Familial lung cancer: A thirteen-year prospective analysis of participants with germline EGFR T790M pathologic variant.

10617 Background: Lung cancer in never-smokers is the eighth leading cause of cancer-related mortality in the United States. Familial lung cancer, a rare syndrome associated with germline EGFR pathologic variants (PV) such as T790M (accounting for 0.3-0.9% of lung adenocarcinomas), is a recently identified cause of non-tobacco-related lung cancer. Data on this population is limited. We describe a 13-year prospective analysis, the longest thus far to study the natural history. Methods: From2011 to 2024, 19 participants enrolled in a National Cancer Institute study of EGFR germline PV (NCT01306045).Eligibility included: (1) lung cancer diagnosis (invasive or pre-invasive) with two affected family members, (2) first-degree relative of someone with a germline EGFR PV, (3) T790M detected in lung cancer tumor before tyrosine kinase inhibitor, (4) significant family history of lung cancer, or (5) EGFR germline PV detected externally. Participants with germline EGFR PV were followed prospectively. Germline EGFR PV carriers completed risk-based screening computed tomography. Germline EGFR PV participants with lung cancer were followed while completing guideline-directed treatment and surveillance. Lung nodules were examined using standard radiologic assessment. Results: Of 19 enrolled participants, seven (37%) had germline EGFR T790M. Demographics of EGFR germline T790M versus not include mean age at enrollment (46, 56), gender (female 4, 9), white/African American/Asian race (6/1/0, 10/0/2), and current/former/never smoker (0/6/1, 0/4/7). Of the seven participants with EGFR T790M, three (43%) had lung adenocarcinoma diagnosed on average at age 63 (range, 53-80), two as stage I and one as stage IV. The other four (57%) did not have lung cancer during the study period. At diagnosis with germline EGFR T790M (average age 31, range 26-36), all four participants without cancer had multiple bilateral pulmonary nodules and/ or ground glass opacities (GGO) which, over 6-10 years, remained stable to slightly larger, with increased numbers. One germline EGFR T790M participant developed multiple primary lung adenocarcinomas (invasive, minimally invasive, in situ) over 26 months and metastasis 14 months later. One primary started with ground glass components and became solid and larger over 26 months. The two participants with stage IV lung adenocarcinoma survived 15 and 67 months. Conclusions: Our study confirms that germline EGFR T790M carriers present as early as the third decade of life with multiple bilateral GGOs that can remain dormant for years before exhibiting malignant behavior. Long-term surveillance imaging is necessary, and volumetric changes can potentially be automatically quantified using artificial tools. However, further studies are needed to define a risk-based schedule and examine the role of prophylactic therapy, such as osimertinib. Clinical trial information: NCT01306045 .