data in Caucasian patients (n=476).

Results

EGFR mutations were detected in 23 of the 121 specimens from African-American patients (19%, 95% CI 13–27%), while KRAS mutations were found in 21 (17%, 95% CI 12−25%). There was no significant difference between frequencies of EGFR mutations comparing African-American and Caucasian patients, 19% vs. 13% (61/476, 95% CI 10–16%) (p=0.11). KRAS mutations were more likely among Caucasians, 26% (125/476, 95% CI 23−30%) (p=0.04).

Conclusions

This is the largest study to date examining the frequency of mutations in lung adenocarcinomas in African-Americans. Although KRAS mutations were somewhat less likely, there was no difference between the frequencies of EGFR mutations in African-American patients as compared to Caucasians. These results suggest that all patients with advanced lung adenocarcinomas should undergo mutational analysis prior to initiation of therapy.

Purpose

Patients with EGFR-mutant lung adenocarcinoma develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) after a median of 10–16 months. In half of these cases a second EGFR mutation, T790M, underlies acquired resistance. We undertook this study to examine the clinical course of patients harboring the T790M mutation following progression on TKI.

Experimental design

EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective re-biopsy protocol where post-progression tumor specimens were collected for molecular analysis. Post-progression survival and characteristics of disease progression were compared in patients with and without T790M.

Results

We identified T790M in the initial re-biopsy specimens from 58/93 patients (62%, 95% confidence interval 52%–72%). T790M was more common in biopsies of lung/pleura tissue and lymph nodes than in more distant sites (p=0.014). Median post-progression survival was 16 months (interquartile range 9–29 months); patients with T790M had a significantly longer post-progression survival (p=0.036). Patients without T790M more often progressed in a previously uninvolved organ system (p=0.014) and exhibited a poorer performance status at time of progression (p=0.007).

Conclusions

Among patients with acquired resistance to EGFR TKIs, the presence of T790M defines a clinical subset with a relatively favorable prognosis and more indolent progression. Knowledge of T790M status is therefore important for the clinical care of these patients as well as for the optimal design and interpretation of clinical trials in this setting.

Introduction

Dual inhibition of SRC and EGFR -dependent pathways may overcome acquired resistance to EGFR-TKIs for patients with lung adenocarcinoma with EGFR mutations. The SRC-inhibitor dasatinib demonstrates anti-tumor activity in gefitinib-resistant cells lines and xenografts. Dasatinib is tolerable for patients with advanced non-small cell lung cancer, and in combination with erlotinib.

Methods

We conducted this phase II study of dasatinib 70 mg twice daily in patients with EGFR-mutant lung adenocarcinoma and acquired resistance to EGFR-TKIs. After a protocol amendment based upon evolving data about both drugs, patients received dasatinib at a dose of 100 mg daily with continued erlotinib after developing acquired resistance. Enrolled patients either harbored an activating mutation in EGFR or experienced clinical benefit with single-agent erlotinib or gefitinib, followed by RECIST documented progression while being treated with an EGFR-TKI.

Results

Twenty-one patients were enrolled, nine under the original trial design and 12 after the protocol amendments. We observed no complete or partial responses (0% observed rate, 95% CI 0–18%). The median time to progression was 0.5 months (range 0.2–1.8 months) in patients treated with dasatinib, and 0.9 months (range 0.4–5 months) for patients treated with dasatinib and erlotinib in combination. Pleural effusions and dyspnea were frequent toxicities.

Conclusions

Dasatinib has no activity in patients with EGFR-mutant lung adenocarcinoma with acquired resistance to erlotinib and gefitinib.

