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J.B. Sorensen



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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-002 - Intratumor variation of biomarker expression by immunohistochemistry in resectable non-small cell lung cancer (ID 134)

      09:30 - 16:30  |  Author(s): J.B. Sorensen

      • Abstract

      Background
      Prognostic and predictive biomarkers are increasingly used to customize treatment of patients with solid tumors. Intra- and inter-tumor heterogeneous distribution of biomarker expression are potential confounders for use of biomarkers, as small biopsies may not necessarily truly reflect the pattern of biomarker expression. It may also be an important factor in chemoresistance, as tumors with heterogeneous biomarker expression may potentially harbor chemoresistant tumor clones.

      Methods
      Immunohistochemical evaluation of expression of excision repair cross complementation group 1 (ERCC1), epidermal growth factor receptor (EGFR), class III-β-tubulin (TUBB-3), Thymidylate synthase (TS), Ki-67 and ribonucleotide reductase M1 (RRM1) was performed in 15 separate areas in each of 6 small microscopically completely resected adenocarcinomas of the lung in order to elucidate any heterogeneous distribution.

      Results
      Clinically relevant biomarker heterogeneity with respect to expression of EGFR, ERCC1, RRM1, TUBB-3, and Ki-67 was observed in 4 (66%), 4 (66%), 2 (33%), 3 (50%) and 5 (83%) out of 6 tumors, respectively. Thus, heterogeneity could potentially allocate these tumors erroneously into high or low expressers by chance alone, according to previously reported cut-off values. In contrast, TS was almost completely homogenously distributed.

      Conclusion
      Most biomarkers examined, except for TS, showed clinically significant intratumor heterogeneity in 33% to 87% of tumors examined. This heterogeneity may influence results in studies investigating the therapeutic impact of predictive biomarkers in NSCLC.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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      P2.06-020 - Pretreatment thymidylate synthase protein expression levels remains stable during paclitaxel and carboplatin treatment in non-small cell lung cancer (ID 1945)

      09:30 - 16:30  |  Author(s): J.B. Sorensen

      • Abstract

      Background
      Thymidylate synthase (TS) is a potential predictive marker for efficacy of treatment with pemetrexed. The current study aimed at investigating whether TS expression changes during non-pemetrexed chemotherapy of non-small cell lung cancer (NSCLC) thus making rebiopsy necessary for deciding on pemetrexed second line treatment.

      Methods
      TS immunohistochemístry was performed on biopsies and available resection specimens from 65 NSCLC patients stage T1-3N0-2 treated with preoperative carboplatin and paclitaxel (NAC-group) and 53 NSCLC patients stage T1-4N0-1 treated with surgery without preceding chemotherapy (OP-group) served as controls. The diagnostic biopsies and subsequent resection samples were compared in order to evaluate for concordance in TS expression in groups with and without preoperative chemotherapy.

      Results
      No statistically significant change in TS expression was observed between diagnostic biopsies and subsequent surgical resections of primary tumors in either the OP-group (p=0.186) or the NAC-group (p=0.542). Primary tumors were discordant between diagnostic biopsies and resection specimens when TS expression was dichotomized into high (H-score>150) and low (H-score ≤150), in 45% and 33% in the OP-group and NAC-group, respectively (p=0. 288).

      Conclusion
      The discordance observed between paired serial samples likely reflects intratumoral heterogeneity of TS expression and highlights the need of sufficient representative material for TS expression analysis if this biomarker is to be used for treatment selection.. TS expression in primary tumors remained unchanged and new biopsies for deciding on 2nd line pemetrexed do not seem warranted based on the current results.

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      P2.06-021 - Is RRM1 a predictive marker for vinorelbine efficacy - the results from a cohort of malignant pleural mesotheliomas treated with cisplatin and vinorelbine. (ID 3104)

      09:30 - 16:30  |  Author(s): J.B. Sorensen

      • Abstract

      Background
      In a recently published study our group proposes a possible predictive impact of immunohistochemically detected RRM1 on vinorelbine efficacy in advanced NSCLC. This thesis was based on results from a randomized phase III trial comparing triplet-chemotherapy (paclitaxel, cisplatin, gemcitabine) to standard doublet-therapy (cisplatin, vinorelbine). We found that increased expression of RRM1 was associated with significantly decreased progression-free survival (PFS) and overall survival (OS) only in the patients receiving cisplatin-vinorelbine therapy. These findings were suprising since the overexpression of RRM1 is conventionally associated with resistance towards the chemotherapeutic agent gemcitabine, which is a potent inhibitor of ribonucleotide reductase (RNR). RNR is an essential enzyme for DNA synthesis that converts ribonucleoside di-phosphates into deoxyribonucleoside di-phosphates. The enzyme consists of a large sub-unit (RRM1) and a small sub-unit (RRM2). Vinorelbine is a spindle-poison and resistance towards this agent has never been associated with RRM1 over-expression. It has however been shown that vinorelbine can reduce the repair of radiotherapy-induced DNA damage in small-cell lung-cancer cell-lines, pointing to a possible interaction between vinorelbine and the DNA repair system. This study aimed at further exploring the possible predictive value of immunohistochemically detected RRM1 in patients receiving vinorelbine therapy. For this purpose we chose a cohort of malignant pleural mesothelioma patients treated with cisplatin and vinorelbine in a phase II trial.

