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Mattia Boeri
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MA03 - Lung Cancer Screening - Next Step (ID 896)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 10:30 - 12:00, Room 206 AC
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MA03.03 - Prolonged Low-Dose Computed Tomography (LDCT) Screening Beyond 5 Years Reduces Overall and Lung Cancer Specific Mortality (ID 13227)
10:40 - 10:45 | Author(s): Mattia Boeri
- Abstract
- Presentation
Background
The National Lung Screening Trial (NLST) showed that lung cancer screening (LCS) by low-dose computed tomography (LDCT) improves the overall survival. The NLST and most of the LCS trials were limited to a 5-year period, therefore there is no prospective evidence about the optimal duration of LCS. The aim of this study was to assess the potential benefit of long term LC screening beyond 5 years, notably its effect in 10-year overall and LC specific mortality.
a9ded1e5ce5d75814730bb4caaf49419 Method
The Multicenter Italian Lung Detection (MILD) trial prospectively enrolled 4,099 participants, randomized to either LDCT arm (n=2,376) or control arm (n=1,723); 38,561 person-years of follow-up were accumulated between 2005 and March 2017. The primary outcomes were 10-year overall and LC specific mortality. Moreover, a Landmark Analysis was used to test the long-term effect of LCS, beyond 5 years (notably by selective exclusion of events that occurred < 5 years). Cumulative mortality were evaluated using Kaplan-Meier estimator and differences among groups were tested using Log-rank test, adjusted for sex, age and pack-years. The prognostic value of assigned arm in predicting mortality was investigated by Cox’s proportional-hazard’s regression adjusted for the above variables.
4c3880bb027f159e801041b1021e88e8 Result
In the whole 10-year LCS, LDCT arm showed a protective non-statistically significant trend for reduction of overall mortality (HR: 0.82, 95% CI 0.63 to 1.07) and a significant 41% reduced risk of LC mortality (HR 0.59, 95% CI 0.38 to 0.92), compared to the control arm.
Beyond the 5th year of screening, LDCT arm showed a significant 29% reduction of overall mortality (HR: 0.71, 95% CI 0.50 to 0.99), and a significant 62% reduced risk of LC mortality (HR 0.38, 95% CI 0.20 to 0.74) (Figure 1).
8eea62084ca7e541d918e823422bd82e Conclusion
Prolonged LDCT screening beyond 5 years reduces overall mortality, and it is most beneficial in further reduction of LC specific mortality.
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MA04 - Novel Approaches with IO (ID 900)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 1
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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MA04.06 - PD-1 Blockade Promotes Hyperprogressive Disease in NSCLC Through Macrophages Activation via Antibody-Fc/FcR Interaction (ID 12334)
14:05 - 14:10 | Author(s): Mattia Boeri
- Abstract
- Presentation
Background
In a subset of patients, named hyperprogressors (HPs), immunotherapy seems to paradoxically boost tumor growth. However, neither pathological and clinical features nor the underlying biological mechanism have been identified. We dissected the role of tumor-myeloid cells crosstalk as possible players.
a9ded1e5ce5d75814730bb4caaf49419 Method
HPs were defined on the basis of clinical and radiological features. Baseline histological samples from patients treated with immune checkpoints inhibitors (ICI) were evaluated by immunohistochemistry for myeloid and lymphoid markers. We tested the effect on tumor growth of murine and human ICI in T-cell deficient mice injected with human lung cancer cell lines and PDXs bearing different genotypes (EGFR+, KRAS+, STK11+ and wt). Innate immune microenvironment was evaluated by FACS analysis and immunohistochemistry. In vitro studies of ICI binding functional modulation were performed in human myeloid cells from patients and healthy donors.
4c3880bb027f159e801041b1021e88e8 Result
In a clinical series of 187 patients treated with ICI, hyperprogression was observed in 40 (26.3%) cases. All available HP pre-treatment tissue samples (11 cases) showed CD163+CD33+PD-L1+Arginase-A1+ clustered epithelioid macrophages infiltrating the tumor foci also expressing FcRs including CD32b. No differences in T cell compartment were observed. Murine and human PD1 blocking mAbs induced a boost of tumor growth in H460 xenografs in imunocompromised mice. A similar effect was observed in EGFR+ but not in KRAS+ and wt PDXs treated with human anti-PD1. Notably, no hyperprogression was observed after treatment with murine and human anti PD-1 F(ab)2. Hyperprogressive tumors were enriched in arginase+ myeloid-macrophage cells and fibrotic features. ICI bind in vitro to human macrophages and monocytes via Fc/FcR interactions, likely involving CD32b (FcgRIIb) and triggering functional polarization.
8eea62084ca7e541d918e823422bd82e Conclusion
Our results provide evidence that FcR triggering on macrophages by ICI delivers a signaling cascade promoting a functional reprogramming of these cells toward a more aggressive pro-tumorigenic behavior eventually inducing hyperprogression in a subset of patients with distinctive immune and genetic profile. A validation prospective study in ongoing.
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