Non-small Cell Lung Research Articles

Targeted molecular profiling of solid tumours-Indian tertiary cancer centre experience.

Molecular Profiling of solid tumours is extensively used for prognostic, theranostic, and risk prediction. Next generation sequencing (NGS) has emerged as powerful method for molecular profiling. The present study was performed to identify molecular alterations present in solid tumours in Indian tertiary cancer centre. Study included 1140 formalin Fixed paraffin embedded samples. NGS was performed using two targeted gene panels viz. Ampliseq Focus panel and Sophia Solid Tumor Plus Solution. Data was analyzed using Illumina's Local Run Manager and SOPHiA DDM software. Variant interpretation and annotations were done as per AMP/ACMG guidelines. Total 896 cases were subjected to NGS after excluding cases with suboptimal nucleic acid quality/quantity. DNA alterations were detected in 64.9% and RNA fusions in 6.9% cases. Among detected variants, 86.7% were clinically relevant aberrations. Mutation frequency among different solid tumours was 70.8%, 67.4%, 64.4% in non-small cell lung (NSCLC), lung squamous cell carcinomas and head neck tumours respectively. EGFR, KRAS, BRAF, ALK and ROS1were commonly altered in NSCLC. Gastrointestinal tumours showed mutations in 63.6% with predominant alterations in pancreatic (88.2%), GIST (87.5%), colorectal (78.7%), cholangiocarcinoma (52.9%), neuroendocrine (45.5%), gall bladder (36.7%) and gastric adenocarcinomas (16.7%). The key genes affected were KRAS, NRAS, BRAF and PIK3CA. NGS evaluation identified co-occurring alterations in 37.7% cases otherwise missed by conventional assays. Resistance mutations were detected in progressive lung tumours (39.5%) against EGFR TKIs and ALK/ROS inhibitors. This is the largest Indian study on molecular profiling of solid tumours providing extensive information about mutational signatures using NGS.

Clinical Factors Associated With 30-Day Mortality Among Patients Undergoing Radiation Therapy for Brain Metastases

Existing brain metastasis prognostic models do not identify patients at risk of very poor survival after radiation therapy (RT). Identifying patient and disease risk factors for 30-day mortality (30-DM) after RT may help identify patients who would not benefit from RT. All patients who received stereotactic radiosurgery (SRS) or whole-brain RT (WBRT) for brain metastases from January 1, 2017, to September 30, 2020, at a single tertiary care center were included. Variables regarding demographics, systemic and intracranial disease characteristics, symptoms, RT, palliative care, and death were recorded. Thirty-day mortality was defined as death within 30 days of RT completion. The Kaplan-Meier method was used to estimate median overall survival. Univariate and multivariable logistic regression models were used to assess associations between demographic, tumor, and treatment factors and 30-DM. A total of 636 patients with brain metastases were treated with either WBRT (n=117) or SRS (n=519). The most common primary disease types were non-small cell lung (46.7%) and breast (19.8%) cancer. Median survival time was 6 months (95% CI, 5-7 months). Of the 636 patients, 75 (11.7%) died within 30 days of RT. On multivariable analysis, progressive intrathoracic disease (hazard ratio [HR], 4.67; 95% CI, 2.06-10.60; P=.002), progressive liver and/or adrenal metastases (HR, 2.20; 95% CI, 1.16-3.68; P=.02), and inpatient status (HR, 4.51; 95% CI, 1.78-11.42; P=.002) were associated with dying within 30 days of RT. A higher Karnofsky Performance Status (KPS) score (HR, 0.95; 95% CI, 0.93-0.97; P < .001), synchronous brain metastases at time of initial diagnosis (HR, 0.45; 95% CI, 0.21-0.96; P=.04), and outpatient palliative care utilization (HR, 0.45; 95% CI, 0.20-1.00; P=.05) were associated with surviving more than 30 days after RT. Multiple factors including a lower KPS, progressive intrathoracic disease, progressive liver and/or adrenal metastases, and inpatient status were associated with 30-DM after RT. A higher KPS, brain metastases at initial diagnosis, and outpatient palliative care utilization were associated with survival beyond 30 days. These data may aid in identifying which patients may benefit from brain metastasis-directed RT.

