Non-small Cell Lung Cancer Adenocarcinoma Research Articles

ОСОБЕННОСТИ МЕТАБОЛИЗМА ЭПИТЕЛИАЛЬНОЙ ОПУХОЛИ ПРИ ЕЁ МЕЗЕНХИМАЛЬНОМ ПЕРЕХОДЕ

The epithelial tumors of various localizations are capable of producing reactive oxygen species that stimulate their epithelial-mesenchymal transformation. For tumors of non-small cell lung cancer (NSCLC), gastric and intestinal adenocarcinomas (GIAC) their metabolic heterogeneity was established. By the results of analysis in morphologically homogeneous tumors of the same localization we detected clusters of tumors characterized by increased activity of xanthine oxidase, superoxide dismutase, decreased activity of glutathione peroxidase (negative relation with pathology (ρ = -0,465, p < 0,05)). Thus, glutathione peroxidase activity was minimal in the second GIAC cluster, 1.4-fold lower, and 1.8-fold lower in their first cluster than in NSCLC tumors of the corresponding clusters. In the second NSCLC cluster, it was 1.5-fold lower than in their first cluster. Against this background, superoxide dismutase activity in tumors of different localizations included in the second clusters, on the contrary, increased 2-fold in NSCLC and 1.7-fold in GIAC, respectively. It leads to increased production of hydrogen peroxide in the tumor. Increase of adenosine deaminase activity detected (positive strong correlation (Spearman rank correlation coefficient ρ = 0,805, p < 0.01)) may be accompanied by a decrease of adenosine levels and its regulatory effects preventing tumor aggressive properties. Correlation of enzymatic activity with pathology was established. In different localization tumors the possibility of metabolic stimulation of tumor epithelial-mesenchymal transformation was revealed.

SURG-09. EFFICACY OF A BIWEEKLY 3-STAGE STEREOTACTIC RADIOSURGERY FOR LARGE BRAIN METASTASES: THE EFFECT OF EGFR TYROSINE-KINASE INHIBITOR ON TUMOR RESPONSE AND CLINICAL OUTCOMES

Abstract Stereotactic radiosurgery(SRS) is one of primary treatment modalities for brain metastases(BM), however local control and radiation necrosis of large BM remain challenging. To overcome these limitations, biweekly 3-stage SRS for LBM was performed in this study. Total 53 patients were treated for 62 LBM. Female was 27(50.9%), and mean age was 63.7±11.8years. The mean KPS was 79.2±9.0 and GPA score was 1.9±0.7. Non-small cell lung cancer(NSCLC) was the most common primary cancer in 31 patients, others include 6 small cell lung cancer(SCLC), 9 gastro-intestinal tract cancer, 5 gynecological cancer, and etc. Epidermal growth factor receptor(EGFR) mutation was identified in 13 patients, and EGFR tyrosine-kinase inhibitor(TKI) was used in 10 patients during and after staged SRS. The mean tumor volume was 19.1cm3. The mean marginal dose of 11.7Gy was delivered to the 50% isodose line based on new treatment planning every two weeks. The mean tumor volume at the second and third stage was 14.8cm3 and 11.0cm3, respectively. The lesions from squamous cell carcinoma of NSCLC decreased most rapidly, and followed by gynecological cancer, SCLC and adenocarcinoma of NSCLC(volume ratio at 3rd stage was 0.39, 0.53, 0.56, and 0.64, respectively). The most significant factor related with tumor volume reduction at 3rd stage was usage of EGFR-TKI(p=0.016; LR analysis). The mean overall survival(OS) was 15.3months, and estimated OS were 62% and 46% at 6 and 12months. In the multivariate analysis, KPS(OR=0.918; 95% CI,0.871-0.968; p=0.002) and usage of EGFR-TKI(OR=0.216; 95% CI,0.059-0.790; p=0.021) were significantly associated with OS. The mean OS of the group of usage of EGFR-TKI was significantly longer than that of the others(20.7months, and 13.1months; p=0.029; log-rank test). The biweekly 3-stage SRS seems to be effective treatment for patients with LBM, especially in patients who were treated with EGFR-TKI during and/or after SRS, also cautiously considering the primary tumor origin.

