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M. Conron



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    O17 - Anatomical Pathology I (ID 128)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      O17.07 - Prevalence, morphology and natural history of FGFR1-amplified lung cancer detected by FISH and SISH (ID 2776)

      11:35 - 11:45  |  Author(s): M. Conron

      • Abstract
      • Presentation
      • Slides

      Background
      Fibroblast growth factor receptor 1 (FGFR1), which codes for a receptor tyrosine kinase, was recently reported to be amplified in 20% of lung squamous cell carcinoma (SqCC). In vitro and preclinical tests suggest that FGFR1 amplification is a therapeutic target. Our aims were to investigate the prevalence of FGFR1 amplification by fluorescence in situ hybridization (FISH) and determine correlation with outcome in an Australian cohort of resected lung cancer. We also correlated results of FGFR1 FISH with silver in situ hybridization (SISH).

      Methods
      A clinically-annotated tissue microarray was constructed from resected lung cancer tissue collected from 1996-2012. FGFR1 FISH and SISH were performed according to manufacturer’s protocols, with SISH performed on Ventana benchmark XT platform. FGFR1 FISH and SISH were scored by one pathologist, with high level amplification defined as ratio of FGFR1/centromere 8 ≥ 2, or tumor cell percentage with ≥ 15 signals ≥ 10%, or average number of FGFR1 signals/tumor cell nucleus ≥ 6, and low level amplification as tumor cell percentage with ≥ 5 signals ≥ 50%. Results of FGFR1 FISH and SISH were compared. Patient outcome related to FGFR1-amplified tumors was assessed and compared to patients with SqCC, or with a morphologic component of, or immunoprofile of SqCC, but normal FGFR1 copy number.

      Results
      Of 406 tumors tested, there were 191 pure SqCC, 28 carcinomas with a SqCC component, 24 large cell carcinomas with an immunoprofile of SqCC, 115 adenocarcinomas, 22 pulmonary neuroendocrine tumors, and 28 other carcinomas without a morphologic component or immunoprofile of SqCC. FGFR1 amplification was assessable in 368 tumors. FGFR1 amplification was identified with FISH in 50 tumors, 48 (48/225; 21.3%) of which were either pure SqCC or a carcinoma with morphologic component or immunoprofile of SqCC. Only two cases were completely of non-squamous origin (2/143; 1.4%, p<0.00001). FGFR1 SISH was performed in 385 tumors, with 347 tumors assessable. Of 46 FGFR1 FISH-amplified tumors assessed with FGFR1 SISH, all showed FGFR1 amplification with SISH, whilst all other tumors tested were negative. Survival from radically treated FGFR1-amplified tumors was similar to all others with a squamous component (73% versus 60% 5-yr survival, HR 0.68, p=0.25; Figure 1).Figure 1

      Conclusion
      FGFR1 amplification with FISH was identified in 21.3% of pure SqCC or carcinomas with a morphologic component or immunoprofile of SqCC, but only 1.4% of completely non-squamous tumors. All adenocarcinomas and neuroendocrine tumors were negative. FGFR1 SISH showed 1:1 correlation to FGFR1 FISH.

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    O19 - Support and Palliation I (ID 138)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Nurses
    • Presentations: 1
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      O19.03 - Perceptions and attitudes to early integration of palliative care for patients with incurable lung cancer (ID 2588)

      10:50 - 11:00  |  Author(s): M. Conron

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer is the leading cause of death from cancer in Australia with the majority of patients diagnosed with late stage incurable disease. Although there is evidence of patient benefit from early involvement with specialist palliative care, this may not translate into clinical practice. The aim of this study was to explore clinicians’ perceptions and attitudes to Palliative Care referral.

      Methods
      A modified validated self-report palliative care referral questionnaire (Johnson, 2008) was given to doctors and nurses working in the multi-disciplinary lung cancer teams at three teaching hospitals in metropolitan Melbourne. Participants were asked whether listed items had contributed to referral (9 triggers) or non referral (15 barriers) of their patients. Level of agreement with 22 attitudinal and perception items explored clinicians’ views about palliative care.

      Results
      55 questionnaires were distributed and 42 completed (76% response rate). Respondents had a median of 6 years (interquartile range 3-12) of experience practicing in their specialty. One-third (14/42) were doctors working in Medical Oncology, 26% (11/42) in Respiratory Medicine, 19% (8/42) in Radiation Oncology, and 12%, (5/42) in Surgical Oncology, plus two oncology nurses and one physician trainee.93% of respondents agreed that early referral to Palliative Care is beneficial to patients and 95% agreed that Palliative Care can benefit patients receiving active treatment. The majority (69%) of clinicians believe that their relationship with the patient continues when she/he elects to have specialist palliative care. 71% indicated that it is not difficult to refer a patient they have cared for a long time and have a close relationship with. Almost two-thirds (64%) disagreed that when they first bring up palliative care patients give up hope. However, only 60% of respondents agreed that all advanced cancer patients should be referred to Palliative Care. The most frequently cited reasons for referral were for physical symptoms. The majority reported that Palliative Care is either very important or important for patients with psycho-social issues or foreseeable future psycho-social issues, yet only half of respondents agreed that psycho-social issues would trigger a referral to Palliative Care. When asked for the main reasons for not referring to Palliative Care, 60% agreed they do not refer when the patient has no symptoms and 60% also agreed they do not refer if they can manage the patients’ symptoms themselves. However, only 38% of clinicians reported they were well trained to take care of the symptoms of advanced cancer patients. Issues related to patients not understanding or accepting their prognosis were cited as barriers to referral by more than a third of clinicians.