Evolution in the Presence and Evidence Category of Radiation Therapy Treatment Recommendations in the National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology

The changes in the recommended use of radiation therapy (RT) in the presence of expanding systemic cancer therapies and technological advances are poorly characterized. We sought to understand the recommended utilization of RT across a broad range of malignancies by examining National Comprehensive Cancer Network (NCCN) Guidelines. We conducted a comprehensive review and categorization of RT recommendations, with their subsequent supporting evidence categories, in 3 versions of NCCN Guidelines, specifically years 2000, 2009, and 2019. These NCCN Guidelines were individually examined for RT-specific recommendations among the 10 most common tumors. The presence of RT as a recommended modality was recorded for each tumor type in each guideline. Recommendation categories including Category 1, 2A, 2B, and 3 were tallied and compared with examine totals and percentage distributions in each tumor type. A total of 3858 NCCN recommendations were individually reviewed. The presence of a recommendation inclusive of RT increased from incidence of 205 in the year 2000 to 992 in the year 2019 (383%). In the 2019 NCCN Guidelines, the most Category 1 RT recommendations were found within small cell lung (13%), non-small cell lung (5%), breast (5%), bladder (2%), rectal (2%), and non-Hodgkin lymphoma (1%). Pancreatic, uterine, prostate, melanoma, kidney, and colon cancer guidelines had no Category 1 RT recommendations. Rectal cancer had 31 (27%) preferred recommendations. The majority (89%) of 2019 RT recommendations were for initial therapy, and 9% were specific to salvage therapy. Tumor sites with the highest proportion of RT Category 1 evidence were small cell lung (29%), non-small cell lung (24%), and breast cancer (24%). The frequency of recommendations for using RT in NCCN Guidelines has increased by >300% in the past 20 years among the 10 most common malignancies. Consideration of the quality of evidence supporting these recommendations by tumor type is useful to identify specific malignancies in need of higher-level evidence supporting the role of RT.

Design, synthesis, modeling studies and biological evaluation of pyrazole derivatives linked to oxime and nitrate moieties as nitric oxide donor selective COX-2 and aromatase inhibitors with dual anti-inflammatory and anti-neoplastic activities

Two new series of pyrazole derivatives 10a-f and 11a-f with selective COX-2 inhibition pharmacophore and oxime/nitrate moieties as NO donor moiety were designed, synthesized and tested for anti-inflammatory, cytotoxic activities and NO release. Compounds 10c, 11a, 11e were more selective for COX-2 isozyme (S.I. = 25.95, 22.52 and 21.54 respectively) in comparison to celecoxib (S.I. = 21.41). Regarding anti-cancer activity, all synthesized compounds were screened by the National Cancer Institute (NCI), Bethesda, USA for anticancer activity against 60 human cancer cell lines representing the following cancer types: leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast cancers. Compounds 10c, 11a, 11e were found to be the most potent inhibitors on breast, ovarian and melanoma cell lines (MCF-7, IGROV1 and SK-MEL-5), compound 11a causing 79 % inhibition in case of MCF-7, 78.80 % inhibition in case of SK-MEL-5 and unexpected cell growth −26.22 % inhibition in case of IGROV1 (IC50 = 3.12, 4.28, 4.13 μM respectively). On the other hand, compounds 10c and 11e showed lower inhibition on the same cell lines with IC50 = 3.58, 4.58, 4.28 μM respectively for 10c, IC50 = 3.43, 4.73, 4.43 μM respectively for 11e. Furthermore, DNA-flow cytometric analysis showed that compound 11a induces cell cycle arrest at G2/M phase leading to cell proliferation inhibition and apoptosis. Additionally, these derivatives examined against F180 fibroblasts to investigate their selectivity indexes. The pyrazole derivative with internal oxime 11a was the most potent compound against most used cell lines especially MCF-7, IGROV1 and SK-MEL-5 (IC50 = 3.12, 4.28, 4.13 μM respectively) with 4.82-fold selectivity towards MCF-7 than F180 fibroblasts. Moreover, oxime derivative 11a showed potent aromatase inhibitory activity (IC50 16.50 μM) when compared with reference compound letrozole (IC50 15.60 μM). All compounds 10a-f and 11a-f released NO in a slow rate (0.73–3.88 %) and the six derivatives 10c, 10e, 11a, 11b, 11c and 11e were the highest NO releasers (3.88, 2.15, 3.27, 2.27, 2.55 and 3.74 % respectively). Herein structure based and ligand based studies were implemented to under stand and evaluate the compounds activity for further in vivo and preclinical studies. Docking mode of final designed compounds with celecoxib (ID: 3LN1) represented that their triazole ring adopted as the core aryl in Y shaped structure. Regarding aromatase enzyme inhibition, docking was carried out with ID: 1 M17. The internal oxime series was more active as anticancer because of their ability to form extra HBs with receptor cleft.

