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Chantale Bernatchez



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    MA06 - PDL1, TMB and DNA Repair (ID 903)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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      MA06.02 - Prospective Immunogenomic Profiling of Non-Small Cell Lung Cancer: Genomic and Immune Profiling Updates from Project ICON (ID 13523)

      13:35 - 13:40  |  Author(s): Chantale Bernatchez

      • Abstract
      • Presentation
      • Slides

      Background

      Our previous work has demonstrated that higher level of genomic complexity is associated with more heterogeneous neoantigen repertoire, suppressed T cell repertoire and postsurgical relapse in localized non-small cell lung cancers (NSCLC) highlighting the complex interaction of tumor molecular and immune landscape and their impact on cancer biology and patient survival. We launched the ICON Project (Immune Genomic Profiling of NSCLC) to prospectively delineate the molecular and immune landscape of early stage NSCLC and their impact on patient survival through a multidisciplinary approach. Here we report the updated genomic and immune analyses.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Surgical specimens from stage I-III NSCLC were subjected to whole-exome and RNA sequencing for mutational analysis, in silico neoantigen prediction and gene expression analysis as well as T cell receptor sequencing, cytometry by time-of-flight and multiplex immunofluorescence staining.

      4c3880bb027f159e801041b1021e88e8 Result

      From 2016-2018, 127 patients were accrued and 50 surgical samples have undergone WES, RNAseq, TCR sequencing and immune phenotyping. Median age is 66 yrs (range: 39-86), 52% (26/50) were female and 76% (38/50) former smokers. 76% (38/50) are non-squamous carcinomas and 24% (12/50) squamous cell carcinomas. 34% have stage I disease (17/50), 30% stage II (15/50), 34% stage III (17/50) and 2% stage IV (1/50). The majority of patients had upfront surgery (45/50; 90%). With median follow-up of 19 months, 15 patients have relapsed. Median tumor mutational burden is 7.8mut/Mb and predicted neoantigen burden was 10/sample (range: 0-250). Predicted neoantigen burden is significantly correlated with tumor mutational burden (r=0.41, p=0.002). The most commonly mutated genes are TP53, KRAS, CDKN2A, PIK3CA, EGFR, BRAF, GRIN2A and ATM. C->A transversions and C->T transitions were the most common mutational subtypes. PD-1 expression and regulatory T-cell (CD4+/FoxP3+) infiltration are significantly increased in tumor tissue compared to normal tissue (p=0.003 and p=0.02 respectively), while CD3, CD8, granzyme B and CD45RO are decreased in tumor tissue compared to normal lung.

      8eea62084ca7e541d918e823422bd82e Conclusion

      NSCLC tumors have an immunosuppressive microenvironment compared to tumor adjacent normal lung tissues. Clinical data will be adequate to conduct genomic and immune profiling comparisons across different clinical subgroups. Mutational and neoantigen profiling are consistent with previously reported studies and correlations between molecular and immune landscapes and its impact on patient survival are ongoing.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    MA23 - Early Stage Lung Cancer: Present and Future (ID 926)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 10:30 - 12:00, Room 105
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      MA23.02 - Circulating Tumor DNA Analysis with a Novel Variant Classifier for Recurrence Detection in Resected, Early-Stage Lung Cancer (ID 13498)

      10:35 - 10:40  |  Author(s): Chantale Bernatchez

      • Abstract
      • Presentation
      • Slides

      Background

      ctDNA is a blood-based biomarker with promising potential in lung cancer for minimal residual disease (MRD) assessment and early detection of recurrence. However, data regarding feasibility are limited, especially for stage I-II disease.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      We performed longitudinal plasma ctDNA profiling of early-stage lung cancer patients (pts) that underwent resection at MD Anderson Cancer Center from Apr 2016 to Jan 2017. Plasma ctDNA was analyzed from pre-operative and multiple post-operative time points until disease recurrence. ctDNA profiling was performed using a 30kb Digital Sequencing panel (Guardant Health) covering SNVs in 21 genes and indels in 9 genes that are commonly present in lung cancer. ctDNA profiles from ~30,000 lung cancer pts were used to train a classifier to exclude non-tumor related mutations.