RADT-02. IMPACT OF SINGLE AND DUAL IMMUNE CHECKPOINT BLOCKADE ON RISK OF RADIATION NECROSIS AND LOCAL CONTROL AMONG PATIENTS WITH BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY

Abstract PURPOSE Single and dual immune checkpoint inhibition (ICPI) are common treatment options for patients, particularly with melanoma and non-small cell lung cancer (NSCLC). While data suggest a cancer control benefit of combining stereotactic radiosurgery (SRS) and ICPI, we hypothesized that concurrent dual ICPI and SRS increases risk for radiation necrosis (RN). METHODS We retrospectively reviewed patients with metastatic melanoma or NSCLC treated with SRS for intact brain metastases from 2014-2020. Patients were stratified by receipt of dual ICPI, single ICPI, and SRS alone. Concurrent ICPI was defined as treatment within 30 days of SRS. RN and local control (LC) were biopsy confirmed or determined radiographically and longitudinally, in combination with clinical assessment and steroid use. Kaplan-Meier estimates were used to compare rates of RN and LC between cohorts. RESULTS 673 brain lesions from 93 patients met inclusion criteria [median (Q1, Q3): 5.0 (2.0-10.0) lesions per patient]. Median follow-up was 8.1 months (95% CI: 7.3-8.7). Histologies included melanoma (53.5%), adenocarcinoma NSCLC (27.3%), squamous cell NSCLC (6.1%), and NSCLC NOS (6.1%). 88 lesions from 25 patients (27%) developed RN and 11 (13%) were biopsy-proven. ICPI use was enriched among lesions that developed RN (85.2%) versus those that did not (19.8%). RN was associated with concurrent ICPI (p< 0.001). Freedom from RN at 6 months was 80% for dual ICPI, 82% for single ICPI, and 97% for SRS alone; 12-month rates were 78% in each ICPI cohort and 95% with SRS alone (p=0.0002). LC differed among dual (97.5%), single (88.7%), and no ICPI (79.7%, p < 0.001). There was a trend toward improved LC with RN (96.6% vs 91.8%; p=0.087). CONCLUSIONS In a large cohort of brain metastases, we observed increased risk of RN and improved LC with SRS plus concurrent dual or single ICPI. Awareness of these associations is critical for patient management.

Impact of Single and Dual Immune Checkpoint Blockade on Risk of Radiation Necrosis among Patients with Brain Metastases Treated with Stereotactic Radiosurgery

<h3>Purpose/Objective(s)</h3> While stereotactic radiosurgery (SRS) is often an efficacious treatment for brain metastases, it carries a significant risk of radionecrosis (RN). Single and dual immune checkpoint inhibition (ICPI) have emerged as common treatment options for many patients, particularly those with melanoma and non-small cell lung cancer (NSCLC). Frequently, patients with brain metastases treated with SRS will also receive ICPI. While data suggest a cancer control benefit of combining SRS and ICPI, we hypothesized that concurrent receipt of dual ICPI with SRS increases the risk for RN. <h3>Materials/Methods</h3> We performed a retrospective review of serial patients with metastatic melanoma or NSCLC treated with SRS for intact brain metastases from 2014-2020 at our single institution. Patients were stratified by receipt of dual vs. single ICPI vs. SRS alone. RN was biopsy confirmed or determined radiographically, in combination with clinical assessment and steroid use. Kaplan-Meier estimates were used to compare rates of RN between cohorts. <h3>Results</h3> 673 brain lesions from 93 patients met inclusion criteria [median (Q1, Q3): 5.0 (2.0-10.0) lesions per patient]. Median follow-up of lesions was 8.1 months (95% CI: 7.3, 8.7). Median age and Karnofsky Performance Status of patients were 64.5 years and 90, respectively. Most (82.8%) lesions were supratentorial and histologies included melanoma (53.5%), adenocarcinoma NSCLC (27.3%), squamous cell NSCLC (6.1%), and NSCLC NOS (6.1%). In the entire cohort, 88 lesions from 25 patients (27%) developed RN. 77 (87%) lesions were diagnosed clinico-radiographically and 11 (13%) were biopsy-proven. ICPI use was highly enriched among lesions that developed RN (85.2%) versus those that did not (19.8%). Freedom from RN at 6 months was 80% for dual ICPI, 82% for single ICPI, and 97% for SRS alone; 12-month rates were 78% in each of the ICPI cohorts and 95% with SRS alone (P=0.0002). Rates of symptomatic RN, as measured by frequency of neurologic complications and hospitalization, were not significantly increased with the addition of ICPI to SRS. <h3>Conclusion</h3> In a large cohort of SRS-treated brain metastases, we observed an increased risk of RN among patients who received either dual or single ICPI concurrently with SRS. These results may guide clinical decision-making when performing radiographic surveillance of brain metastases following SRS. Prospective studies to validate these findings are warranted.

Immunotherapy combined with chemotherapy improved clinical outcomes over bevacizumab combined with chemotherapy as first-line therapy in adenocarcinoma patients.

