Heather Lin

Induction Chemotherapy and Cetuximab for Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Results From a Phase II Prospective Trial

PURPOSE To determine the potential efficacy of combining cetuximab with chemotherapy in patients with advanced nodal disease, we conducted a phase II trial with induction chemotherapy (ICT) consisting of six weekly cycles of paclitaxel 135 mg/m(2) and carboplatin (area under the curve = 2) with cetuximab 400 mg/m(2) in week 1 and then 250 mg/m(2) (PCC). PATIENTS AND METHODS Forty-seven previously untreated patients (41 with oropharynx primaries; 33 men, 14 women; median age, 53 years; performance status of 0 or 1) with squamous cell carcinoma of the head and neck (SCCHN; T1-4, N2b/c/3) were treated and evaluated for clinical and radiographic response. After ICT, patients underwent risk-based local therapy, which consisted of either radiation, concomitant chemoradiotherapy, or surgery, based on tumor stage and site at diagnosis. Results After induction PCC, nine patients (19%) achieved a complete response, and 36 patients (77%) achieved a partial response. The most common grade 3 or 4 toxicity was skin rash (45%), followed by neutropenia (21%) without fever. At a median follow-up time of 33 months, locoregional or systemic disease progression was observed in six patients. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 87% (95% CI, 78% to 97%) and 91% (95% CI, 84% to 99%), respectively. Human papillomavirus (HPV) 16, found in 12 (46%) of 26 biopsies, was associated with improved PFS (P = .012) and OS (P = .046). CONCLUSION ICT with weekly PCC followed by risk-based local therapy seems to be feasible, effective, and well tolerated. PFS is promising, and this sequential treatment strategy should be further investigated. Patients with HPV-positive tumors have an excellent prognosis.

Distinct Patterns of Cytokine and Angiogenic Factor Modulation and Markers of Benefit for Vandetanib and/or Chemotherapy in Patients With Non–Small-Cell Lung Cancer

PURPOSE There is an unmet need for biomarkers for identifying patients likely to benefit from anticancer treatments, selecting dose, and understanding mechanisms of resistance. Plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptor 2 (sVEGFR-2) are known to be modulated by VEGF pathway inhibitors. It is unknown whether chemotherapy or VEGFR inhibitor/chemotherapy combinations induce changes in these or other cytokines and angiogenic factors (CAFs) and whether such changes could be markers of benefit. METHODS Thirty-five plasma CAFs were analyzed using multiplexed bead arrays and enzyme-linked immunosorbent assays from 123 patients with non-small-cell lung cancer in a randomized phase II study who received vandetanib, a VEGFR and epidermal growth factor receptor inhibitor, monotherapy carboplatin and paclitaxel (CP), or the combination (VCP). Changes in CAFs at days 8, 22, and 43 from baseline were correlated with progression risk. RESULTS VEGF increased and sVEGFR-2 decreased by day 43 in the vandetanib arm, whereas a distinct pattern was observed in the CP and VCP arms, with significant decreases in interleukin (IL) -12, IL-1 receptor antagonist, and matrix metalloproteinase 9 (MMP-9) and increased macrophage chemoattractant protein 1. In each treatment arm, changes in different markers were associated with progression risk. For example, increases in IL-8 with VCP, MMP-9 with CP, and VEGF with vandetanib monotherapy were associated with increased progression risk, and increase in intercellular adhesion molecule 1 with vandetanib was associated with decreased risk. CONCLUSION Vandetanib and chemotherapy treatment led to distinct patterns of CAF changes; the combination resembled chemotherapy alone. Changes in specific CAFs correlated with clinical outcome, but markers differed for each treatment arm. CAF profiling may provide insights into the biologic effects of treatment and identify drug-specific markers of activity and clinical benefit.