      4c3880bb027f159e801041b1021e88e8 Result

      A total of 40 pts were included in this analysis, comprised of the first 17 pts with recurrence in the longitudinal study and 23 consecutive pts without recurrence. This cohort was primarily stage I and II (15 [38%], 16 [40%]). Histology included adenocarcinoma (29 [73%]), SCC (6 [15%]), and SCLC (2 [5%]). 58% had adjuvant therapy. Median follow-up was 17.7 (3.4 – 24.5) months and median time to recurrence was 7.1 (3.4 – 16.5) months in this selected cohort. At least one ctDNA alteration was detected in 55% (21/38) of pts with evaluable pre-op samples and in 22% (8/37) of pts at 4 weeks post-op. Presence of ctDNA at 4 weeks post-op heralded eventual recurrence with 43% sensitivity and 91% specificity (75% PPV, 73% NPV) and was significantly associated with worse recurrence free survival (p=0.022, HR 6.52; 95% CI 1.3 – 32.6), while also accounting for stage. In the absence of the variant classifier, an additional 7/37 pts had non-tumor alterations detected at 4 weeks post-op with a recurrence sensitivity and specificity of 57.1% and 69.6%. ctDNA was identified in 76% (13/17) of pts prior to or at the time of recurrence. The median interval between ctDNA detection and radiographic recurrence was 91 days.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Detection of post-op ctDNA, as early as 4 weeks after resection of early-stage lung cancer, is associated with significantly increased risk of recurrence. Accurate detection of ctDNA in this MRD setting is enabled by a highly sensitive sequencing platform that incorporates a novel variant classifier to enhance clinical specificity.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.03 - Biology (Not CME Accredited Session) (ID 935)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.03-12 - PD-L1 Expression is Predominant in CD68+ Tumor-Associated Macrophages in Stage I-III Non-Small Cell Lung Cancers (ID 13340)

      16:45 - 18:00  |  Author(s): Chantale Bernatchez

      • Abstract
      • Slides

      Background

      PD-L1 tumor expression is a leading biomarker in metastatic non-small lung cancer (NSCLC). Its role and expression in surgically resectable lung cancers is not yet defined. The association between PD-L1 expression on tumor and CD68+ tumor-associated macrophages (TAMs) and the inflammatory cells within the tumor microenvironment continues to be studied. We analyzed 97 surgically resected lung cancers utilizing immunofluorescence profiling and flow cytometry (n=47) with the aim of defining PD-L1 expression and its association with tumor inflammatory cells.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Multiplex immunofluorescence profiling of lung cancers was performed with the focus on malignant cells (MC), MC PD-L1%, CD3+, CD8+, PD-1+ cells, CD68+, CD68+ PD-L1%, and CD20+ cells. Data on cell populations were expressed as the number of cells per mm2, PD-L1 expression as percentage. Flow cytometry was performed on freshly disaggregated tumor samples. The associations of cell populations with clinical and pathologic characteristics were assessed using Spearman's rank correlation coefficient and Wilcoxon rank-sum test.

      4c3880bb027f159e801041b1021e88e8 Result

      97 patients, 55 (57%) female and 42 (43%) male, with median tumor size 4.0 cm underwent surgical resection for pathologic stage I (N=39), stage II (N=34), and stage III (N=24) NSCLC. 85 (88%) were former smokers, 12 (12%) never smokers. 62 (65%) had adenocarcinoma, 25 (25%) squamous cell carcinoma, 10 (10%) other histology. Neoadjuvant chemotherapy was administered in 16 (16%) patients. R0 resection was achieved in 89 (92%) patients. At the median follow-up duration of 16 months, 18 patients experienced recurrence.