No definite conclusion has yet to be reached for the first-line treatment combined with chemotherapy for advanced adenocarcinoma NSCLC patients with negative driver genes. This study sought to compare the clinical outcomes of Beva+ChT and IO+ChT as first-line treatment for this population and investigated whether the statuses of BM, PD-L1 expression, and KRAS and TP53 mutations could influence the results. The clinical data of patients with adenocarcinoma NSCLC who received first-line therapy were retrospectively collected and the patients were assigned to the IO+ChT and Beva+ChT groups. The disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were evaluated between the two groups. The survival effects of BM, PD-L1 expression, and KRAS and TP53 mutations were also evaluated. From April 2018 to October 2020, a total of 105 patients with first-line therapy were included in our analysis; 54 (51.4%) patients were included in the IO+ChT group and 51 (48.6%) patients were included in the Beva+ChT group. The results showed that OS (NR vs. 18.3 m, p= 0.011) and PFS (14.9m vs. 6.3 m, p <0.001) were superior in patients in the IO+ChT group than in patients in the Beva+ChT group. Further analysis revealed that the OS (median OS: NR vs. 14.7 months, p= 0.039) and PFS (median PFS: 18.5 vs. 5.5 months, p< 0.001) advantages of the IO+ChT group were also seen in the PD-L1 > 1% subgroup but were not seen in the PD-L1 < 1%, BM or KRAS mutation subgroups. ICIs combined with ChT improved clinical outcomes over Beva combined with ChT as first-line therapy for adenocarcinoma patients without driver gene alterations, especially in patients with PD-L1 ≥ 1%.

Pembrolizumab leading to complete resolution of non-small cell lung cancer and microsatellite instability stable colon adenocarcinoma; two birds one stone

Introduction: Staging of non-small cell lung cancer is crucial in predicting patient prognosis and more importantly, determining cancer management. In patients without driver mutations, PD-L1 tumor proportion score evaluation becomes vital in dictating treatment, as immunotherapy can be recommended. These agents have been shown to lead to excellent outcomes, even in patients with late-stage disease. Case Report: A 69-year-old male with a history of chronic obstructive pulmonary disease (COPD) presented with worsening dyspnea found to have lung collapse from a large hilar soft tissue mass causing obstruction of the left mainstem bronchus. After malignancy workup, the patient was diagnosed with non-small cell lung cancer clinically staged as IIIB. An incidental finding of microsatellite instability colon cancer was also found during workup. Pembrolizumab treatment was initiated and led to near resolution of both tumors. Conclusion: Stage IIIB non-small cell lung cancer has an overall poor prognosis. Biomarker testing in our case prior to starting concurrent chemoradiation revealed the malignancy to have a 100% tumor proportion score for PD-L1, the fundamental reason why our patient’s treatment was successful. Based on our findings, we advocate for all patients with non-small cell lung cancer regardless of stage to undergo biomarker testing prior to therapy initiation. Furthermore, the resolution of PD-L1 negative microsatellite instability stable colon cancer after pembrolizumab therapy supports further investigation of the utility and mechanism of PD-1/PD-L1-based therapy in PD-L1 negative colon cancer.

Nintedanib plus docetaxel after progression on first-line immunochemotherapy in patients with lung adenocarcinoma: Cohort C of the non-interventional study, VARGADO.

Immune checkpoint inhibitors (ICIs) with or without chemotherapy represent first-line standard of care for patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. The most appropriate second-line therapy after failing immunochemotherapy remains an open question. Nintedanib, an oral triple angiokinase inhibitor that targets the vascular endothelial growth factor receptor, fibroblast growth factor receptor, and, platelet-derived growth factor receptor, in combination with docetaxel, is approved for treatment of advanced NSCLC (adenocarcinoma histology) following progression on first-line chemotherapy. VARGADO (NCT02392455) is an ongoing, prospective, non-interventional study investigating the efficacy and safety of nintedanib plus docetaxel following first-line chemotherapy with or without ICIs in patients with locally advanced, metastatic, or locally recurrent NSCLC of adenocarcinoma histology. This analysis focuses on Cohort C, which enrolled patients who had received prior first line chemotherapy with ICIs. Patients received second-line docetaxel (75 mg/m²) by intravenous infusion on Day 1, plus oral nintedanib (200 mg twice daily) on Days 2-21 of each 21-day cycle during routine clinical care. The primary endpoint is overall survival (OS) rate 1 year after the start of treatment with nintedanib plus docetaxel. Secondary endpoints include progression-free survival (PFS), OS, and disease control rate (DCR). Safety was also assessed. Among 137 patients treated, the median age was 63 years (range, 37-84); 57 patients (41.6%) were female, most patients had Eastern Cooperative Oncology Group performance status of 0 (28.5%) or 1 (43.1%); 118 (86.1%) had stage IV NSCLC and 27 (19.7%) had brain metastases. Most (n=120, 87.6%) patients had received pembrolizumab/pemetrexed/platinum-based chemotherapy as first-line treatment. In 80 patients with available response data, the DCR was 72.5% (complete response: 1.3%; partial response: 36.3%; stable disease: 35.0%). Median progression-free survival was 4.8 months (95% confidence interval: 3.7-6.6). OS data were immature. Grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to treatment discontinuation were reported in 62 (45.3%), 50 (36.5%), and 40 patients (29.2%), respectively. This analysis indicates that nintedanib plus docetaxel represents an effective second-line treatment option in patients with advanced adenocarcinoma NSCLC following progression on first-line immunochemotherapy. The safety profile was manageable with no unexpected signals.

