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M. Varella-Garcia
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MTE28 - Implementation of Precision Medicine in Routine Practice: The Latin American Experience (Ticketed Session) (ID 321)
- Event: WCLC 2016
- Type: Meet the Expert Session (Ticketed Session)
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 07:30 - 08:30, Lehar 3-4
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MTE28.02 - Implementation of Precision Medicine in Routine Practice: The Latin American Experience (ID 6591)
08:00 - 08:30 | Author(s): M. Varella-Garcia
- Abstract
- Presentation
Abstract:
Implementation of Precision Medicine in Routine Practice: The Latin American Experience – Part 1 Marileila Varella-Garcia, PhD The increasing application of the concept of precision medicine (PM) in the last decade has revolutionized health care. Under this concept, the approach to disease treatment and prevention takes into account individual variability in genes, environment, and lifestyle to more accurately predict treatment and prevention strategies for a particular disease in specific patient subsets. PM has been progressing faster among infectious diseases and neoplasia, with emphasis in non-small cell lung cancer (NSCLC) among the solid tumors. However, we are still far away from a stable scenario to which we should adjust. The field is in continuous evolution with constant new discoveries and proposals. The implementation of PM for lung cancer has dramatically impacted several medical areas mainly in two basic aspects: the molecular diagnosis and the therapy regimen. The first involves questions such as how to collect and process specimen for testing, which tests to apply and in which level, how to define scoring criteria and cut-offs for variables with continuous distribution in the population, how to interpret and validate clinical assays, and how to properly communicate with the multidisciplinary team. The second involves questions pertinent to understanding the molecular diagnostic, access to and cost of new and old drugs, evaluation of side effects, selection of combination or sequential regimens, definition of clinical progression and resistance, and proper communication with the multidisciplinary team. Our discussion will primarily address molecular testing in lung cancer in Latin America countries (LATAM). One of the medical areas most largely affected by the changes accompanying PM is Pathology. The new specialty of Molecular Pathology has emerged to focus on the sub-microscopic aspects of disease by examination of molecules within tissues and bodily fluids. Molecular Pathology encompasses aspects of anatomic and clinical pathology as well as molecular biology, biochemistry, genetics, and bioinformatics. Molecular lung cancer testing in LATAM is centralized in the main cities of several countries and usually performed in laboratories of few large, private or public hospitals, mostly belonging to academic institutions. Examples of those laboratories are located in the Hospital Italiano and Hospital Roffo in Buenos Aires, Argentina; in the Instituto Nacional do Cancer in Rio de Janeiro and Instituto AC Camargo in Sao Paulo, Brazil; in the Universidad Catolica de Chile; in the Fundacion Santa Fe de Bogota and Fundacion Valle de Lili in Colombia, and in the Instituto Nacional de Cancerologia in Mexico City. There are also few commercial laboratories that offer standard tests under good laboratory practices. Examples are the laboratories Hermes Pardini and Consultoria em Patologia in Brazil, Argenomics and Biomarkers in Argentina, and ROE in Peru. The implementation of molecular testing poses important challenges to pathology practices in commercial and academic institutions, and efforts to overcome them have been extensively discussed. It is well recognized that changes in two organizational levels are required, one related to personnel and another related to equipment and technology. In terms of personnel, there is a need to increase multi-disciplinary communication affecting all areas including oncologists or surgeons requesting the tests, professionals (surgeons, pulmonologists, interventionists) collecting the specimens, technologists processing and handling the specimens, pathologists performing histology diagnosis and molecular testing interpretation, lab scientists (biologists, biotechnologists, biochemists) executing assays and interpreting the results, and bioinformaticians handling computer-generated data. The interdisciplinary work in the anatomic and clinical pathology laboratory must be intensified and personnel with distinct expertise and no clinical experience must be added and integrated to the team. The role of the pathologist in the communication and integration among team members (clinical/medical and laboratory group) is crucial. Interestingly, the work environment in a complex molecular testing laboratory has changed to demand personnel not only with excellent hard technical skills but also with soft skills such as active listening, coordination, adaptability, punctuality, problem solving, and friendly personality. The lab success relies in that each team member clearly understands his/her role and the value of efficient communication among team members, which is mainly modulated by the pathologists. Most of the LATAM laboratories already performing molecular testing have increased and strengthened this interdisciplinary work using biologists and biotechnologists originally trained in research fields. Nevertheless, the continuous update with the evolving field required from the pathologists, the scarceness of trained bioinformaticians for data sequencing analysis, and the vigorous integration of the entire professional team are still challenging personnel issues to be addressed. Data from at least 15 of the highest populated LATAM countries regarding their efforts in initiating and expanding molecular testing for lung cancer and the strengths and challenges faced have been surveyed and results will be discussed.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-035 - EGFR FISH as Potential Predictor of Necitumumab Benefit with Chemotherapy in Squamous NSCLC: Subgroup Analyses from SQUIRE (ID 5708)
14:30 - 14:30 | Author(s): M. Varella-Garcia
- Abstract
Background:
Necitumumab (Neci) is a monoclonal antibody directed against the human epidermal growth factor receptor (EGFR). In the SQUIRE trial (NCT00981058), the addition of Neci to gemcitabine plus cisplatin (Gem-Cis) in squamous cell lung cancer resulted in a significant advantage in terms of overall survival (OS), but the expression of EGFR assessed by immunohistochemistry was not able to robustly predict the benefit from Neci. In a post-hoc analysis of SQUIRE, EGFR gene copy number gain determined by fluorescence in situ hybridization (FISH) showed a trend towards improved OS (HR=0.70) and progression-free survival (PFS) (HR=0.71) with the addition of Neci. We present the analysis of granular EGFR-FISH data from SQUIRE to examine the potential predictive role of high polysomy (HP) vs gene amplification (GA) as both were included in the “FISH-positive” category.
