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N.P. Rizk



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    MO26 - Anatomical Pathology II (ID 129)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO26.03 - In Patients with Stage I Lung Adenocarcinoma, Tumor Budding Is a Significant Prognostic Factor for Recurrence, Independent of the IASLC/ATS/ERS Classification, and Correlates with a Protumor Immune Microenvironment (ID 2917)

      10:30 - 12:00  |  Author(s): N.P. Rizk

      • Abstract
      • Presentation
      • Slides

      Background
      In 2011, the IASLC/ATS/ERS proposed a new classification for lung adenocarcinoma (ADC) that has powerful prognostic value. However, tumors in each subtype may still include heterogeneous prognostic subgroups - especially in the acinar, papillary, and solid subtypes, in which the majority of tumors are classified. Recently, immune markers such as CD markers and cytokines have been identified as prognostic factors in lung cancer. In this study, we investigate whether tumor budding further stratifies prognosis for stage I lung ADC, independent of the IASLC/ATS/ERS classification, and whether it correlates with prognostic immune markers.

      Methods
      All available tumor slides from patients with therapy-naive, surgically resected solitary stage I lung ADC (1995-2009) were reviewed (n=1038). Tumors were classified according to the IASLC/ATS/ERS classification. Mitoses were counted at 10 high-power fields (HPFs) (x400 magnification). Tumor budding (tumor nest composed of <5 cells) was assessed, at 10 HPFs (x200 magnification), in areas with the smallest tumor nests and was graded by the maximum number of budding : 0, 0/HPF; 1, 1-4/HPF; 2, 5-9/HPF, and 3, ≥10/HPF. Tissue microarrays were constructed from tumoral and stromal cores, and immunostaining for CD3, FoxP3, IL-7R, and IL-12Rβ2 was performed. Lymphocytes positive for CD3 and FoxP3 were scored in tumor and stroma, and tumors were classified using our recently reported FoxP3/CD3 risk index (JCO 2013). Tumoral expression of IL-7R and IL-12Rβ2 was dichotomized by the sum of intensity (0-3) and distribution (1, 1%-50%; 2, >50%) scores: negative (total score <1) and positive (≥1). Recurrence-free probability (RFP) was estimated using the Kaplan-Meier method; multivariate analyses were performed using the Cox proportional hazards model.

      Results
      RFP was lowest for patients with budding grade 3 (n=180; 5-year RFP, 69%; p<0.001), followed by grade 2 (n=139; 75%), 1 (n=189; 81%), and 0 (n=530; 89%). Budding grade was dichotomized into negative (grades 0-1) or positive (grades 2-3) using colorectal cancer criteria. The RFP for patients with positive budding (n=319; 5-year RFP, 72%) was significantly lower than that for patients with negative budding (n=719; 87%; p<0.001), which was confirmed in a subgroup analysis limited to stage IA (p=0.004) and IB (p<0.001) patients. Tumor budding further stratified RFP in patients with acinar (p<0.001), papillary (p=0.027), and solid (p=0.015) tumors. Budding was more frequently observed in tumors with high-grade histology (solid and micropapillary; p<0.001), lymphovascular invasion (p<0.001), and high mitotic count (p<0.001). Tumor budding was positively correlated with stromal CD3+ lymphocytes (p<0.001), stromal FoxP3+ (p<0.001), FoxP3/CD3 risk index (high FoxP3, low CD3) in stroma (p<0.001), and tumoral IL-7R expression (p<0.001). In multivariate analysis, tumor budding was an independent prognostic factor for recurrence (HR=1.13; p=0.002).

      Conclusion
      Tumor budding was a significant prognostic factor in stage I lung ADC, independent of IASLC/ATS/ERS classification, and it correlated with a protumor immune microenvironment (high FoxP3+ lymphocyte infiltration and high IL-7R expression). These findings may inform therapeutic decisions and stratify patients for additional therapy, including immunotherapy.

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    O09 - General Thoracic Surgery (ID 100)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Surgery
    • Presentations: 1
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      O09.01 - Sites, Symptoms, CT Scan Findings and Survival in Patients with Recurrence After Curative-Intent Surgical Resection for Stage I Lung Adenocarcinoma (ID 2907)

      16:15 - 17:45  |  Author(s): N.P. Rizk

      • Abstract
      • Presentation
      • Slides

      Background
      The purpose of this study is to examine the patterns of recurrence for stage I lung adenocarcinoma and to identify clinicopathologic factors associated with post-recurrence survival (PRS).

      Methods
      We performed a retrospective review of 1027 patients with stage I lung adenocarcinoma who underwent a surgical resection between 1999 and 2009 (median follow-up 35 months). The manner of recurrence detection, either by scheduled CT scan, presentation with new symptoms, or by other means, was noted. Tumors were classified using the new IASLC/ATS/ERS nomenclature and grading as low (adenocarcinoma in situ, minimally invasive adenocarcinoma, or lepidic-predominant), intermediate (papillary-predominant or acinar-predominant), and high (micropapillary-predominant, solid-predominant, colloid-predominant, or invasive mucinous) grade. The Kaplan-Meier method was used to analyze recurrence-free survival (RFS). Log-rank tests and Cox proportional hazard models were used to analyze the association between predictive factors and PRS.