233 (PB113) - TNG908 is a brain-penetrant, MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted cancer

TNG908 is a clinical stage MTA-cooperative PRMT5 inhibitor that leverages the synthetic lethal interaction between PRMT5 inhibition and MTAP deletion. TNG908 was discovered using structure-based design following an initial high-throughput screening campaign. TNG908 is 15X selective for MTAPnull cell lines over isogenic MTAPWT cell lines and has marked selectivity for MTAP-deleted cancer cell lines independent of lineage in a large, diverse cell line panel. Oral administration of TNG908 drives dose-dependent, MTAPnull-selective antitumor activity in xenograft models, including durable tumor regressions in models representing glioblastoma, non-small cell lung cancer (adenocarcinoma and squamous), mesothelioma, cholangiocarcinoma, urothelial carcinoma, and others.

Stage IV Non-small Cell Lung Adenocarcinoma in Complete Response for 5 Years Post-first-line Nivolumab Immunotherapy: Are We Talking about a Cure?

Background: Metastasis of the Central Nervous System (CNS) is one of the frequently occurring complications of advanced Non-Small Cell Lung Cancer (NSCLC) and has been observed in 24–44% of patients. Patients suffering from NSCLC along with CNS metastases have a generally poor prognosis.&#x0D; Case Report: A 57-year-old nonalcoholic, non-diabetic, heavy smoker male patient was diagnosed with stage IV NSCLC (non-small cell lung cancer) (Adenocarcinoma), PD-L1 expression 80% with liver, spleen, and brain metastases. In June 2016, the patient was diagnosed with Stage III-A EGFR wild right-sided lung adenocarcinoma (T4N0M0), for which he underwent Curative Concurrent chemo-radiotherapy in Jordan, followed by two cycles of Etoposide plus CDDP (Cisplatin). In February 2017, the patient came to the hospital with the chief complaint of massive hemoptysis. His CT scan showed an appearance in keeping with the right upper-lobe cavitating tumor with possible contralateral lung, splenic, and hepatic metastases. The patient was offered pneumonectomy but refused it. Interventional radiology (IR) tumor embolization of the apical and posterior (A1 and A2) branches of the right superior pulmonary artery with no procedural complication was performed to stop the bleeding.&#x0D; At the end of that same month, on February 28, 2017, he presented to emergency with seizures, for which a contrast CT scan showed two enhancing lesions, one of the left parietal lobe posteriorly 1.8 cm with marked white matter oedema causing a mass effect and the effacement of the posterior horn of the left lateral ventricle. The second is a small ring-enhancing deposit of the right occipital lobe 6 mm with surrounding oedema.&#x0D; The liver biopsy failed to show any malignancy. After the MDT discussion, the largest lesion in the brain was removed and a small lesion was kept. The left occipital metastasis was resected and was found to be a metastatic adenocarcinoma of lung origin. It was positive for TTF-1 and positive for Moc 31. P63 and CK5/6 were negative (no squamous component is seen). No brain radiotherapy was offered. First-line palliative Nivolumab was started on March 20, 2017. Nivolumab first proved to be highly successful against brain metastases. However, it was discontinued as the patient developed myelitis after seven months of continuous treatment. After the discontinuation and improvement of myelitis symptoms, Nivolumab was resumed. The amazing thing about this treatment approach was that his disease was completely cleared up and he had been in complete remission for five years. Additionally, all of his tumor indicators had decreased and normalized.&#x0D; Conclusion: Our case report demonstrated a full response to first-line Nivolumab in a patient with PD-L1-positive NSCLC having visceral and brain metastases. However, our patient suffered from myelitis, which may have been a Nivolumab-related adverse event.&#x0D; The important point is that he has been achieving a durable complete response for nearly 5 years, so are we talking about the certain biology of a tumor that can be cured by immunotherapy?