Upregulated stromal EGFR and vascular remodeling in mouse xenograft models of angiogenesis inhibitor–resistant human lung adenocarcinoma

Angiogenesis is critical for tumor growth and metastasis, and several inhibitors of angiogenesis are currently in clinical use for the treatment of cancer. However, not all patients benefit from antiangiogenic therapy, and those tumors that initially respond to treatment ultimately become resistant. The mechanisms underlying this, and the relative contributions of tumor cells and stroma to resistance, are not completely understood. Here, using species-specific profiling of mouse xenograft models of human lung adenocarcinoma, we have shown that gene expression changes associated with acquired resistance to the VEGF inhibitor bevacizumab occurred predominantly in stromal and not tumor cells. In particular, components of the EGFR and FGFR pathways were upregulated in stroma, but not in tumor cells. Increased activated EGFR was detected on pericytes of xenografts that acquired resistance and on endothelium of tumors with relative primary resistance. Acquired resistance was associated with a pattern of pericyte-covered, normalized revascularization, whereas tortuous, uncovered vessels were observed in relative primary resistance. Importantly, dual targeting of the VEGF and EGFR pathways reduced pericyte coverage and increased progression-free survival. These findings demonstrated that alterations in tumor stromal pathways, including the EGFR and FGFR pathways, are associated with, and may contribute to, resistance to VEGF inhibitors and that targeting these pathways may improve therapeutic efficacy. Understanding stromal signaling may be critical for developing biomarkers for angiogenesis inhibitors and improving combination regimens.

Immunohistochemical Expression of Basic Fibroblast Growth Factor and Fibroblast Growth Factor Receptors 1 and 2 in the Pathogenesis of Lung Cancer

Purpose: To identify the patterns of protein expression of basic fibroblast growth factor (bFGF) and FGF receptors 1 and 2 in non-small cell lung carcinoma (NSCLC) and their role in the early pathogenesis of squamous cell carcinoma (SCC) of the lung. Experimental Design: Archived tissue from NSCLC (adenocarcinoma and SCC; n = 321) and adjacent bronchial epithelial specimens (n = 426) were analyzed for the immunohistochemical expression of bFGF, FGFR1, and FGFR2, and the findings were correlated with clinicopathologic features of the patients. Results: High expression of bFGF, FGFR1, and FGFR2 was shown in most NSCLC tumors. The pattern of expression for all markers varied according to tumor histologic type and cellular localization. Cytoplasmic expression scores were significantly higher in tumors than in normal epithelia. Nuclear bFGF (P = 0.03) and FGFR1 (P = 0.02) levels were significantly higher in women than in men. Although cytoplasmic FGFR1 expression was significantly higher (P = 0.002) in ever smokers than in never smokers, nuclear FGFR1 (P = 0.0001) and FGFR2 (P = 0.003) expression was significantly higher in never smokers. Different prognostic patterns for the expression of these markers were detected for both NSCLC histologic types. Dysplastic changes showed significantly higher expression of all markers compared with squamous metaplasia. Conclusions: bFGF, FGFR1, and FGFR2 are frequently overexpressed in SCC and adenocarcinoma of the lung. bFGF signaling pathway activation may be an early phenomenon in the pathogenesis of SCC and thus an attractive novel target for lung cancer chemopreventive and therapeutic strategies.

Revisiting Stage IIIB and IV Non-small Cell Lung Cancer: Analysis of the Surveillance, Epidemiology, and End Results Data

BACKGROUND The purpose of this population-based study is to provide a detailed analysis of survival outcome of patients with stage IIIB and IV non-small cell lung cancer (NSCLC) enrolled in the Surveillance, Epidemiology and End Results (SEER) program. METHODS We retrieved, from the SEER database, data on demographics, disease extension (size, extent of primary tumor, and nodal status), histology, primary treatment modality, and survival time of NSCLC cases diagnosed between 1998 and 2003 (n = 138,063). Cases were reclassified into separate T4 (satellite, invasive, or pleural effusion) and M1 (ipsilateral, contralateral, or distant) categories based on the extent of the primary tumor and the location of metastatic disease. Univariate and multivariate analyses were performed to assess the effects of each variable on survival. RESULTS For stage IIIB NSCLC, T4 satellite had the best prognosis (comparable to T2 lesions), followed by T4 invasive and T4 pleural effusion. For stage IV, M1 ipsilateral had the best prognosis, followed by M1 contralateral and M1 distant. Nodal status remained a powerful determinant of survival, particularly for patients with T4 satellite, T4 invasive, M1 ipsilateral, and, to a less extent, M1 contralateral. Other prognostic variables were identified within each subgroup. CONCLUSIONS In this report, we present the most comprehensive analysis performed to date of patients with stage IIIB and IV NSCLC enrolled in the SEER program. The survival trends observed here suggest that T4 satellite lung cancer cases should be redefined as T2b, and not T3 as recently proposed for the upcoming TNM classification, seventh edition.