High Expression of C-C Chemokine Receptor Type 5 in Urothelial Carcinoma When Compared to Other Common Malignancies Based on a Novel, Quantitative Immunohistochemistry Assay and Scoring System From FFPE Tissue not Requiring Antigen Retrieval

Purpose: To compare C-C chemokine receptor type 5 (CCR5) expression in urothelial carcinoma tissue to other common malignancies using a specific CCR5 inhibitor-based assay. Methods: We used an immunohistochemistry (IHC) assay to compare the expression of CCR5 in urothelial carcinoma to different types of common cancer. The IHC assay was based on labeled PRO140 (PRO140 CCR5 Hu IgG4a), a CCR5 inhibitor with potential therapeutic uses. The expression levels were compared using Percent Scores and H-Score methods. Results: Quantification of CCR5 expression utilized a panel of 63 evaluable samples from 9 cancer indications as follows: 6 UC, 7 non-small cell lung (NSCL) adenocarcinoma, 9 NSCL squamous cell carcinoma, 5 triple negative breast cancer, 5 breast cancer, 7 pancreatic cancer, 9 colorectal cancer, 7 head, and neck cancer, and 8 sarcoma. Overall, most of the 63 cases evaluated tended to have either H-Scores &gt;175 (highly reactive) (24/63) or &lt;100 (low or non-reactive) (32/63). Urothelial cancer had the highest expression (H score=183.3), while sarcoma exhibited the most moderate expression of CCR5 (H score =23.6). Conclusions: We show, for the first time, a high expression of CCR5 in the tissue of urothelial carcinoma using an assay based on a safe and effective receptor inhibitor. Our findings may have therapeutic implications if validated in more extensive studies.

Dose Delays, Dose Reductions, and Relative Total Dose Intensity in Patients With Advanced Cancer Who Exercised During Neoadjuvant Chemotherapy Treatment.

When it comes to chemotherapy, maintaining the dose and schedule of treatment are of vital importance, as clinical evidence suggests that dose intensity is associated with optimal treatment outcomes for various tumors. Yet, reduced dose intensity is a common method of mitigating the chemotherapy-induced side effects. Exercise has been shown to attenuate chemotherapy-related symptoms that frequently cluster together. Understanding this, we conducted a retrospective analysis in patients with advanced disease treated with adjuvant or neoadjuvant chemotherapy regimens and who completed exercise training during treatment. Data were collected retrospectively in a chart review of 184 patients, aged 18 years or older and treated for Stage IIIA-IV cancer. Data collection included baseline patient demographics and clinical characteristics, including age at diagnosis, cancer stage at initial diagnosis, chemotherapy regimen, and planned dose and schedule. Cancer types included brain (6.5%), breast (35.9%), colorectal (8.7%), non-Hodgkin's lymphoma (7.6%), Hodgkin's lymphoma (11.4%), non-small cell lung (16.8%), ovarian (10.9%), and pancreatic (2.2%). All patients completed at least 12 weeks of prescribed, individualized exercise. Each program included cardiovascular, resistance training, and flexibility components, under the supervision of a certified exercise oncology trainer once a week. RDI was measured for each myelosuppressive agent in a regimen over the entire chemotherapy course and then averaged across the myelosuppressive agents in a regimen. An RDI of less than 85% was designated as the clinically meaningful threshold for reduction in RDI based on previously published studies. A considerable proportion of patients across regimens had dose delays (18.3%-74.3%) and dose reductions (18.1%-84.6%). Between 12% and 83.9% of patients missed at least 1 dose of a myelosuppressive agent that was part of their standard regimen. Overall, 50.8% of patients received less than 85% of the RDI. In short, patients with advanced cancer and an exercise adherence above 84.3% saw fewer chemotherapy dose delays and dose reductions. These delays and reductions occurred significantly less frequently compared to the published norms in the sedentary population (P < .05).

Expression of plant-produced anti-PD-L1 antibody with anoikis sensitizing activity in human lung cancer cells via., suppression on epithelial-mesenchymal transition.

Immune checkpoint antibodies in cancer treatment are receptor-ligand pairs that modulate cancer immunity. PD-1/PD-L1 pathway has emerged as one of the major targets in cancer immunotherapy. Atezolizumab, the first anti-PD-L1 antibody approved for the treatment of metastatic urothelial, non-small cell lung, small cell lung and triple-negative breast cancers, is produced in Chinese Hamster Ovary (CHO) cells with several limitations i.e., high-production costs, low-capacity yields, and contamination risks. Due to the rapid scalability and low production costs, the transient expression in Nicotiana benthamiana leaves was investigated by co-infiltration of Agrobacterium tumefaciens GV3101 cultures harboring the nucleic acid sequences encoding for Atezolizumab heavy chain and light chain in this study. The transient expression of Atezolizumab in transformed N. benthamiana accumulated up to 86.76 μg/g fresh leaf weight after 6 days of agroinfiltration (OD 600 nm: 0.4) with 1:1 ratio of heavy chain to light chain. The structural and functional characteristics of plant-produced Atezolizumab was compared with commercially available Tecentriq® from CHO cells with similar binding efficacies to PD-L1 receptor. The direct anti-cancer effect of plant-produced anti-PD-L1 was further performed in human lung metastatic cancer cells H460 cultured under detachment condition, demonstrating the activity of anti-PD-L1-antibody on sensitizing anoikis as well as the suppression on anti-apoptosis proteins (Bcl-2 and Mcl-1) and modulation of epithelial to mesenchymal regulating proteins (E-cadherin, N-cadherin, Snail and Slug). In conclusion, this study manifests plants as an alternative cost-effective platform for the production of functional monoclonal antibodies for use in cancer therapy.