EP08.02-022 Investigating Partners in Crime: Osimertinib Resistance Mechanisms in Non-small Cell Lung Cancer Using Focused CRISPR Screen

Non-small cell lung cancer (NSCLC) is the most prevalent and detrimental cancer type, accounting for 85% of all lung cancer cases. EGFR mutations, which can be targeted by tyrosine kinase inhibitors (TKIs), have been addressed as one of the cancer driving mechanisms in NSCLC adenocarcinomas. Osimertinib, a third generation EGFR-TKI, has been recently approved for clinical use in the first-line treatment of advanced NSCLC. Unfortunately, the long-standing obstacle in EGFR-TKI treatments, including Osimertinib, is the inevitable resistance.

1143P Effect of best response to first-line (1L) treatment (tx) on outcomes with second-line (2L) nintedanib (NIN) + docetaxel (DOC) for patients (pts) with lung adenocarcinoma after 1L immune checkpoint inhibitor (ICI) combination therapy

1L ICI combination therapy has transformed the tx paradigm for non-oncogene-addicted NSCLC. Acquired resistance to ICI therapy could be influenced and reversed by the use of subsequent anti-angiogenic therapy. In this setting, non-interventional data may help to guide post-progression therapeutic decision making. We therefore examined tx outcomes with 2L NIN + DOC with respect to response to 1L ICI combination therapy, and performance status (ECOG PS) at baseline. In this analysis of Cohort C of the ongoing, non-interventional VARGADO study (NCT02392455), eligible pts had locally advanced, metastatic or locally recurrent adenocarcinoma NSCLC and received 2L NIN + DOC in routine clinical practice after failure on 1L ICI combined with chemotherapy. The primary endpoint is 1-year survival rate (not yet mature). Tumour response was according to investigator review. In 176 pts enrolled in Cohort C, median age was 63 years (range: 37–84), 106 pts (60.2%) were men, 138 pts (78.4%) had an ECOG PS 0–1, and 157 pts (89.2%) had received prior 1L pembrolizumab-based combination therapy. In the overall population, objective response rate and disease control rate with 2L NIN + DOC were 35.0% (42/120 pts) and 68.3% (82/120 pts), respectively. Median PFS was 4.8 months (95% CI: 3.5–5.3) and no clear differences were seen with respect to best response to 1L therapy. Median OS was 8.1 months (95% CI: 6.3–11.2) in the overall population. There was a possible association between OS benefit with 2L tx and partial response (PR) as best response to 1L therapy (median OS 9.1 months [95% CI: 5.4–18.3]) especially in those pts with ECOG PS 0–1 (median OS 11.2 months [95% CI: 5.2–21.0]). Our results support 2L NIN + DOC as an effective tx option in pts with advanced adenocarcinoma NSCLC following 1L ICI combination therapy. Best response to 1L tx and ECOG PS may be valuable surrogate markers associated with clinical benefit of 2L NIN + DOC. These findings warrant further evaluation of the effect of these parameters on 2L tx outcomes after 1L ICI combination therapy.

906P A pilot study of a lung cancer screening program with low-dose computed tomography in high-risk individuals in Greece

Greece is one of the European countries with the highest prevalence of smoking. Low-dose computed tomography (LDCT) has been proposed as a useful tool for the early detection of lung cancer, with the potential to reduce death rates. Given the fact that Greece has no National Lung Cancer Screening program, the pilot REGISTRY study was designed to assess the effects of baseline screening with LDCT in high-risk individuals. From January 2016 to March 2022, 1500 individuals aged > 45 years with smoking history of at least 15 pack-years, were recruited in the study. Former smokers needed to quit within 15 years from study entry to be eligible. Each participant was advised to undergo annual screening with LDCT for ten years and the evaluation was based on the updated NCCN guidelines. A high rate of adherence to screening (90.1%) was reported. The median age of participants was 63 years and the number of pack years ranged from 15 to 72 (median 30 years). In total, 697 subjects (46,4%) reported at least one comorbidity including hypertension, diabetes mellitus, COPD and/or prior cancer. The rate of positive screening tests was 0,66% (10 of 1500 patients). Eight patients were diagnosed with cancer at baseline LDCT, while the rest within two years from initiation of screening. All ten patients were diagnosed with non-small cell lung cancer (adenocarcinoma=5 and squamous cell carcinoma N=5). All patients underwent surgery. Seven patients were diagnosed with stage I, two with stage II and one with stage III disease. Real-world data from this pilot study in Greece are concordant with large randomized phase III screening trials and confirm the utility of LDCT as a potent strategy for the early detection of lung cancer. A National Lung Cancer screening program should become a priority for Greek health policy makers.

79P Molecular characterization of KRAS NSCLC all stages: A single-center cohort

Kirsten rat sarcoma viral oncogene mutation (KRASm) is detected in approximately 25% of non-small cell lung cancer (NSCLC) adenocarcinoma patients (pts). As Next-generation sequencing (NGS) has been increasingly employed, diverse KRASm subtypes (subt) with different prognoses, incidences of co-mutations and characteristics have been described.