Methods:
Suitable specimens from SQUIRE patients underwent FISH analysis. Probe hybridization was performed in a central laboratory and each sample was analyzed using the Colorado EGFR scoring criteria. FISH was considered positive in cases of HP (≥40% cells with ≥4 EGFR copies) or GA (EGFR/CEP7 ≥2 or ≥10% cells with ≥15 EGFR copies). The correlation of granular FISH parameters with clinical outcomes was assessed.
Results:
FISH analysis was available for 557 patients (out of 1093); 208 patients (37.3%) were FISH+, including 167 (30.0%) with HP and 41 (7.4%) with GA. The outcome data for HP and GA are reported below:HIGH POLYSOMY GENE AMPLIFICATION Neci+Gem-Cis (N=89) Gem-Cis (N=78) Neci+Gem-Cis (N=22) Gem-Cis (N=19) Median OS in months (95% CI) 12.58 (11.04-16.00) 9.53 (7.16-12.48) 14.78 (10.02-31.51) 7.62 (4.99-16.10) Hazard ratio within subgroup (interaction model) 0.77 (0.55-1.08) p = 0.133 0.45 (0.21-0.93) p = 0.033 Interaction p value 0.189 Median PFS in months(95% CI) 6.08 (5.59-7.59) 5.13 (4.24-5.72) 7.36 (4.27-11.40) 5.55 (2.79-8.34) Hazard ratio within subgroup (interaction model) 0.70 (0.50-0.99) p = 0.044 0.69 (0.33-1.45) p = 0.334 Interaction p value 0.980
Conclusion:
The OS benefit from the addition of Neci to Gem-Cis appeared to be more pronounced in the small subset of patients with GA when compared to HP, but the same trend was not observed for PFS. The potential predictive value of different EGFR FISH parameters should be evaluated in future studies.
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P2.03b-053 - Role of KRAS Mutation Status in NSCLC Patients Treated on SWOG S0819, a Phase III Trial of Chemotherapy with or without Cetuximab (ID 6113)
14:30 - 14:30 | Author(s): M. Varella-Garcia
- Abstract
Background:
The S0819 phase III study of chemotherapy and bevacizumab (by patient/physician choice) with or without cetuximab in NSCLC showed no benefit from the addition of cetuximab, either overall or within the EGFR FISH-positive subset. Secondary analysis suggested an overall survival benefit in EGFR FISH-positive squamous cell carcinoma (SCC) (Herbst WCLC 2015, Hirsch ASCO 2016). In colorectal cancer (CRC), benefit from EGFR monoclonal antibodies such as cetuximab is limited to patients with RAS wild type (WT) tumors; however, in NSCLC, previous studies have not been sufficiently powered to make this determination. We prospectively incorporated KRAS mutation testing in S0819 to determine whether it predicts cetuximab efficacy. Since KRAS mutations are rare in SCC, we focused this analysis on nonSCC.
Methods:
KRAS mutation status was determined using the Therascreen KRAS test (Qiagen), conducted in a CLIA-certified diagnostic laboratory at the UC Davis Comprehensive Cancer Center. This test is FDA-approved for KRAS diagnostics in metastatic CRC, and identifies 6 mutations at codon 12 (G12A,D,R,C,S,V) plus G13D.
Results:
KRAS mutation status was available for 448 nonSCC patients, and mutations were identified in 150 cases (33%). Amino acid substitutions matched the expected distribution for a NSCLC population, with 52% harboring G12C and 17% with G12V. No significant differences were observed between KRAS-mut and WT populations for PFS (HR=1.15 (0.94-1.42); p=0.18) or OS HR=1.10 (0.89-1.37); p=0.39). Furthermore, no differences in outcomes between arms were observed based on KRAS mutation status (Table). The KRAS WT, EGFR FISH+ molecular subset (hypothetically the most likely subgroup to benefit from cetuximab) showed no statistical differences in outcomes between arms. Figure 1
Conclusion:
Determination of KRAS mutation status did not identify a subgroup of nonSCC patients with differential outcome from addition of cetuximab to front-line chemotherapy. In contrast to CRC, cetuximab does not appear to confer benefit to patients with KRAS-WT nonSCC NSCLC.