      CD68+ cells were less abundant than MC within tumor environment (median 120 cell/mm2 vs 4699, p<0.0001). However, PD-L1% expression was significantly higher on CD68+ vs MC within the tumor (median 33% vs 0.02%, p<0.0001); this was true for all stages. CD68+ PD-L1% in SCC was higher compared to adenocarcinoma (median 55% vs 30%, p=0.26). Induction chemotherapy increased CD68+ PD-L1% (median 31% no chemo vs 58%, p=0.05) without affecting the proportion of effector CD8+ TIL expressing its receptor, PD-1 (p=0.757). Tumors with > median CD68+ PD-L1% expression were associated with higher CD3+ (p=0.006), CD8+ (p=0.06), and CD68+ (p=0.004) cell numbers within the tumor.

      8eea62084ca7e541d918e823422bd82e Conclusion

      In early NSCLC PD-L1% expression appears to be predominant in CD68+ TAMs rather than in malignant cells. Higher than median PD-L1% expression on CD68+ is associated with increased in CD3+ and CD8+ T cells. Further studies are required to understand the role of CD68+PD-L1 cells within tumor microenvironment, the influence of neoadjuvant chemotherapy or immunotherapy regimens on these cells, and their effect on outcomes.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P3.09 - Pathology (Not CME Accredited Session) (ID 975)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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      P3.09-27 - Histopathologic Parameters Define Features of Treatment Response to Neoadjuvant Chemotherapy in Non-Small Cell Lung Cancer (ID 14257)

      12:00 - 13:30  |  Author(s): Chantale Bernatchez

      • Abstract

      Background

      Previous studies indicate that neoadjuvant chemotherapy improves survival in patients with loco-regionally advanced non-small cell lung cancer (NSCLC). The amount of residual viable tumor has been associated with long-term overall survival. This histopathologic measure has potential to become a standard method for evaluation of the effectiveness of neoadjuvant therapy regimens. However, adequate comparison of chemotherapy-treated and untreated lung cancers is lacking. We analyzed histopathologic characteristics of resected NSCLC with and without prior neoadjuvant chemotherapy.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Histopathologic assessment was performed of specimens obtained from patients enrolled on the immunogenomic lung cancer study (ICON), which integrates clinical, pathologic, immune, genomic and outcome data from surgically resected NSCLC. Cases included material from 10 patients who underwent neoadjuvant chemotherapy and 10 patients treated with primary surgery (adenocarcinoma, n=5; squamous cell carcinoma, n=5; for each cohort). Hematoxylin and eosin-stained tumor sections (mean, 6; range, 3-10) were evaluated and semiquantitatively scored for parameters commonly attributed to treatment response. The percentage of viable tumor was estimated by comparison to the proportion of fibrosis and necrosis on each slide. Additional parameters analyzed included the presence of inflammation, tertiary lymphoid structures (TLS), macrophages, lymphovascular invasion (LVI), cholesterol clefts, giant cells and neovascularization (score 0-3). For each patient, the results for all slides were averaged to determine a mean value. P values were calculated using the Mann-Whitney test.

      4c3880bb027f159e801041b1021e88e8 Result

      All histopathologic parameters typically associated with treatment response could also be identified in untreated specimens, albeit in different proportions. Compared to the untreated cohort, samples after chemotherapy were characterized by lower proportion of viable tumor (42.4% vs 67.7%, p=0.04) and higher degrees of fibrosis (46.6% vs 26.6%, p=0.08), and necrosis (11.0 % vs 5.6%, p=0.35). Among the additional parameters, similar scores were seen for inflammation (1.54 vs 1.46, p=0.60), TLS (1.00 vs 0.80, p=0.47), LVI (0.16 vs 0.23, p=0.62), and neovascularization (both 0) while macrophages (0.94 vs 0.12, p=0.20), cholesterol clefts (0.92 vs 0.13, p= 0.03) and giant cells (0.80 vs 0.40, p=0.17) were more common among the neoadjuvant cohort.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Histopathologic variables commonly associated with chemotherapy treatment response can also be identified in treatment naïve lung cancers. However, the amount of viable tumor, fibrosis and cholesterol clefts are parameters strongly associated with neoadjuvant therapy. These results highlight the importance of assessing the type and extent of treatment response. Analysis of larger patient cohorts will reveal potential prognostic value in primary tumors, chemotherapy-treated, and eventually immunotherapy-treated tumors.

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