Perforator number predicts fat necrosis in a prospective analysis of breast reconstruction with free TRAM, DIEP, and SIEA flaps

BACKGROUND Breast reconstruction using flaps from the lower abdomen can be compromised by fat necrosis. The muscle-sparing free transverse rectus abdominis musculocutaneous (TRAM), deep inferior epigastric perforator (DIEP), and superficial inferior epigastric artery (SIEA) flaps are techniques that have evolved in an effort to decrease abdominal donor-site morbidity. Each flap in this evolution, however, includes fewer perforating blood vessels. The authors hypothesized that flaps with fewer perforators are less well perfused and therefore more likely to suffer fat necrosis. METHODS The authors prospectively studied the incidence of fat necrosis and number of perforators in 228 consecutive abdominal free flap breast reconstructions. RESULTS The incidence of fat necrosis was 14, 25, 5, and 19 percent for SIEA flaps and flaps with one to two, three to five, and more than five perforators, respectively. The incidence of fat necrosis was significantly associated with the number of perforators (p = 0.007), smoking (p = 0.02), and inclusion of zone 3 of flaps (p = 0.05). The lowest risk of fat necrosis occurs in flaps with three to five perforators, which are predominantly muscle-sparing TRAM flaps. The risk of fat necrosis is highest in flaps with one or two perforators, which are predominantly DIEP flaps. SIEA flaps, and flaps with poor perforators in which greater than five perforators were included, had an intermediate risk of fat necrosis. CONCLUSIONS The risk of fat necrosis in breasts reconstructed with free muscle-sparing TRAM, DIEP, and SIEA flaps increases as the number of perforators supplying the flap decreases. Breast reconstruction using DIEP and SIEA flaps may decrease abdominal donor-site morbidity compared with muscle-sparing TRAM flap techniques, but these flaps also carry a higher risk of fat necrosis that can compromise the breast reconstruction.

High Expression of Folate Receptor Alpha in Lung Cancer Correlates with Adenocarcinoma Histology and Mutation

Introduction: Folate receptor alpha (FR&agr;) and reduced folate carrier-1 (RFC1) regulate uptake of folate molecules inside the cell. FR&agr; is a potential biomarker of tumors response to antifolate chemotherapy, and a target for therapies using humanized monocloncal antibody. Information on the protein expression of these receptors in non–small-cell lung carcinoma (NSCLC) is limited. Material and Methods: Expressions of FR&agr; and RFC1 were examined by immunohistochemistry (IHC) in 320 surgically resected NSCLC (202 adenocarcinomas and 118 squamous cell carcinomas) tissue specimens and correlated with patients’ clinico-pathologic characteristics. Folate receptor &agr; gene (FOLR1) mRNA expression was examined using publicly available microarray datasets. FR&agr; expression was correlated with thymidylate synthase and p53 expression in NSCLCs, and with epidermal growth factor receptor (EGFR) and V-Ki-ras2 Kirsten rat sarcoma viral (KRAS) gene mutations in adenocarcinomas. Results: NSCLC overexpressed FR&agr; and RFC1. In a multivariate analysis, lung adenocarcinomas were more likely to express FR&agr; in the cytoplasm (OR = 4.39; p < 0.0001) and membrane (OR = 5.34; p < 0.0001) of malignant cells than squamous cell carcinomas. Tumors from never-smokers were more likely to express cytoplasmic (OR = 3.35; p<0.03) and membrane (OR = 3.60; p=0.0005) FR&agr; than those from smokers. In adenocarcinoma, EGFR mutations correlated with higher expression of membrane FR&agr; and FOLR1 gene expressions. High levels of FR&agr; expression was detected in 42 NSCLC advanced metastatic tumor tissues. Conclusions: FR&agr; and RFC1 proteins are overexpressed in NSCLC tumor tissues. The high levels of FR&agr; in lung adenocarcinomas may be associated to these tumors’ better responses to antifolate chemotherapy and represents a potential novel target for this tumor type.