Inhibition of the CD47-SIRPα axis for cancer therapy: A systematic review and meta-analysis of emerging clinical data

CD47-SIRPα interaction acts as a "don't eat me" signal and is exploited by cancer to downregulate innate and adaptive immune surveillance. There has been intense interest to develop a mechanism of blockade, and we aimed to analyze the emerging data from early clinical trials. We performed a systematic review and meta-analysis of relevant databases and conference abstracts including clinical trials using CD47 and/or SIRPα inhibitors in cancer treatment. Nonlinear mixed models were applied for comparison of response and toxicity. We retrieved 317 articles, 24 of which were eligible. These included 771 response-evaluable patients with hematologic (47.1%) and solid tumors (52.9%). Of these, 6.4% experienced complete response, 10.4% partial response, and 26.1% stable disease for a 16.7% objective response rate (ORR), 42.8% disease control rate, and 4.8-month median duration of response. ORR was significantly higher for hematologic cancers (25.3%) than solid cancers (9.1%, p=0.042). Comparing by mechanism, seven CD47 monoclonal antibodies (mAbs) and six selective SIRPα blockers were given alone or combined with checkpoint inhibitors, targeted therapy, and/or chemotherapy. In solid cancers, selective SIRPα blockade showed a higher ORR (16.2%) than anti-CD47 mAbs (2.8%, p=0.079), which was significant for combination therapies (ORR 28.3% vs 3.0%, respectively, p=0.010). Responses were seen in head and neck, colorectal, endometrial, ovarian, hepatocellular, non-small cell lung, and HER2+gastroesophageal cancers. Dose-limiting toxicity (DLT) was seen in 3.3% of patients (5.4% anti-CD47 mAbs, 1.4% selective SIRPα blockers; p=0.01). The frequency of treatment-related adverse events (TRAEs) ≥grade 3 was 18.0%, similar between the two groups (p=0.082), and mostly laboratory abnormalities. For anti-CD47 mAbs, the most common toxicities included grade 1-2 fatigue (27.2%), headache (21.0%), and anemia (20.5%). For selective SIRPα blockers, these included grade 1-2 infusion reaction (23.1%) and fatigue (15.8%). Anti-CD47 mAbs were significantly more likely than selective SIRPα blockers to cause grade 1-2 fever, chills, nausea/vomiting, headache, and anemia. In conclusion, combination therapies using selective SIRPα blockade had higher response rates in solid tumors than anti-CD47 mAb combinations. Hematologic changes were the main TRAEs, and selective SIRPα blockers seemed to have a better grade 1-2 toxicity profile. Treatment was well-tolerated with minimal DLTs.

Inhibitory Effect of α1 Receptor Antagonists on Paclitaxel-Induced Peripheral Neuropathy in a Rodent Model and Clinical Database.

The anticancer drug, paclitaxel, is widely used for ovarian, breast, non-small cell lung, and gastric cancers; however, it induces peripheral neuropathy as a side effect. There is insufficient evidence-based prophylaxis, and new prophylaxis and treatment methods are required. We examined the effect of α1-receptor antagonists on paclitaxel-induced peripheral neuropathy using Sprague-Dawley rats and a large adverse event database. The repeated administration of doxazosin or tamsulosin significantly reduced the response threshold to paclitaxel administration in animal models. In the sciatic nerve tissue, axonal degeneration and myelopathy were significantly suppressed. Furthermore, an analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database suggested that the group using α1 inhibitors showed a lower reporting rate for paclitaxel-related peripheral neuropathy than the group that did not use these inhibitors (odds ratio (95% confidence interval): tamsulosin 0.21 (0.08-0.56), p &lt; 0.01, doxazosin 0.41 (0.10-1.65), p = 0.195; any α1 receptor antagonist 0.54 (0.38-0.76), p &lt; 0.01). Thus, doxazosin and tamsulosin may inhibit the development of paclitaxel-induced peripheral neuropathy by suppressing neurodegeneration, particularly axonal degeneration and myelopathy.