Survival benefits of primary tumor surgery for synchronous brain metastases: A SEER-based population study with propensity-matched comparative analysis.

Evidence about the prognostic value of primary tumor surgery (PTS) in patients with brain metastatic malignancies is ambiguous and controversial. This study assessed the survival benefits of primary tumor surgery in patients with brain metastases (BMs). Adults patients with BMs that originated from lung, breast, kidney, skin, colon, and liver diagnosed between 2010 and 2018 were derived from the Surveillance, Epidemiology, and End Results database (SEER). Propensity score matching (PSM) was used to balance the bias between patients with or without PTS. Then the prognostic value of PTS was estimated by Kaplan-Meier analysis and Cox proportional hazard regression models. A total of 32,760 patients with BMs secondary to non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer, renal cancer, melanoma, colorectal cancer, and liver cancer were identified from the database. After PSM at 1:1 ratio, PTS appeared to significantly prolong cause-specific survival (CSS) time for patients with BMs secondary to NSCLC, breast cancer, renal cancer, and colorectal cancer (hazard ratio [HR]=0.60 [0.53-0.68], 0.56 [0.43-0.73], 0.47 [0.37-0.60], and 0.59 [0.37-0.95], respectively, all p < 0.05). Patients with earlier T and N classifications, no extracranial metastasis, and cancer-specific subtypes (adenocarcinoma in NSCLC, hormone receptor-negative breast cancer) may derive more survival benefits from PTS when suffering from BMs. This population-based study supported PTS could provide survival benefits for patients with BMs secondary to NSCLC, breast cancer, renal cancer, and colorectal cancer. More emphasis should be put on PTS of selected patients with BMs.

From Automated Synthesis to In Vivo Application in Multiple Types of Cancer-Clinical Results with [68Ga]Ga-DATA5m.SA.FAPi.

Radiolabeled FAPI (fibroblast activation protein inhibitors) recently gained attention as widely applicable imaging and potential therapeutic compounds targeting CAF (cancer-associated fibroblasts) or DAF (disease-associated fibroblasts in benign disorders). Moreover, the use of FAPI has distinct advantages compared to FDG (e.g., increased sensitivity in regions with high glucose metabolism, no need for fasting, and rapid imaging). In this study, we wanted to evaluate the radiochemical synthesis and the clinical properties of the new CAF-targeting tracer [68Ga]Ga-DATA5m.SA.FAPi. The compound consists of a (radio)chemically easy to use hybrid chelate DATA.SA, which can be labeled at low temperatures, making it an interesting molecule for ‘instant kit-type’ labeling, and a squaric acid moiety that provides distinct advantages for synthesis and radiolabeling. Our work demonstrates that automatic synthesis of the FAP inhibitor [68Ga]Ga-DATA5m.SA.FAPi is feasible and reproducible, providing convenient access to this new hybrid chelator-based tracer. Our studies demonstrated the diagnostic usability of [68Ga]Ga-DATA5m.SA.FAPi for the unambiguous detection of cancer-associated fibroblasts of various carcinomas and their metastases (NSCLC, liposarcoma, parotid tumors, prostate cancer, and pancreas adenocarcinoma), while physiological uptake in brain, liver, intestine, bone, and lungs was very low.

Molecular profiling of human non-small cell lung cancer by single-cell RNA-seq

BackgroundLung cancer, one of the most common malignant tumors, exhibits high inter- and intra-tumor heterogeneity which contributes significantly to treatment resistance and failure. Single-cell RNA sequencing (scRNA-seq) has been widely used to dissect the cellular composition and characterize the molecular properties of cancer cells and their tumor microenvironment in lung cancer. However, the transcriptomic heterogeneity among various cancer cells in non-small cell lung cancer (NSCLC) warrants further illustration.MethodsTo comprehensively analyze the molecular heterogeneity of NSCLC, we performed high-precision single-cell RNA-seq analyses on 7364 individual cells from tumor tissues and matched normal tissues from 19 primary lung cancer patients and 1 pulmonary chondroid hamartoma patient.ResultsIn 6 of 16 patients sequenced, we identified a significant proportion of cancer cells simultaneously expressing classical marker genes for two or even three histologic subtypes of NSCLC—adenocarcinoma (ADC), squamous cell carcinoma (SCC), and neuroendocrine tumor (NET) in the same individual cell, which we defined as mixed-lineage tumor cells; this was verified by both co-immunostaining and RNA in situ hybridization. These data suggest that mixed-lineage tumor cells are highly plastic with mixed features of different types of NSCLC. Both copy number variation (CNV) patterns and mitochondrial mutations clearly showed that the mixed-lineage and single-lineage tumor cells from the same patient had common tumor ancestors rather than different origins. Moreover, we revealed that patients with high mixed-lineage features of different cancer subtypes had worse survival than patients with low mixed-lineage features, indicating that mixed-lineage tumor features were associated with poorer prognosis. In addition, gene signatures specific to mixed-lineage tumor cells were identified, including AKR1B1. Gene knockdown and small molecule inhibition of AKR1B1 can significantly decrease cell proliferation and promote cell apoptosis, suggesting that AKR1B1 plays an important role in tumorigenesis and can serve as a candidate target for tumor therapy of NSCLC patients with mixed-lineage tumor features.ConclusionsIn summary, our work provides novel insights into the tumor heterogeneity of NSCLC in terms of the identification of prevalent mixed-lineage subpopulations of cancer cells with combined signatures of SCC, ADC, and NET and offers clues for potential treatment strategies in these patients.

