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M.B. Schabath
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ORAL 24 - CT Detected Nodules - Predicting Biological Outcome (ID 122)
- Event: WCLC 2015
- Type: Oral Session
- Track: Screening and Early Detection
- Presentations: 1
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ORAL24.07 - Behavior Differences of Screen-Detected Lung Cancers in the CT Arm of the National Lung Screening Trial (NLST) (ID 587)
11:50 - 12:01 | Author(s): M.B. Schabath
- Abstract
Background:
Lung cancer screening identifies cancers with heterogeneous behaviors. In addition to screen-detected incidence lung cancers, screening also identifies prevalence cancers at the baseline screen and interval lung cancers diagnosed following a negative screen at any time point prior to the next screening round. To date, few studies have performed a comprehensive analyses comparing prevalence and interval lung cancers and screen-detected lung cancers based on sequence of screening results in the NLST.
Methods:
The entire CT arm of the NLST was reconstructed according to baseline and follow-up screening results (positive vs. negative screen). Lung cancers immediately following a positive baseline (T0), and prior to the T1 screen, formed the prevalence cancers (PC); interval cancers (IC) were defined as lung cancers diagnosed following a negative screen at any point prior to the next screening round. Two screen-detected lung cancer (SDLC) cohorts were identified based on one (SDLC1) or two (SDLC2) prior positive screens and two screen-detected lung cancer cohorts following one (SDLC3) or two (SDLC4) prior negative screens. Differences in patient characteristics, progression-free survival (PFS), and overall survival (OS) were assessed.
Results:
Since there were no differences in patient characteristics and outcomes between SDLC1 and SDLC2 and between SDLC3 and SDLC4, the four screen-detected cancer case groups were combined into two combined SDLC case groups (SDLC1/SDLC2 and SDLC3/SDLC4). The lung cancer-specific death rate was higher for SDLC3/SDLC4 compared to SDLC1/SDLC2 lung cancers (136.6/1,000 person-years vs. 71.3/1,000 person-years, P < 0.001). PFS and OS were significantly lower for SDLC3/SDLC4 than SDLC1/SDLC2 (P < 0.004; P < 0.002, respectively). Overall, PFS and OS were highest in SDLC1/SDLC2 and lowest in the interval cancers (Figure 1); PFS and OS for the prevalence cancers were intermediate between SDLC1/SDLC2 and SDLC3/SDLC4. All findings were consistent when stratified by stage and histology. Multivariable Cox proportional models revealed that the SDLC3/SDLC4 case groups were associated with significantly poorer PFS (HR=1.72; 95% CI 1.19-2.48) and OS (HR=1.62; 95% CI 1.08-2.45) compared to SDLC1/2 lung cancers (HR=1.00). Figure 1
Conclusion:
This post hoc analysis reveals novel insight to the heterogeneity of lung cancers diagnosed in a screening population. As with interval cancers diagnosed following a negative screen, lung tumors that arise in a lung environment ostensibly free of lung nodules are likely more rapidly growing and aggressive which results in significantly poorer outcomes. Additional research will be needed to understand the potential translational implications of these findings and to reveal biological differences of screen-detected tumors.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-002 - Protein Signaling Analysis of KRAS Mutant Lung Adenocarcionomas Reveals Variable MAPK and mTOR Pathway Activation (ID 2280)
09:30 - 09:30 | Author(s): M.B. Schabath
- Abstract
Background:
Despite the numerous efforts made to target KRAS directly, this protein is still undruggable. A number of therapeutics that target linked KRAS pathway members have been tested, but their efficacy in KRAS mutant lung adenocarcinoma is still controversial. Understanding the biochemically linked protein signaling network associated with a KRAS mutation may lead to the identification of therapeutic targets to identify patients that may benefit from a therapeutic agent targeting KRAS downstream substrates.
Methods:
Thirty-four archived samples from surgically-treated KRAS mutant adenocarcinomas were included in this study. Samples were collected at the H.Lee Moffitt Cancer Center & Research Institute (Tampa, FL) and at the Santa Maria della Misericordia Hospital (Perugia, Italy). Pure cancer epithelial cell subpopulations were isolated using Laser Capture Microdissection. The expression/activation level of 155 proteins was then measured by Reverse Phase Protein Microarray, a high-throughput semi-quantitative platform.