The Prognostic and Therapeutic Potential of DNA Damage Repair Pathway Alterations and Homologous Recombination Deficiency in Lung Cancer.

Lung cancer remains the second most commonly diagnosed cancer worldwide and the leading cause of cancer-related mortality. The mapping of genomic alterations and their role in lung-cancer progression has been followed by the development of new therapeutic options. Several novel drugs, such as targeted therapy and immunotherapy, have significantly improved outcomes. However, many patients with lung cancer do not benefit from existing therapies or develop progressive disease, leading to increased morbidity and mortality despite initial responses to treatment. Alterations in DNA-damage repair (DDR) genes represent a cancer hallmark that impairs a cell's ability to prevent deleterious mutation accumulation and repair. These alterations have recently emerged as a therapeutic target in breast, ovarian, prostate, and pancreatic cancers. The role of DDR alterations remains largely unknown in lung cancer. Nevertheless, recent research efforts have highlighted a potential role of some DDR alterations as predictive biomarkers of response to treatment. Despite the failure of PARP inhibitors (main class of DDR targeting agents) to improve outcomes in lung cancer patients, there is some evidence suggesting a role of PARP inhibitors and other DDR targeting agents in benefiting a distinct subset of lung cancer patients. In this review, we will discuss the existing literature on DDR alterations and homologous recombination deficiency (HRD) state as predictive biomarkers and therapeutic targets in both non-small cell lung and small cell lung cancer.

Single Fraction vs. Fractionated Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM Multicenter Cohort Study

<h3>Purpose/Objective(s)</h3> Preoperative (preop) stereotactic radiosurgery (SRS) is a feasible alternative to postoperative (postop) SRS with potential benefits in adverse radiation effect (ARE) and meningeal disease compared to postop SRS. Most reported studies of preop SRS utilized single fraction (fx) SRS. The goal of this study was to compare outcomes and toxicity of single fraction preop SRS with fractionated (3-5 fx) preop stereotactic radiotherapy (FSRT). <h3>Materials/Methods</h3> Patients (pts) with brain metastases (BM) from solid cancers, of which at least 1 lesion was treated with preop SRS or FSRT and underwent planned resection were included from 6 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included classically radiosensitive or non-solid cancers and prior or planned whole brain radiotherapy. RT dose, fractionation, and interval between preop RT and surgery was per individual institutional protocol. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Propensity score matched (PSM) analyses were performed. <h3>Results</h3> The cohort included 378 pts with 389 preop RT treated index lesions. Most pts had non-small cell lung (47.9%), breast (16.1%), or melanoma (11.4%) cancer. The majority of pts (61.1%) had a single BM and 95.4% underwent gross total resection (GTR). SRS was used for 328 (84.3%) lesions with FSRT used for 61 (15.7%). Most FSRT (93.4%) was 3 fx, with the remainder being 5 fx. Median prescribed dose for FSRT and SRS was 24 Gy and 15 Gy, respectively. There were baseline imbalances between cohorts. The FSRT cohort had significantly more use of planning target volume (PTV) margin expansion > 1 mm (64% vs. 5.2%), more pts with multiple BM (54% vs. 38%), and larger median gross tumor volume (GTV, 12.3 cc vs. 9.7 cc). In univariate analysis, preop FSRT was associated with significantly lower rate of cavity local recurrence (LR) than SRS (1-year: 2.8% vs. 14.1%, p=0.02). PSM yielded 57 matched pairs. There were no significant residual imbalances in the PSM cohorts. Median imaging FU period was 8 months for both groups. FSRT was associated with significantly lower cavity LR compared with SRS (1-year: 3% vs. 17.9%, p=0.02). There were no differences in ≥ grade 2 ARE (7.4% vs. 4.9%, p=0.34), meningeal disease (2% vs. 4%, p=0.81), or distant brain failure (21.8% vs. 37.4%, p=0.25). No grade 3 - 5 ARE events occurred. Overall survival (OS) was significantly higher with FSRT in PSM analysis as well (1-year: 71.2% vs. 52.1%, p=0.04). <h3>Conclusion</h3> Preop FSRT (3-5 fx) is associated with significantly reduced risk of cavity LR and improved OS compared with preop single fx SRS. Both preop FSRT and SRS show notably low rates of ARE and meningeal disease. Three fx preop FSRT may be a preferred option for neoadjuvant RT of larger or higher risk lesions. Additional confirmatory studies are needed. A randomized trial of preop SRS versus postop SRS is currently being designed (NRG BN012).