MMAP-07 IMPACT OF SINGLE AND DUAL IMMUNE CHECKPOINT BLOCKADE ON RISK OF RADIATION NECROSIS AMONG PATIENTS WITH BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY

PURPOSEWhile stereotactic radiosurgery (SRS) is often an efficacious treatment for brain metastases, it carries a significant risk of radionecrosis (RN). Single and dual immune checkpoint inhibition (ICPI) have emerged as common treatment options for many patients, particularly those with melanoma and non-small cell lung cancer (NSCLC). While data suggest a cancer control benefit of combining SRS and ICPI, we hypothesized that concurrent receipt of dual ICPI with SRS increases the risk for RN. METHODSWe performed a retrospective review of serial patients with metastatic melanoma or NSCLC treated with SRS for intact brain metastases from 2014-2020 at our single institution. Patients were stratified by receipt of dual vs. single ICPI vs. SRS alone. RN was biopsy confirmed or determined radiographically, in combination with clinical assessment and steroid use. Kaplan-Meier estimates were used to compare rates of RN between cohorts. RESULTS673 brain lesions from 93 patients met inclusion criteria [median (Q1, Q3): 5.0 (2.0-10.0) lesions per patient]. Median follow-up of lesions was 8.1 months (95% CI: 7.3, 8.7). Most (82.8%) lesions were supratentorial and histologies included melanoma (53.5%), adenocarcinoma NSCLC (27.3%), squamous cell NSCLC (6.1%), and NSCLC NOS (6.1%). In the entire cohort, 88 lesions from 25 patients (27%) developed RN. 77 (87%) lesions were diagnosed clinico-radiographically and 11 (13%) were biopsy-proven. ICPI use was highly enriched among lesions that developed RN (85.2%) versus those that did not (19.8%). Freedom from RN at 6 months was 80% for dual ICPI, 82% for single ICPI, and 97% for SRS alone; 12 month rates were 78% in each of the ICPI cohorts and 95% with SRS alone (P=0.0002). CONCLUSIONSIn a large cohort of SRS-treated brain metastases, we observed an increased risk of RN among patients who received either dual or single ICPI concurrently with SRS.

Prognostic implications of cellular senescence in resected non-small cell lung cancer.

BackgroundCure and long-term survival for non-small cell lung cancer (NSCLC) remains hard to achieve. Cellular senescence, an emerging hallmark of cancer, is considered as an endogenous tumor suppressor mechanism. However, senescent cancer cells can paradoxically affect the surrounding tumor microenvironment (TME), ultimately leading to cancer relapse and metastasis. As such, the role of cellular senescence in cancer is highly controversial.MethodsIn 155 formalin-fixed paraffin-embedded (FFPE) samples from surgically resected NSCLC patients with pathological tumor-node-metastasis (pTNM) stages I–IV (8th edition), cellular senescence was assessed using a combination of four immunohistochemical senescence markers, i.e., lipofuscin, p16INK4a, p21WAF1/Cip1 and Ki67, and correlated to clinicopathological parameters and outcomes, including overall survival (OS) and disease-free survival (DFS).ResultsA tumoral senescence signature (SS) was present in 48 out of 155 NSCLC patients, but did not correlate to any clinicopathological parameter, except for p53 mutation status. In a histologically homogenous patient cohort of 100 patients who fulfilled the following criteria: (I) one type of histology, i.e., adenocarcinoma, (II) without known epidermal growth factor receptor (EGFR) mutation, (III) curative (R0) resection and (IV) no neoadjuvant systemic therapy or radiotherapy, the median OS and DFS for patients with a tumoral SS (n=30, 30.0%) compared to patients without a tumoral SS (n=70, 70.0%) was 53 versus 141 months (P=0.005) and 45 versus 55 months (P=0.25), respectively. In multiple Cox proportional hazards (Cox PH) model analysis correcting for age, pTNM stage I–III and adjuvant therapy, a tumoral SS remained a significant prognostic factor for OS (HR =2.03; P=0.014).ConclusionsThe presence of a tumoral SS particularly based on high p16INK4a expression significantly affects OS in NSCLC adenocarcinoma. In this light, adjuvant senolytic therapy could be an interesting strategy for NSCLC patients harboring a tumoral SS, ultimately to improve survival of these patients.

