who had undergone a lobectomy with mediastinal lymph node dissection were retrospectively reviewed. Comprehensive histological subtyping was used to estimate the percentage of each histological subtype and to identify the predominant subtype. Tumors were classified according to the proposed new IASLC/ATS/ERS adenocarcinoma classification. Statistical analyses were made including Kaplan-Meier and Cox regression analyses. There were 323 females (63%) and 191 males (37%) with a median age of 69 years (33-89 years) and 298 stage IA and 216 stage IB patients. Three overall prognostic groups were identified: low grade: adenocarcinoma in situ (n ¼ 1) and minimally invasive adenocarcinoma (n ¼ 8) had 100% 5-year disease-free survival; intermediate grade: non-mucinous lepidic predominant (n ¼ 29), papillary predominant (n ¼ 143) and acinar predominant (n ¼ 232) with 90, 83 and 84% 5-year disease-free survival, respectively; and high grade: invasive mucinous adenocarcinoma (n ¼ 13), colloid predominant (n ¼ 9), solid predominant (n ¼ 67) and micropapillary predominant (n ¼ 12), with 75, 7170 and 67%, 5-year disease-free survival, respectively (Po0.001). Among the clinicopathological factors, stage 1B versus 1A (Po0.001), male sex (Po0.008), high histological grade (Po0.001), vascular invasion (P ¼ 0.002) and necrosis (Po0.001) were poorer prognostic factors on univariate analysis. Both gross tumor size (P ¼ 0.04) and invasive tumor size adjusted by the percentage of lepidic growth (Po0.001) were significantly associated with disease-free survival with a slightly stronger association for the latter. Multivariate analysis showed the prognostic groups of the IASLC/ATS/ERS histological classification (P ¼ 0.038), male gender (P ¼ 0.007), tumor invasive size (P ¼ 0.026) and necrosis (P ¼ 0.002) were significant poor prognostic factors. In summary, the proposed IASLC/ATS/ERS classification of lung adenocarcinoma identifies histological categories with prognostic differences that may be helpful in

breast cancer in carriers of mutations in BRCA1 or BRCA2 is critical for guiding decisions concerning cancer prevention options. Many previous studies have reported on the cumulative risk to various ages (penetrance) of breast cancer in carriers. The recent literature primarily has involved studies of breast cancer incidence in the relatives of probands identified without consideration of family history. This literature has included studies of self-selected volunteers,1 but there appears to be some degree of consensus that the most reliable approach is to use populationbased ascertainment.2-8 Most of this literature has been focused on the magnitude of the risk, with relatively little attention being paid to the degree by which risk may vary among carriers.Population-based studies to date have used incident cases from existing casecontrol investigations as probands. Estimates of risk based on studies of in- ContextThe risk of breast cancer in BRCA1 and BRCA2 mutation carriers has been examined in many studies, but relatively little attention has been paid to the degree to which the risk may vary among carriers.Objectives To determine the extent to which risks for BRCA1 and BRCA2 carriers vary with respect to observable and unobservable characteristics. Main Outcome Measure Incidence of breast cancer in first-degree female relatives of the probands was examined and compared on the basis of proband characteristics and on the basis of variation between families.Results Among the 1394 participants with unilateral breast cancer, 73 (5.2%) were identified as carriers of deleterious mutations (42 with BRCA1 and 31 with BRCA2). Among the 704 participants with contralateral breast cancer, 108 (15.3%) were identified as carriers of deleterious mutations (67 with BRCA1 and 41 with BRCA2). Among relatives of carriers, risk was significantly associated with younger age at diagnosis in the proband (P=.04), and there was a trend toward higher risk for relatives of contralateral breast cancer vs unilateral breast cancer participants (odds ratio, 1.4 [95% confidence interval, 0.8-2.4]; P=.28). In addition, there were significant differences in risk between carrier families after adjusting for these observed characteristics. ConclusionThere exists broad variation in breast cancer risk among carriers of BRCA1 and BRCA2 mutations.

Although the primary end point was not met, axitinib exhibited clinical activity with tumor shrinkage achieved in the majority of patients with progressive disease before trial enrollment. Analysis of MYB biomarkers and genomic profiling suggests the hypothesis that 4q12 amplified ACCs are a disease subset that benefit from TKI therapy.

Durable benefits with pemetrexed-based therapies in RET-rearranged lung cancers are comparable with ALK- and ROS1-rearranged lung cancers. When selecting therapies for patients with RET-rearranged lung cancers, pemetrexed-containing regimens should be considered.

Objectives The Hedgehog pathway has been implicated in small cell lung cancer (SCLC) tumor initiation and progression. Pharmacologic blockade of the key Hedgehog regulator, Smoothened, may inhibit these processes. We performed a phase I study to determine the maximum tolerated dose (MTD) of sonidegib (LDE225), a selective, oral Smoothened antagonist, in combination with etoposide/cisplatin in newly diagnosed patients with extensive stage SCLC. Materials and methods Patients received 4–6 21-day cycles of etoposide/cisplatin with daily sonidegib. Patients with response or stable disease were continued on sonidegib until disease progression or unacceptable toxicity. Two dose levels of sonidegib were planned: 400 mg and 800 mg daily, with 200 mg daily de-escalation if necessary. Next generation sequencing was performed on available specimens. Circulating tumor cells (CTCs) were quantified at baseline and with disease evaluation. Results Fifteen patients were enrolled. 800 mg was established as the recommended phase II dose of sonidegib in combination with etoposide/cisplatin. Grade 3 or greater toxicities included: anemia (n = 5), neutropenia (n = 8), CPK elevation (n = 2), fatigue (n = 2), and nausea (n = 2). Toxicity led to removal of one patient from study. Partial responses were confirmed in 79% (11/14; 95% CI: 49–95%). One patient with SOX2 amplification remains progression-free on maintenance sonidegib after 27 months. CTC count, at baseline, was associated with the presence of liver metastases and after 1 cycle of therapy, with overall survival. Conclusions Sonidegib 800 mg daily was the MTD when administered with EP. Further genomic characterization of exceptional responders may reveal clinically relevant predictive biomarkers that could tailor use in patients most likely to benefit.