Elevated BCRP/ABCG2 expression confers acquired resistance to gefitinib in wild-type EGFR-expressing cells.

Background The sensitivity of non-small cell lung cancer (NSCLC) patients to EGFR tyrosine kinase inhibitors (TKIs) is strongly associated with activating EGFR mutations. Although not as sensitive as patients harboring these mutations, some patients with wild-type EGFR (wtEGFR) remain responsive to EGFR TKIs, suggesting that the existence of unexplored mechanisms renders most of wtEGFR-expressing cancer cells insensitive. Methodology/Principal Findings Here, we show that acquired resistance of wtEGFR-expressing cancer cells to an EGFR TKI, gefitinib, is associated with elevated expression of breast cancer resistance protein (BCRP/ABCG2), which in turn leads to gefitinib efflux from cells. In addition, BCRP/ABCG2 expression correlates with poor response to gefitinib in both cancer cell lines and lung cancer patients with wtEGFR. Co-treatment with BCRP/ABCG2 inhibitors enhanced the anti-tumor activity of gefitinib. Conclusions/Significance Thus, BCRP/ABCG2 expression may be a predictor for poor efficacy of gefitinib treatment, and targeting BCRP/ABCG2 may broaden the use of gefitinib in patients with wtEGFR.

Histologic Patterns and Molecular Characteristics of Lung Adenocarcinoma Associated With Clinical Outcome

Lung adenocarcinoma is histologically heterogeneous and has 5 distinct histologic growth patterns: lepidic, acinar, papillary, micropapillary, and solid. To date, there is no consensus regarding the clinical utility of these patterns.

EZH2 Protein Expression Associates with the Early Pathogenesis, Tumor Progression, and Prognosis of Non–Small Cell Lung Carcinoma

Purpose: Enhancer of zeste homolog 2 (EZH2) promotes carcinogenesis by epigenetically silencing tumor suppressor genes. We studied EZH2 expression by immunohistochemistry in a large series of non–small cell lung carcinomas (NSCLC) in association with tumor characteristics and patient outcomes. Experimental Design: EZH2 immunohistochemistry expression was analyzed in 265 normal and premalignant bronchial epithelia, 541 primary NSCLCs [221 squamous cell carcinomas (SCC) and 320 adenocarcinomas] and 36 NSCLCs with paired brain metastases. An independent set of 91 adenocarcinomas was also examined. EZH2 expression was statistically correlated with clinico-pathological information, and EGFR/KRAS mutation status. Results: EZH2 expression was significantly (P < 0.0001) higher in SCCs compared with adenocarcinomas and in brain metastasis relative to matched primary tumors (P = 0.0013). EZH2 expression was significantly (P < 0.0001) elevated in bronchial preneoplastic lesions with increasing severity. In adenocarcinomas, higher EZH2 expression significantly correlated with younger age, cigarette smoking, and higher TNM stage (P = 0.02 to P < 0.0001). Higher EZH2 expression in adenocarcinoma was associated with worse recurrence-free survival (RFS; P = 0.025; HR = 1.54) and overall survival (OS; P = 0.0002; HR = 1.96). Furthermore, lung adenocarcinomas with low EZH2 levels and high expression of the lineage-specific transcription factor, TTF-1, exhibited significantly improved RFS (P = 0.009; HR = 0.51) and OS (P = 0.0011; HR = 0.45), which was confirmed in the independent set of 91 adenocarcinomas. Conclusion: In lung, EZH2 expression is involved in early pathogenesis of SCC and correlates with a more aggressive tumor behavior of adenocarcinoma. When EZH2 and TTF-1 expressions are considered together, they serve as a prognostic marker in patients with surgically resected lung adenocarcinomas. Clin Cancer Res; 19(23); 6556–65. ©2013 AACR.