The Healthy Eating Index (HEI) was developed by the US Department of Agriculture with the goal of quantifying adherence to the Dietary Guidelines for Americans. The purpose of this study was to evaluate the impact of the HEI-2005 score and each of its components on endometrial cancer risk in a population-based case–control study in New Jersey. A total of 424 cases and 398 controls completed a Food Frequency Questionnaire, which was used to derive the HEI-2005 score. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression while adjusting for potential covariates, which included all major endometrial cancer risk factors. The adjusted OR for women in the highest quartile when compared to the lowest quartile was 0.83 (95% CI: 0.52–1.34). For the meat and beans component comprising meat, eggs, poultry, fish, and beans, the OR was 0.70 (95% CI: 0.45–1.11; p for trend: 0.07), with little evidence of an association with any of the individual foods. There was no indication of an association for any of the other components of the HEI or of effect modification by body mass index. This study suggested limited value for the HEI-2005 in predicting endometrial cancer risk.

Tumor biomarkers provide a quantitative tool for following tumor progression and response to therapy. However, investigations of clinically useful tumor biomarkers are time-consuming, costly, and limited by patient and tumor heterogeneity. In addition, assessment of biomarkers as indicators of therapy response is confounded by the concomitant use of multiple therapeutic interventions. Herein we report our use of a clinically relevant orthotopic animal model of malignant pleural mesothelioma for investigating tumor biomarkers. Utilizing multi-modality imaging with correlative histopathology, we demonstrate the utility and accuracy of the mouse model in investigating tumor biomarkers – serum soluble mesothelin-related peptide (SMRP) and osteopontin (OPN). This model revealed percentage change in SMRP level to be an accurate biomarker of tumor progression and therapeutic response – a finding consistent with recent clinical studies. This in vivo platform demonstrates the advantages of a validated mouse model for the timely and cost-effective acceleration of human biomarker translational research.

We evaluated the role of tea and coffee and substances added (sugar/honey, creamers, and milk) on endometrial cancer risk in a population-based case–control study in six counties in New Jersey, including 417 cases and 395 controls. Multivariate odds ratios (OR) and 95% confidence intervals (CI) were computed using unconditional logistic regression. There was a moderate inverse association with coffee consumption, with an adjusted OR of 0.65 (95% CI: 0.36–1.17) for women who reported more than two cups/day of coffee compared to none. Tea consumption appeared to increase risk (OR: 1.93; 95% CI: 1.08–3.45), but after including the variables sugar/honey and cream/milk added to tea in the model, the risk estimate was attenuated and no longer statistically significant (OR: 1.77; 95% CI: 0.96–3.28 for those consuming more than one cup/day of tea compared to nonusers). There was a suggestion of a decreased risk associated with green tea, but the confidence interval included one (adjusted OR for one or more cups/week vs. none: 0.75; 95% CI: 0.48–1.18). We found an association with adding sugar/honey to tea, with those adding two or more teaspoons/cup having an OR of 2.66 (95% CI: 1.42–4.98; p for trend <0.01) after adjusting for relevant confounders. For sugar/honey added to coffee the corresponding OR was 1.43 (95% CI: 0.81–2.55). Our results indicate that sugars and milk/cream added to coffee and tea should be considered in future studies evaluating coffee and tea and endometrial cancer risk.

Background

We undertook this study to characterize the relationship between survival of patients with stage IIIB/IV Non-Small Cell Lung Cancer (NSCLC) and pack years of cigarette smoking.

Methods

We analyzed data from patients with stage IIIB/IV NSCLC who had completed a prospective smoking questionnaire. We evaluated the impact of pack years of cigarette smoking, age, sex, Karnofsky Performance Status (KPS), and presence of weight loss >5% on overall survival using univariate and multivariate analyses.

Results

Smoking history and clinical data were available for 2,010 patients with stage IIIB/IV NSCLC (1004 women, 1006 men). Seventy percent (1409) smoked >15 pack years, 13% (270) were former and current smokers who had smoked ≤ 15 pack years, and 16% (331) were never smokers (<100 lifetime cigarettes). Never smokers had a longer median survival relative to former or current smokers (17.8 months vs 11.3 months, log rank p<0.001). Among smokers, patients with ≤ 15 pack year history of smoking had a longer median survival than patients who had smoked > 15 pack years (14.6 months vs 10.8 months, log rank p =0.03). As the number of pack years increased, the median overall survival decreased (log rank p <0.001). Multivariate analysis showed that history of smoking was an independent prognostic factor (Hazard Ratio 1.36; p<0.001).