The Association Between Gastroesophageal Reflux Disease and Non-Small Cell Lung Cancer: A Retrospective Case-Control Study.

BackgroundLung cancer is a leading cause of mortality in the USA. Non-small cell lung cancer (NSCLC) contributes to 85% of all lung cancers. It is the most prevalent subtype amongst non-smokers, and its incidence has risen in the last 20 years. In addition, gastroesophageal reflux disease (GERD) has been associated with several lung pathologies, namely idiopathic pulmonary fibrosis and asthma. We aimed to investigate the association between GERD and NSCLC by performing a retrospective, multicenter, case-control study. This is the first study of this nature to be carried out in the USA.MethodsData were retrieved from 17 Northwell health care facilities in the New York area between the years 2010 and 2018. Inclusion criteria were patients > 18 years of age with NSCLC (large cell, adenocarcinoma, and squamous cell). They were appropriately matched with controls based on age, gender, weight, comorbidities, and medication use. Our exposure group had a diagnosis of GERD based on the International Classification of Diseases, Ninth/10th Revision (ICD 9/10) codes and endoscopic, in addition to histological evidence if present. We excluded patients with secondary lung cancers, esophageal adenocarcinoma, other primary malignancies, Barrett’s esophagus, and smokers. Logistic regression was conducted to determine the adjusted odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between NSCLC and GERD.ResultsA total of 1,083 subjects were included in our study: 543 (50%) patients were diagnosed with NSCLC. In this population, GERD was twice as prevalent compared to controls (20.4% vs. 11.6%, P < 0.001). Multivariate analysis demonstrated that GERD was associated with a higher risk of NSCLC compared to matched controls (OR = 1.86, 95% CI = 1.26 - 2.73). In addition, GERD patients treated with either antihistamines or proton pump inhibitors did not demonstrate an overall reduced risk of NSCLC (OR = 1.01, 95% CI = 0.48 - 2.12).ConclusionsOur study demonstrates that GERD is associated with a higher risk of NSCLC, irrespective of GERD treatment. We postulate that GERD patients suffer from chronic micro-aspirations leading to a prolonged inflammatory state within the lung parenchyma, triggering specific proliferative signaling pathways that may lead to malignant transformation.

Identification of KRASG12C Mutations in Circulating Tumor DNA in Patients With Cancer.

PURPOSEKRAS is the most mutated proto-oncogene that has been identified in cancer, and treatment of patients with KRAS mutations remains an arduous challenge. Recently, KRASG12C mutation has attracted special interest because it is now considered potentially druggable with recently developed covalent small-molecule KRASG12C inhibitors. Nevertheless, to date, there have been no large-scale analyses of liquid biopsy that include testing for KRASG12C. Here, we performed a comprehensive analysis of KRASG12C mutations in multiple cancer types, as detected by circulating tumor DNA.METHODSWe conducted a 5-year retrospective review of KRASG12C mutations in patients with cancer who had undergone Guardant360 testing between July 1, 2014, and June 30, 2019; our study included treatment-naive and previously treated patients with metastatic solid tumors.RESULTSKRASG12C mutations were identified in 2,985 of 80,911 patients (3.7%), across > 40 tumor types. KRASG12C mutations were detected most frequently in patients with nonsquamous non–small-cell lung cancer (NSCLC; 7.5%), NSCLC of all subtypes (6.9%), cancer of unknown primary (4.1%), colorectal cancer (3.5%), squamous NSCLC (2.0%), pulmonary neuroendocrine tumors (1.9%), and pancreatic ductal adenocarcinoma (1.2%) and cholangiocarcinoma (1.2%). KRASG12C mutations were predominantly clonal (clonality > 0.9%) in patients with lung adenocarcinoma, non-NSCLC, cancer of unknown primary, NSCLC, and pancreatic ductal adenocarcinoma, and patients with colorectal cancer and breast cancer had bimodal distribution of clonal and subclonal KRASG12C mutations.CONCLUSIONOur study demonstrates the feasibility of using circulating tumor DNA to identify KRASG12C mutations across solid tumors; the highest detection rate was in lung cancer, as previously reported in the literature.