Frameless Fractionated Stereotactic Radiosurgery for Brain Metastases: An Institutional Series of 89 Cases

<h3>Purpose/Objective(s)</h3> Cobalt-60 stereotactic radiosurgery (SRS) conventionally involves frame-based immobilization and single-fraction treatment. However, certain anatomical and technical factors, including large lesion size, close proximity to critical structures, and prior radiation treatment, necessitate fractionated SRS, which requires mask-based immobilization. We present a large institutional experience with mask-based fractionated SRS for large, retreated, or critically-located brain metastases. <h3>Materials/Methods</h3> All patients treated with frameless fractionated SRS for brain metastases between March 2017 and August 2021 at a single institution were identified. Patient, tumor, and treatment variables were abstracted. The primary outcome was one-year local control (LC), which was analyzed with the Kaplan-Meier method. This study was approved by the institution's IRB. <h3>Results</h3> Seventy-four patients with a total of 89 brain metastases were treated. The median follow-up time was seven months. The median age at treatment was 64 years. Sixty-two percent of patients were female. The most common primary tumors were breast (24.7%), non-small cell lung (24.7%), small-cell lung (7.9%), renal cell (6.7%), and melanoma (6.7%). For the majority (62.9%) of tumors, the indication for fractionation was retreatment; other indications were large size (21.3%), critical location (12.4%), and medical comorbidity (3.4%). For all tumors, the mean maximal linear size was 35.5 mm; for tumors fractionated due to size, the mean size was 45.8 mm. The median total dose was 2,750 cGy (range: 1,620-3,000), and the median dose per fraction was 600 cGy (range: 405-900); the most common dose-fractionations were 3,000 cGy in 600 cGy per fraction (42.7% of patients) and 2500 cGy in 500 cGy per fraction (31.5% of patients). The mean target volume was 17.6 cc (range: 0.13-120.0), and the mean maximum dose was 4,980 cGy (range: 3,240-6,000). For 91% of treatments, the prescription isodose line was 50 to 59% (mean, 54%). Target coverage was 100% in all but one case, where it was 99%. For lesions near the brainstem, mean brainstem maximum point dose (MPD) was 9.78 Gy and mean brainstem mean dose was 3.56 Gy. For lesions near the optic pathway, mean optic nerve MPD was 14.39 Gy, mean optic nerve mean dose was 6.2 Gy, mean optic chiasm MPD was 11.7 Gy, and mean optic chiasm mean dose was 5.4 Gy. LC at 12 months was 91%. Nineteen percent of patients experienced acute grade 1-2 toxicity; one patient experienced acute grade 3 fatigue, and there was no other grade 3 or higher acute toxicities. Seventeen percent of patients had grade 1-2 radiation necrosis (RN); there were no cases of grade 3 or higher RN. <h3>Conclusion</h3> Cobalt-60 frameless fractionated SRS for brain metastases offers excellent local control. This treatment modality is technically feasible, offers excellent sparing of critical structures, and has minimal toxicity. Frameless fractionated SRS should be considered for large, retreated, or critically located metastases.

Risk Factors for Progression and Toxicity after Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM Multicenter Cohort Study

<h3>Purpose/Objective(s)</h3> Preoperative (preop) stereotactic radiosurgery (SRS) is a feasible alternative to postoperative (postop) SRS with potential benefits in adverse radiation effect (ARE) and meningeal disease (MD) compared to postop SRS. The goal of this study was to determine risk factors for progression and toxicity after preop SRS in an expanded multicenter cohort. <h3>Materials/Methods</h3> Patients with brain metastases (BM) from solid cancers, of which at least 1 lesion was treated with preop SRS and underwent planned resection were included from 6 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included classically radiosensitive or non-solid cancers and prior or planned whole brain radiotherapy (WBRT). SRS dose, fractionation, and interval between preop SRS and surgery was per individual institutional protocol. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Radiographic MD was categorized as nodular (nMD) or classical "sugarcoating" (cMD). <h3>Results</h3> The cohort consisted of 378 patients with 389 preop SRS treated index lesions. Most patients (61.1%) had a single BM, underwent gross total resection (GTR, 95.4%), and had non-small cell lung (NSCLC, 47.9%), breast (16.1%), or melanoma (11.4%) cancer. Median dose was 15 Gy in 1 fraction to a median gross tumor volume (GTV) of 10.1 cc. Median interval between preop SRS and surgery was 2 days. Median cranial imaging follow-up interval was 9.5 months overall and 17.5 months for alive patients. The 2-year cavity local recurrence (LR) rate was 14.5%. Multivariable analysis (MVA) for LR demonstrated subtotal resection (STR, vs. GTR), single fraction SRS (vs. fractionated), larger GTV, gastrointestinal (GI) primary (vs. NSCLC), active systemic disease, and piecemeal resection (vs. en bloc) to be associated with higher risk of LR. Of note, interval between preop SRS and surgery was not significant. The 2-year any grade ARE rate was 7.7%. MVA for ARE demonstrated only larger planning target volume (PTV) margin expansion as associated with higher risk of ARE. The 2-year rate of MD was 5.6%. Most MD (76%) was classical type, with the remainder being nodular type. MVA for MD demonstrated STR (vs. GTR) and breast or melanoma histology (vs. NSCLC) as associated with higher risk of MD. Of note, posterior fossa location and type of surgical resection were not significant. <h3>Conclusion</h3> Preop SRS demonstrates overall excellent rates of cavity LR, ARE, and MD in this expanded multicenter cohort study. We have identified several tumor and treatment factors that are significantly associated with risk of cavity LR, ARE, and MD after treatment with preop SRS. Minimizing likelihood of STR and treating with fractionated preop SRS for larger higher risk tumors may lead to improved outcomes. A randomized trial of preop versus postop SRS is currently being designed (NRG BN012).