      Methods
      Fifty-four consecutive patients with MPM, were enrolled between February 2003 and September 2006 into a phase II trial with cisplatin and vinorelbine. The formalin-fixed paraffin-embedded bioptic tumor specimens from these MPM patients were retrospectively evaluated for RRM1 expression by immunohistochemistry (IHC) using an H-score. The cut-off point was chosen as the upper quartile value of the H-scores to separate positive (H-score ≥upper quartile) from negative (H-score

      Results
      Sixty-six patients had enough tumor tissue for IHC. The upper quartile H-score was 3 yielding 15 positive and 34 (69%) negative tumors in the cisplatin-vinorelbine treated group. In the carboplatin-pemetrexed treated group there were 6 positive and 11 (64%) negative tumors. There was a significant overall survival advantage only in the RRM1-negative patients treated with cisplatin and vinorelbine (log rank p= 0.002). This group had a two-year survival rate of 47% opposed to 13 % for the RRM1-positive tumors treated with this combination. In the carboplatin-pemetrexed-treated group there were no differences in overall survival according to marker status, with two-year survival rates of 0% and 9% in the RRM1-positive and –negative group respectively.

      Conclusion
      Patients with RRM1-negative tumors treated with cisplatin-vinorelbine combination therapy had a prolonged overall survival. There was no survival advantage in the RRM1-negative group when patients were treated with carboplatin and pemetrexed. Our study suggest a possible role of RRM1 in predicting efficacy of cisplatin-vinorelbine combination chemotherapy ,also in MPM, which supports the similar finding from our group in NSCLC patients. Thus, RRM1 may be a biomarker for vinorelbine though the results require further validation.

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    P2.10 - Poster Session 2 - Chemotherapy (ID 207)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.10-004 - Addition of bevacuzimab (BEV) to pemetrexed (PEM) plus cisplatin (CIS) induction and PEM maintenance therapy in 1st line setting for treatment of advanced nonsquamous non small cell lung cancer (NS-NSCLC) - final results and safety update from a phase 2 study (ID 234)

      09:30 - 16:30  |  Author(s): J.B. Sorensen

      • Abstract

      Background
      1st line PEM+CIS induction chemotherapy (CT) followed by PEM maintenance and 1st line BEV-based CT followed by BEV maintenance offer clinical benefit (progression-free and overall survival; PFS and OS) in NS-NSCLC. This study explored efficacy and safety of 1st line induction PEM+CIS+BEV followed by maintenance PEM+BEV.

      Methods
      Patients with advanced NS-NSCLC and ECOG performance status (PS) 0-1 were planned to receive 4 cycles PEM 500 mg/m[2], CIS 75 mg/m[2], BEV 7.5 mg/kg, given every 3 weeks. In the absence of progressive disease (PD) and in the case of ECOG PS 0-1, patients could continue on PEM+BEV until PD or unacceptable toxicity. All patients received vitamin supplementation as per PEM label. Primary endpoint was PFS; secondary endpoints included OS, response rate and toxicity. PFS without Grade (G)4 toxicity was additionally assessed.

      Results
      109 patients were enrolled in 5 countries. Characteristics: median age 61 years, males/females 59/41%, ECOG PS 0/1 54/46%, stage IIIB/IV 9/91%, adenocarcinoma 91%. 72 patients (66%) received maintenance CT. Overall median (maximum) number of cycles were 8(34) for PEM+BEV and 4(4) for CIS. Median PFS was 6.9 months (90% CI 5.7, 8.3). Table 1 summarizes efficacy data; Table 2 presents G1-4 adverse event (AE) data, including AEs of special interest regarding BEV. 2 patients died from study-drug related toxicity (GI hemorrhage, pneumonia aspiration; during induction CT). Figure 1 Figure 2

      Conclusion
      In this study of PEM+CIS+BEV induction CT followed by PEM+BEV maintenance, median PFS was 6.9 months. The addition of BEV to PEM-CIS induction and PEM maintenance was associated with acceptable and expected toxicities. Main G3/4 toxicities included neutropenia and fatigue, hypertension was less common.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-021 - Changes in epidermal growth factor receptor expression during chemotherapy in non-small cell lung cancer (ID 1959)

      09:30 - 16:30  |  Author(s): J.B. Sorensen

      • Abstract

      Background
      Antibodies targeting epidermal growth factor receptor (EGFR), such as cetuximab, may potentially improve outcome in non-small cell lung cancer (NSCLC) patients with high EGFR expression. The EGFR expression may be heterogeneously distributed within tumors and small biopsies may thus not accurately reveal the EGFR expression and EGFR expression may also change during chemotherapy.

      Methods
      EGFR expression in diagnostic biopsies and resection specimen was compared in 53 NSCLC patients stage T1-4N0-1M0 treated with surgery without preceding chemotherapy (OP-group) and from 65 NSCLC patients stage T1-3N0-2M0 (NAC-group) treated with preoperative carboplatin and paclitaxel were analyzed regarding EGFR expression to evaluate the concordance of EGFR expression between samples.

      Results
      No significant change in EGFR expression H-score was observed when comparing serial samples from either the OP-group (p=0.934) treated with surgery or the NAC-group (p=0.122) treated with preoperative chemotherapy. Discordance between tumors dichotomized according to EGFR expression (high: H-score≥200; low: H-score<200) in diagnostic biopsies and immediate resection specimens was 25% in the OP-group and 33% in the NAC-group (p=0.628).

      Conclusion
      EGFR expression in 25% of diagnostic biopsies may potentially not be accurate compared to the prevailing pattern in the whole tumor based on the larger resection specimens. This may potentially be an obstacle for proper use of antibodies targeting the EGFR in NSCLC. EGFR expression does however not change significantly during paclitaxel and carboplatin and rebiopsies in order to decide on anti-EGFR antibody therapy following chemotherapy does not seem warranted.