Background: Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKIs) develop clinical resistance, most commonly with acquisition of EGFR T790M. Evolutionary modeling suggests that a schedule of twice weekly pulse and daily low-dose erlotinib may delay emergence of EGFR T790M. Pulse dose erlotinib has superior central nervous system (CNS) penetration and may result in superior CNS disease control. Methods:We evaluated toxicity, pharmacokinetics, and efficacy of twice weekly pulse and daily low-dose erlotinib. We assessed six escalating pulse doses of erlotinib.Results: We enrolled 34 patients; 11 patients (32%) had brain metastases at study entry. We observed 3 dose-limiting toxicities in dose escalation: transaminitis, mucositis, and rash. The MTD was erlotinib 1200 mg days 1-2 and 50 mg days 3-7 weekly. The most frequent toxicities (any grade) were rash, diarrhea, nausea, fatigue, and mucositis. 1 complete and 24 partial responses were observed (74%, 95% CI 60-84%). Median progression-free survival was 9.9 months (95% CI 5.8-15.4 months). No patient had progression of an untreated CNS metastasis or developed a new CNS lesion while on study (0%, 95% CI 0-13%). Of the 18 patients with biopsies at progression, EGFR T790M was identified in 78% (95% CI 54-91%).Conclusion: This is the first clinical implementation of an anti-cancer TKI regimen combining pulse and daily low-dose administration. This evolutionary modeling-based dosing schedule was well-tolerated but did not improve progression-free survival or prevent emergence of EGFR T790M, likely due to insufficient peak serum concentrations of erlotinib. This dosing schedule prevented progression of untreated or any new central nervous system metastases in all patients.

Background Patients with recurrent and/or metastatic radioactive iodine refractory thyroid carcinomas (RAI-TC) have limited treatment options. Sorafenib, an oral kinase inhibitor, is FDA approved for the treatment of RAI-TC but demonstrated low response rates (12.2%) as a single agent in the first line setting. We assessed if the addition of the mTOR inhibitor, temsirolimus, to sorafenib could improve upon these results. Methods In this single-institution phase II study, 36 patients with metastatic RAI-TC of follicular origin were treated with the combination of sorafenib (200 mg orally twice daily) and temsirolimus (25mg intravenously weekly). Prior systemic treatment with cytotoxic chemotherapy and targeted therapy, including sorafenib, was permitted. The primary endpoint was radiographic response rate. Results The best response was partial response in 8 (22%), stable disease in 21 (58%), progressive disease in 1 (3%), and 6 patients were not evaluable for a response. Patients with any prior systemic treatment had a response rate of 10% compared to 38% of patients who had no prior systemic treatment. One of 2 patients with anaplastic thyroid cancer had an objective response. Progression free survival at 1 year was 30.5%. The most common grade 3 and 4 toxicities associated with sorafenib and temsirolimus included hyperglycemia, fatigue, anemia, and oral mucositis. Conclusions Sorafenib and temsirolimus appear to be an active combination in RAI-refractory thyroid cancer, especially in patients who received no prior treatment compared to historical data with single-agent sorafenib. Activity is also seen in patients previously treated with sorafenib. This regimen warrants further investigation.

We performed nerve conduction studies (NCSs) on 113 chemical workers, many of whom had occupational exposure to the organophosphorus insecticide chlorpyrifos (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate), to identify dose effects of subclinical neuropathy. In this masked longitudinal study, we estimated historic and interim chlorpyrifos exposures and measured excretion of 3,5,6 trichloro-2-pyridinol (TCP), a chlorpyrifos metabolite. TCP excretion among exposed workers suggested an estimated daily chlorpyrifos exposure averaging about 576-627 microg/day and indicated levels approximately 30% (range 0-250%) of the internal dose received by a typical subject exposed during a working day at the threshold limit value of 200 microg/m3. We modeled NCS results using linear mixed models with repeated measures. Although we found no consistent associations between interim chlorpyrifos exposure and NCS results, we identified several significant associations involving historic chlorpyrifos exposure. Most associations, however, reflected effects at low-exposure levels (< 20 mg/m3 x days) without further effects as exposure increased over a 10-fold range (20-220 mg/m3 x days). This suggested small differences among subjects with low or no chlorpyrifos exposure, rather than a dose-related deterioration among subjects with higher exposures. Two NCS results demonstrating apparent subclinical adverse dose effects showed significant but unexplained interaction with education level. The overall results provide little support for the hypothesis that chronic chlorpyrifos exposures at levels in the range associated with appreciable inhibition of B-esterases produce adverse dose effects on peripheral nerve electrophysiology suggestive of subclinical neuropathy.