Overall survival of individuals with metastatic cancer in Sweden: a nationwide study

AimsConsistent improvements for overall survival (OS) have been reported for individuals with metastatic cancer. Swedish population-based registers allow national coverage and long follow-up time. The aim of this study was to estimate and explore long-term OS of individuals diagnosed with metastatic cancer using Swedish nationwide health registers.MethodsIndividuals with metastatic breast (MBC), non-small cell lung (MNSCLC), ovary (MOC) or colorectal cancer (MCRC) or metastatic malignant melanoma (MMM) were identified in the Swedish national cancer register and national patient registers. Survival was estimated and stratified by available variables. Potential cure fractions were estimated using mixture cure models.ResultsIn total, approximately 69,000 individuals were identified. The most common cancers were MCRC (36.2%) and MNSCLC (29.5%). Men were more frequently diagnosed with MNSCLC, MCRC, and MMM compared to women. Except for MOC, about 50% of individuals were 70 years or older at diagnosis. Throughout the study period survival differed across cancers. The longest median OS was observed for individuals with MOC and MBC. At 10 years of follow-up, the survival curves flatten at a survival rate of approximately 10% for all cancers except MNSCLC. The youngest age groups had the longest median OS. Increased survival was also observed for individuals diagnosed in 2015 and 2018 compared to individuals diagnosed during earlier years. The estimated cure fractions were 4% for MBC, 1.5% for MNSCLC, 6.8% for MCRC, 8.6% for MOC and MMM.ConclusionsLong-term survival has been assessed across all indications except for NSCLC.. The findings may be relevant for healthcare planning to meet the needs of future patients and potential long-term survivors.

High-plex imaging of RNA and proteins at subcellular resolution in fixed tissue by spatial molecular imaging.

Resolving the spatial distribution of RNA and protein in tissues at subcellular resolution is a challenge in the field of spatial biology. We describe spatial molecular imaging, a system that measures RNAs and proteins in intact biological samples at subcellular resolution by performing multiple cycles of nucleic acid hybridization of fluorescent molecular barcodes. We demonstrate that spatial molecular imaging has high sensitivity (one or two copies per cell) and very low error rate (0.0092 false calls per cell) and background (~0.04 counts per cell). The imaging system generates three-dimensional, super-resolution localization of analytes at ~2 million cells per sample. Cell segmentation is morphology based using antibodies, compatible with formalin-fixed, paraffin-embedded samples. We measured multiomic data (980 RNAs and 108 proteins) at subcellular resolution in formalin-fixed, paraffin-embedded tissues (nonsmall cell lung and breast cancer) and identified >18 distinct cell types, ten unique tumor microenvironments and 100 pairwise ligand-receptor interactions. Data on >800,000 single cells and ~260 million transcripts can be accessed at http://nanostring.com/CosMx-dataset .

Goals-of-care and serious illness conversations for patients with cancer with inpatient mortality.