Results:
The protein activation level of ERK (as measured by phosphorylation of T202/Y204), a direct downstream substrate of KRAS activity, was highly variable across KRAS mutant samples. While a subgroup of patients showed, as expected, high activation of ERK, approximately 2/3 of the patients had a comparable ERK activation level to the wild-type counterpart previously analyzed. The activation level of the remaining protein signaling analytes was then compared between samples with high and low ERK activation. Tumors with high levels of ERK activation showed a significant increase in the signaling network of: 1) the MAPK proliferative pathway including Ras-GRF1 S916, Mek 1/2 S217/221, MSK1 S360, p38MAPKinase T180/Y182 (p=0.03, p<0.01, p=0.04, p<0.01 respectively), 2) the AKT-mTOR pathway including Akt S473, AMPKα1 S485, ATP Citrate Lyase S454, LKB1 S428, mTOR S2448, p70S6K T389, p70S6K T412, 4E-BP1 S65 (p<0.01, p<0.01, p<0.01, p<0.01, p<0.01, p<0.01, p=0.02, p=0.03 respectively).
Conclusion:
This analysis suggests that the signaling network of KRAS mutant lung adenocarcinomas, while manifesting expected ERK activation as a group, is highly variable. In fact a majority of KRAS mutant tumors had the same range of MEK-ERK activation as KRAS WT tumors. Analysis of high and low ERK activation in the KRAS mutant tumors revealed druggable protein signaling activation of a number of important targets. If validated in a larger study set, these data may have important clinical implication for the allocation of patients toward more effective and specific targeted treatments.
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P1.11 - Poster Session/ Palliative and Supportive Care (ID 229)
- Event: WCLC 2015
- Type: Poster
- Track: Palliative and Supportive Care
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.11-012 - Process for Developing a Rapid Tissue Donation Program in a Thoracic Program: Ethical and Logistical Considerations (ID 1602)
09:30 - 09:30 | Author(s): M.B. Schabath
- Abstract
Background:
Rapid tissue donation (RTD), also known as “warm autopsy,” is a novel method of tissue procurement for research purposes where tissues from the primary tumor and metastatic sites are collected within 24 hours of patient death. These tissues provide tremendous research possibilities and hope for new cancer treatments. However, recruiting for RTD has ethical challenges such as diminishing patients’ hope and causing distress to Next of Kin (NoK). Presently there is limited RTD education, training, or protocols for biomedical researchers and healthcare professionals (HCPs) to address the psychosocial and ethical aspects of the request for postmortem tissue donation. The purpose of this study was to: i) identify barriers and facilitators to RTD recruitment and tissue collection from key stakeholders; ii) identify the RTD processes used in other organizations and programs; and iii) establish a standardized process for RTD in a Thoracic Oncology Program at a Comprehensive Cancer Center.
Methods:
Mixed methods were used for each of the 3 purposes of the study: i) formative research (surveys and focus groups) was conducted to explore knowledge, perceptions, and barriers and facilitators to patient recruitment to RTD across key stakeholders including HCPs (n= 91), cancer patients/survivors and advocates, caregivers, physicians and clinic staff (n=42); ii) semi-structured interviews with hospice staff, morgue pathologists, funeral home directors, national organ/tissue donation programs (n= 27); and iii) conducted an extensive review of the literature regarding existing models of RTD.
Results:
Results from part 1 of the study identified several barriers including use of the word “autopsy”; discussing RTD during an initial appointment; approaching patients who attended visits alone; having staff discuss RTD with patients; and expecting all physicians would want to assist with recruitment. Facilitators included identifying enthusiastic physicians; establishing that the treating physician should identify who would be a good candidate (interest and willingness); use of the word “donation”; only approaching patients who have expressed interest and are coping well with their diagnosis; engaging family members in the consenting process; developing written educational materials about RTD; and allowing family members the authority to revoke consent after patient death. Results from part 2 identified the need to use a body map to indicate metastatic sites, developing a standardized operation procedure (SOP); restricting the geographic area where patients reside to facilitate quick retrieval; enlisting the help of Hospice, providing training to staff and physicians and developing a mechanism to provide study results to NoK and recognition for donors. Results from part 3 revealed that despite more than 300 publications using tissue collected via RTD, only 1 study actually described the process for obtaining the tissues and consent. Based on these results, a 12-step RTD SOP was developed.
Conclusion:
Ethical guidelines, an SOP, and training for HCPs is needed prior to initiation of an RTD program. A verbatim script is necessary for physicians’ comfort level and to ensure consistent messaging. Our study provides important information about knowledge, attitudes, and logistics related to RTD from all stakeholders and guided the development of a RTD at a Comprehensive Cancer Center.