      Conclusion
      Clinicians involved in the care of patients with incurable lung cancer have positive perceptions and attitudes to Palliative Care but this may not translate into routine referral of all patients with incurable lung cancer. In order to make referral routine, we need education around the perception that only patients with unmanageable symptoms benefit from referral to Palliative Care. Furthermore, additional training of oncologists about symptom management appears desirable since a significant proportion reported a deficiency in this area.

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    O26 - Support and Palliation II (ID 140)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Nurses
    • Presentations: 1
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      O26.03 - Is early integration of palliative care for patients with incurable lung cancer acceptable to Australian healthcare professionals? (ID 2596)

      16:35 - 16:45  |  Author(s): M. Conron

      • Abstract
      • Presentation
      • Slides

      Background
      In a recent landmark US study, metastatic NSCLC patients who received palliative care from the time of diagnosis concurrently with standard oncology management reported improvements in quality-of-life, symptom control, reduction in “aggressive therapies” at end-of-life, and a survival advantage compared to those receiving standard oncology management alone. The aim of this qualitative sub-study was to explore Australian health care professionals’ perceptions of early integration of palliative care for patients with incurable lung cancer.

      Methods
      Members of the lung cancer multi-disciplinary teams of three large metropolitan teaching hospitals in Melbourne were invited to attend a focus group discussion. Data from focus groups were supplemented with interviews from a purposive sample of individual health care providers who were unable to attend the groups. Participants were asked to describe barriers and facilitators to implementation of a model of early integration of palliative care.

      Results
      Three focus groups and six individual interviews were conducted with 28 health care professionals. Key facilitators and barriers to referral (see table) were grouped into 4 themes: 1. Trust; 2. Care Coordination; 3. Ease of Referral; and 4. Perceived patient/family reaction.

      Key themes Issues discussed as facilitators / or barriers
      Trust 1. Confidence in the quality of the palliative care service 2. Palliative care poses a threat to the referrer 3. Past experience with community palliative care
      Care Coordination 1. Integration of concurrent palliative care and "active treatment" 2. Concern about adding to fragmented care and lack of co-ordination 3. Effective Communication between care providers
      Ease of Referral 1. The value of a physical presence of the palliative care provider in the clinic 2. Perception of limited resources
      Perceived patient/family reaction 1. Cultural perceptions about what referral to palliative care means 2. Concern about patient and/or family reaction to referral leading to distress and loss of hope

      Conclusion
      Early involvement of palliative care in patients with incurable lung cancer is acceptable to the majority of treating clinicians. Palliative care services must be embedded into the system, sufficiently resourced and of high quality. For early referral to occur the model ideally involves a physical presence of a palliative care clinician in clinic who is easily accessible for referrals and considered a core team member.

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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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      P3.06-002 - RLIP76 expression is prognostic and predictive of chemotherapy benefit in resected NSCLC (ID 247)

      09:30 - 09:30  |  Author(s): M. Conron

      • Abstract

      Background
      Despite adjuvant chemotherapy improving overall survival of resected Stage II and III non-small cell lung cancer (NSCLC), acute and late toxicities of chemotherapy have highlighted the need to better predict which patients will benefit from treatment. RLIP76 is a ubiquitously expressed multi-functional transporter that is associated with cisplatin and vinorelbine resistance. Our aim was to analyse the prognostic and predictive value of RLIP76 expression in NSCLC.

      Methods
      We identified 367 NSCLC patients resected between 1996 and 2009. A tissue microarray was created and immunohistochemistry (IHC) performed with an anti-human RLIP76 rabbit polycloncal antibody (Millipore, Temecula, CA). The intensity (0-3) and proportion of tumour cells (0-100) with staining was scored. The product of RLIP76 intensity and proportion of tumour cells staining was calculated (range 0-300) and divided into high (>100) and no/low expression (≤100). RLIP76 expression was correlated with clinical features and patient outcome.