Conclusions

More cigarette smoking, measured in pack years, was associated with decreased survival after diagnosis of stage IIIB/IV NSCLC. Trials assessing survival in stage IIIB/IV NSCLC should report detailed cigarette smoking history for all patients.

Phytoestrogens have been shown to exert anti-estrogenic and estrogenic effects in some tissues, including the breast. However, only a few studies have evaluated their role in endometrial cancer risk. We evaluated this association in a population-based case-control study in New Jersey. A total of 424 cases and 398 controls completed an interview, including a food frequency questionnaire with supplemental questions for phytoestrogen foods. Risk estimates were derived using unconditional logistic regression, adjusting for major risk factors for endometrial cancer. There was some suggestion of a decreased risk with quercetin intake (OR: 0.65; 95% CI: 0.41–1.01 for the highest compared to the lowest quartile; p for trend: 0.02). We found limited evidence of an association with any of the lignans evaluated, total lignans, coumestrol, individual isoflavones, total isoflavones, or total phytoestrogens. However, there was some suggestion of an inverse association with total isoflavone intake limited to lean women (BMI <25) (OR for the highest tertile: 0.50, 95% CI: 0.25–0.98) and those with a waist-to-hip ratio ≤0.85 (OR: 0.59; 95% CI: 0.33–1.05). There was no evidence of effect modification by HRT use. This study suggests a reduction in endometrial cancer risk with quercetin intake and with isoflavone intake in lean women.

We studied the relation of medical conditions related to obesity and medications used for these conditions with endometrial cancer. We also investigated the association of other medical conditions and medications with risk. This US population-based case-control study included 469 endometrial cancer cases and 467 controls. Information on putative risk factors for endometrial cancer was collected through personal interviews. We asked women about their medical history and medications used for six months or longer and the number of years each medication was taken. Risk was strongly associated with increasing obesity (p for trend <0.001). Among conditions related to obesity, and after adjustment for age, body mass index (BMI), and other risk factors and conditions, uterine fibroids were independently related to an increased cancer risk (adjusted OR= 1.8, 95%CI= 1.2–2.5). Although hypertension was not significantly related to endometrial cancer after adjustment for age and BMI, use of thiazide diuretics was independently associated with an increased risk (OR= 1.8, 95%CI= 1.1–3.0). Anemia was associated with decreased risk (OR= 0.6, 95%CI= 0.5–0.9). Use of non-steroidal anti-inflammatory drugs was related to a decreased risk (OR= 0.7, 95%CI= 0.5–0.97). To our knowledge, the observation about thiazide diuretics is novel and requires confirmation in other studies and populations.

We investigated the risk associated with variants in three genes involved in estrogen biosynthesis, CYP11A1, CYP17A1, and CYP19A1, in the population-based case control study of Estrogen, Diet, Genetics, and Endometrial Cancer. This study was conducted in New Jersey in 2001–2006 with 417 cases and 402 controls. For CYP11A1, there was no association between the number of [TTTTA]n repeats (D15S520) and risk. For CYP17A1, risk was somewhat lower among women with the C/C genotype at T-34C (rs743572) (adjusted OR=0.65, 95% CI 0.41–1.02). For CYP19A1, risk was lower among women homozygous for the 3-base pair deletion (rs11575899) in exon 4 (adjusted OR=0.44, 95% CI 0.26–0.76), while the number of [TTTA]n repeats was not significantly related to risk: the adjusted OR for n=7/7 repeats vs n>7/>7 repeats was 0.81 (95% CI 0.54–1.23). In stratified analyses, results for CYP19A1 were stronger among women with higher (>27.4) body mass index: for the homozygous deletion, OR=0.30 (95% CI 0.15–0.62); for the n=7/7 genotype, OR=0.49 (95% CI 0.26–0.93). The interaction between the n=7/7 genotype and BMI was statistically significant (p=0.01). The insertion/deletion variant in CYP19A1 appears to be related to risk of endometrial cancer; risk associated with variants in this gene may vary according to BMI.