Actionable genetic alterations (AGAs) are present in many patients with non-squamous, metastatic non-small cell lung cancer (mNSCLC) and guide the selection of targeted therapies. Guidelines support concurrent tissue- and plasma-based molecular sequencing at diagnosis to optimize detection of AGAs. Some patients with mNSCLC have alterations detected in plasma-based molecular testing but not in tissue. The mechanisms underlying this discordance, and associated patient- and tumor-specific features remain uncertain. We conducted a single-center retrospective cohort study using electronic health record data. The cohort included treatment-naïve patients with newly diagnosed non-squamous mNSCLC who underwent concurrent tissue- and plasma-based molecular sequencing between 01/01/2019 and 3/31/2022. 358 patients underwent concurrent tissue- and plasma-based molecular sequencing, 173 (48.3%) were found to harbor AGAs. 113 (65.3%) had alterations identified on both tissue- and plasma-based testing, 42 (24.3%) in tissue-based testing alone, and 18 (10.4%) in plasma-based testing alone. Amongst these 18 patients, 9 (50%) had AGAs in plasma-based sequencing alone due to tissue samples unsuitable for comprehensive testing, 4 (22%) had incomplete tissue-based molecular sequencing panels ordered, and 5 (28%) had no AGAs detected in tissue-based sequencing despite appropriate testing on adequate samples, constituting true tissue-negative cases. The disease control rate by RECIST 1.1 criteria was 100% for the 6 patients with plasma-only AGAs treated with first-line targeted therapy. Concurrent tissue- and plasma-based molecular profiling enhances AGA detection in patients with non-squamous mNSCLC. Concurrent testing may compensate for inadequate solid tumor tissue samples and tumor heterogeneity to enhance the comprehensiveness of molecular sequencing.

333 Background: Family history screening for malignancies informs the need for genetic testing of cancer patients and their families. Associations between heritable mutations and solid malignancies are well-established, but germline contributions to hematologic malignancies may be of similar importance. For instance, the pooled risk of a group of heritable transcription factor mutations including RUNX1, GATA2, and CEBPA may play a role in up to 15% of new cases of leukemia. Standard of care for new patient visits in malignant hematology clinics should involve thorough family screening like that of solid malignancies more classically associated with heredity. Methods: All patients presenting to an academic hospital system's outpatient GI, breast, and leukemia clinics for new patient visits in a 3-month period were identified accounting for 706 participants (breast n=258 (36.5%), GI n=303 (42.9%), leukemia n=145 (20.5%)). Retrospective chart review was completed by EMR report, which aggregated data from individuals identified by their cancer diagnosis. Groups were compared along the following variables: percentage with completed 1^st degree (parents and siblings) family history of malignancy screening, percentage with completed 2^nd degree (grandparents, aunts, and uncles) family history screening. Chi-squared significance testing was completed to identify significant (p<0.05) differences in screening, which was considered completed if entered in the searchable summary information of the patient’s chart. Results: Patients presenting for new patient visits in breast (77.1%) cancer clinic had significantly higher rates of 1^st degree family history of malignancy screening than those presenting with new diagnoses of leukemia (62.1%). The comparison of 1^st degree screening for GI (71.6%) cancer patients and leukemia patients was not significant. Rates of 2^nd degree family history screening were significantly higher for patients with new diagnoses of breast (61.6%) and GI (37.0%) cancers as compared to those with leukemia (24.8%). The combined cohort of GI and breast cancer patients had significantly greater rates of 1^st (74.2%) and 2^nd degree (48.4%) family history screening than patients with new diagnosis of leukemia. Conclusions: There is growing appreciation of heritable germline contributors to leukemia pathogenesis. However, there remains a deficit in clearly documented, easily referenced family history screening for malignancies in patients with new diagnoses of leukemia when compared to patients with new diagnoses of classically heritable solid malignancies.

Tracheal head and neck squamous cell cancer recurrence without metastases may be related to physical displacement of cancer cells.