      Results
      IHC was available for 285 patients, 173(60.7%) of which were male. Number of patients according to stage I, II, III and IV was 150(52.6%), 83(29%), 44(15.4%) and 8(3%), respectively. RLIP76 was overexpressed in 117(41%) specimens. There was no relationship between RLIP76 expression and stage, histology, sex or age. High RLIP76 expression was associated with an improved prognosis on univariate (HR 0.62, CI 9.44-0.90, p=0.012,Figure 1) and multivariate analysis (HR 0.57, CI 0.39-0.83, p=0.003). Adjuvant chemotherapy was also associated with an improved survival on multivariate analysis (HR 0.52, CI 0.33-0.82, p=0.005). When stratifying by RLIP76 expression, the benefit of chemotherapy was limited to patients with no/low expression (HR =0.44, CI 0.24-0.8, p=0.008)(Figure 2). No benefit of chemotherapy was seen in patients with high RLIP76 expression (HR=0.75, CI 0.34-1.63, p=0.5). Figure 1 Figure 2

      Conclusion
      High RLIP76 expression is associated with an improved prognosis in resected NSCLC.Interestingly no/low RLIP76 expression may predict for benefit of adjuvant chemotherapy. Further studies are needed to confirm these results.

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    P3.18 - Poster Session 3 - Pathology (ID 177)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P3.18-007 - Metastatic sites with a major component of solid pattern pulmonary adenocarcinoma are associated with shorter survival with systemic therapy and infrequent EGFR mutations (ID 1790)

      09:30 - 09:30  |  Author(s): M. Conron

      • Abstract

      Background
      The predominant histologic subtype according to the IASCL/ATS/ERS classification has been associated with prognosis in patients undergoing curative surgical resection. It is recommended in the IASLC/ATS/ERS classification that histologic patterns present in small specimens be recorded in the final histopathology report. We investigated the relationship between histologic patterns in metastatic sites, overall survival and EGFR and KRAS mutations.

      Methods
      We identified patients who underwent surgical resection of non-small cell lung carcinoma in metastatic sites from 2000 to 2011. One biopsy site was selected per patient. A pathologist reviewed all slides to confirm the diagnosis of metastatic lung adenocarcinoma, recording all adenocarcinoma histologic patterns present. EGFR and KRAS mutations were scanned by high resolution melting, and confirmed by Sanger sequencing. Clinical data were extracted from the medical records.

      Results
      The 100 patients comprised 66 males, with a median age of 64 years. 85% had stage IV disease, and 15% had unresected stage III disease with mediastinal lymph node sampling. Most were current or former smokers (79%) of ECOG 0/1 (67%). Just over half the patients received systemic therapy (56%). The overall median survival was 10.2 months (95% CI 8.1 – 12.2 months). Metastatic sites included brain (30%), pleura (25%), bone/skeletal muscle (20%), and lymph nodes (mediastinal 18%; chest wall/neck 7%). It was possible in each biopsy to identify a major histologic pattern (Table 1). For patients receiving systemic therapy, survival was significantly shorter for those with a major component of solid pattern tumour in metastases compared to those with major acinar or micropapillary patterns in metastases (Table 1). No survival difference was noted on the basis of ECOG, stage, EGFR or KRAS mutations. For patients who did not receive systemic therapy, the major histologic pattern showed no association with overall survival (Table 1). Worse ECOG was the only significant factor in determining outcome (ECOG 0/1 vs 2+ – hazard ratio 2.18 (1.14 – 4.16, p=0.018)). EGFR mutations were significantly associated with major non-solid pattern histology in metastases (Fisher’s exact = 0.006). No association was observed by KRAS mutation status (Table 1).

      The major histologic component in sites of metastatic adenocarcinoma – overall survival by the use of systemic therapy; presence of EGFR and KRAS mutations (*Comparison across 4 histological types; OS - overall survival, CI - confidence interval, HR - hazard ratio)
      Solid Micropapillary Acinar Papillary Comments
      Major Pattern 50% 20% 29% 1%
      Mutations present n = 50 n = 20 n = 29 n = 1 n=100
      EGFR mutation, n (column %) 2 (4%) 5 (25%) 4 (14%) 1 (100%) Fisher's exact = 0.006 *
      KRAS mutation, n (column %) 18 (36%) 5 (25%) 9 (31%) 0 Fisher's exact = 0.789*
      Systemic Therapy Given n = 29 n = 13 n = 13 n = 1 n=56
      Median OS, months (95% CI) 9.4 (8.3 - 12.2) 18.9 (11.6 - 24.4) 15.9 (10.7 - 24.7) Solid vs MPA HR 0.33 (0.16 - 0.67, p = 0.002) Solid vs Acinar HR 0.32 (0.15 - 0.67, p=0.003)
      No Systemic Therapy n = 21 n = 7 n = 16 n = 0 n=44
      Median OS, months (95% CI) 4.3 (3.3 - 7.4) 4.7 (1.5 - 11.5) 4.4 (1.9 - 16.9) No significant differences

      Conclusion
      Our results suggest that patients with a major component of solid pattern tumour in metastatic sites may be more resistant to systemic therapy as evidenced by shorter overall survival in comparison to those with major micropapillary and acinar pattern tumour in metastases. Furthermore, major solid pattern metastases are unlikely to harbour EGFR mutations. These findings require validation in larger patient cohorts.