      Results
      Of the 1027 patients with follow-up data available, 151(15%) had recurrent disease (table), five-year RFS was 80%. Of the 151 patients with recurrence, 80 (52%) were detected by a scheduled CT scan (51 locoregional and 29 distant). Symptomatic recurrences were seen in 70 (46%) patients (9 locoregional and 61 distant). Overall, 5-year PRS was 27.8%. On multivariate analysis, recurrences identified by new symptoms (HR, 2.15; 95% CI, 1.36- 3.40; p=0.001), a recurrence free interval ≤ 24 months (HR, 2.52; 95% CI, 1.31- 4.84; p=0.006), and tumors with high architectural grade (HR, 1.69; 95% CI, 1.07- 2.67; p=0.024) and vascular invasion (HR, 1.79; 95% CI, 1.14- 2.81; p=0.012) were significantly associated with a worse PRS (Figure).Figure 1Figure 2

      Conclusion
      Our study demonstrates the recurrence patterns in patients who underwent surgical resection for stage I lung adenocarcinoma. We identify a symptomatic recurrence, a recurrence-free interval ≤ 24 months, high architectural grade, and vascular invasion, as independent factors associated with worse post recurrence survival.

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    P1.18 - Poster Session 1 - Pathology (ID 175)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P1.18-019 - Micropapillary Histology Is Associated with Occult Lymph Node Metastasis (pN2) in Patients with Clinically N2-Negative (cN0/N1) Lung Adenocarcinoma (ID 3232)

      09:30 - 16:30  |  Author(s): N.P. Rizk

      • Abstract

      Background
      Among patients with lung adenocarcinoma staged as N2-negative in the mediastinum by PET/CT scan, up to 16% will have occult N2 metastasis (pN2) detected on mediastinoscopy or surgical resection. We investigated the association between histologic subtyping (according to the newly proposed IASLC/ATS/ERS classification) and occult lymph node metastasis in patients with unsuspected N2 disease.

      Methods
      We performed a retrospective review of 297 patients with lung adenocarcinoma (≤2 cm, 51%; >2 cm, 49%) who underwent surgical resection and mediastinal nodal dissection from 2007 to 2009. Mediastinal lymph node disease was assessed preoperatively by FDG-PET/CT scan. Histologic subtyping was performed according to the newly proposed IASLC/ATS/ERS classification.

      Results
      Ninety-three percent of patients had N0 disease, and 7% had N1 disease, as detected by preoperative PET/CT scan. Of the 297 patients, 32 (10.8%) had occult N2 metastasis identified by pathologic examination (9.7% of patients with cN0 disease, 25% of patients with cN1 disease). On univariate analysis, SUVmax of the primary tumor >4 (p=0.001), predominant histologic subtype (p=0.001), presence or absence of lepidic pattern (p<0.001), micropapillary pattern (p=0.009), and solid pattern (p=0.011) were associated with pN2 disease. On multivariate analysis, presence of lepidic pattern (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.14-0.77; p=0.011), presence of micropapillary pattern (OR, 2.58; 95% CI, 1.13-5.92; p=0.025), and SUVmax of the primary tumor >4 (OR, 2.44; 95% CI, 1.03-5.79; p=0.042) were significantly associated with occult N2 metastasis.

      Conclusion
      Micropapillary histology and primary tumor SUVmax >4 on FDG-PET/CT were independently associated with occult N2 metastasis.

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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P3.08-013 - High local control rates with post-operative radiation therapy in incompletely resected non-small cell lung cancer (NSCLC) patients (ID 1659)

      09:30 - 16:30  |  Author(s): N.P. Rizk

      • Abstract

      Background
      Post-operative radiation therapy (PORT) is frequently given to patients with NSCLC who have microscopically positive margins (R1 resection) or gross residual disease (R2 resection) based on oncologic first principles. However, the data to support this practice is scarce. Here we report our institutional experience comparing patients who received PORT in the setting of R0, R1 or R2 resections.

      Methods
      Between 1999 and 2012, 203 patients with NSCLC were treated with PORT in 25-39 fractions to 45-70 Gy. All surgery and PORT were performed at our institution. Twenty-one patients had a sublobar resection, 158 had a lobectomy, and 24 underwent a pneumonectomy. PORT was given to R0 patients with pathologic N2 disease, R1 or R2 resections. Patients with negative margins were compared to patients with residual disease (R1 and R2 resections). Patients with tumor recurrence within the PORT field were recorded as local failures. Local failure-free survival (LFFS), disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method. Univariate analysis was performed using the log-rank test.

      Results
      Fifty-five of 203 patients had residual disease after resection; 45 had R1 and 10 had R2 resections. The predominant histology was adenocarcinoma (80%). Stage at diagnosis was stage I-II in 17 patients, stage III in 186 patients. One-hundred and twenty-six (62%) patients received neoadjuvant and 39 (19%) adjuvant chemotherapy. Median age was 60 years and median KPS before PORT was 80. Median interval from surgery or adjuvant chemotherapy to PORT initiation was 1.6 months (range of 0-3.7 months). With a median follow up of 21 months, local failure occurred in 33/148 (22%) without and 14/55 (25%) patients with residual disease. Two- and 5-year actuarial LFFS rate were 79%/66% for R0 and 75%/58% for R1/R2 resections. Two- and 5-year actuarial DFS rate were 44%/30% for R0 and 48/26% for R1/R2 resections. Two-year and 5-year overall survival (OS) for all patients were 62.4% and 33.1%. LFFS, DFS and OS were not significantly different when comparing R0 to R1/R2 resections. Radiation dose, KPS, T-stage, N-stage, lymphovascular invasion, histology and chemotherapy were all not found to be significantly associated with any endpoint. OS was significantly worse for patients with R2 resection compared to R0/R1 resection (2-year OS 20% vs 64%; p= 0.002) and patients with age >65 (p=0.03). Multivariate analysis will be presented.

      Conclusion
      PORT results in equivalent local control rates after R1 and R2 resections when compared to R0 resections. This suggests that PORT has a significant role in local control of residual disease. However, OS was significantly worse for patients with gross residual disease postoperatively.