184 Background: Goals-of-care (GOC) and serious illness conversations are an integral part of personalized cancer care, particularly toward the end of life (EOL). Eliciting patients (pts)’ preferences and values facilitates informed decision-making throughout the disease course and enables oncologists to provide patient-centered care. Many aspects of GOC discussions and advance care planning (ACP) are inadequately understood, particularly during transitions of care when pts are hospitalized. Methods: We administered surveys to inpatient and outpatient medical oncologists of pts who died while hospitalized from 5/1/2020 to 5/31/2021. Survey items included oncologists’ knowledge of inpatient death, anticipation of pt death within six months of admission, recollection of GOC discussions taking place, and perceived barriers to GOC discussions. To better characterize EOL planning for these pts, retrospective data was collected to identify documentation of GOC discussions, advance directives, and hospice consideration in pts’ electronic health records. Results: For 75 cancer pts who died while hospitalized, 158 surveys were electronically administered with 104 responses (response rate: 66%). Pts characteristics: median age 62 (range 25-89); 63% men; 79% white; median length of hospital stay 7 days (range 1-45). Primary cancer disease type varied: 26.7% gastrointestinal, 18.7% non-small cell lung, 14.7% hematologic, 10.7% sarcoma, 9.3% genitourinary, and 19.9% other cancers. Of 104 completed surveys, responses were received from 40 inpatient and 64 outpatient oncologists. 81 oncologists (77.9%) were aware of the pt’s death prior to survey communication, 68 (65.4%) anticipated the pt’s death within six months of admission, and 67 (64.4%) recalled having a GOC discussion prior to or during the terminal hospitalization. Only 21.3% of pts had documented GOC discussions prior to admission, 33.3% had advance directives, and 22.7% had prior documentation of hospice consideration. Oncologist-reported barriers to GOC discussions included unrealistic expectations from pts or family (25%) and inability for pts to participate due to their clinical condition (15%). Oncologists commented on lack of time, lack of communication between inpatient and outpatient teams, and discordance among multiple inpatient providers as additional barriers. Conclusions: Most oncologists recalled having GOC discussions and anticipated six-month mortality for cancer pts who died while hospitalized. However, documentation of ACP and serious illness communication remained sub-optimal. Ongoing analyses are examining potential associations between patient, provider, and patient-provider relationship factors and oncologists’ survey responses. Addressing barriers to serious illness conversations across different healthcare settings is crucial to providing high-quality EOL care for cancer pts.

First-in-human phase I/II, open-label study of the anti-OX40 agonist INCAGN01949 in patients with advanced solid tumors

BackgroundOX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed...

Autophagy-Related Gene Signature Highlights Metabolic and Immunogenic Status of Malignant Cells in Non-Small Cell Lung Cancer Adenocarcinoma.

Simple SummaryThe role of autophagy in lung cancers is still controversial, mainly because the visualization of autophagy levels in patients remains challenging. One interesting approach consists of studying autophagy at the transcriptomic level. In this line, many transcriptomics analyses performed on autophagy genes focused on the discovery of new biomarkers to predict the efficiency of antitumor therapies. However, the majority of these studies were based on global transcriptomic analysis of the whole tumor microenvironment, and few investigations have been performed on malignant cells themselves. The goal of this study was not to determine another new predictive signature based on autophagy-related genes. Instead, we investigated the expression of autophagy genes to understand the involvement of this process in lung cancer homeostasis. Specifically, we discovered a new autophagy signature that correlates with the metabolic and immunogenic status of malignant cells, supporting the relationship between autophagy and tumor growth in lung cancer patients.Autophagy is a self-degradative mechanism involved in many biological processes, including cell death, survival, proliferation or migration. In tumors, autophagy plays an important role in tumorigenesis as well as cancer progression and resistance to therapies. Usually, a high level of autophagy in malignant cells has been associated with tumor progression and poor prognostic for patients. However, the investigation of autophagy levels in patients remains difficult, especially because quantification of autophagy proteins is challenging in the tumor microenvironment. In this study, we analyzed the expression of autophagy genes in non-small cell lung (NSCLC) cancer patients using public datasets and revealed an autophagy gene signature for proliferative and immune-checkpoint-expressed malignant cells in lung adenocarcinoma (LUAD). Analysis of autophagy-related gene expression profiles in tumor and adjacent tissues revealed differential signatures, namely signature A (23 genes) and signature B (12 genes). Signature B correlated with a bad prognosis and poor overall and disease-specific survival. Univariate and multivariate analyses revealed that this signature was an independent factor for prognosis. Moreover, patients with high expression of signature B exhibited more genes related to proliferation and fewer genes related to immune cells or immune response. The analysis of datasets from sorted fresh tumor cells or single cells revealed that signature B is predominantly represented in malignant cells, with poor expression in pan-immune population or in fibroblast or endothelial cells. Interestingly, autophagy was increased in malignant cells exhibiting high levels of signature B, which correlated with an elevated expression of genes involved in cell proliferation and immune checkpoint signaling. Taken together, our analysis reveals a novel autophagy-based signature to define the metabolic and immunogenic status of malignant cells in LUAD.

The Persistence of Poverty and its Impact on Cancer Diagnosis, Treatment and Survival.

To determine the effect of persistent poverty on the diagnosis, surgical resection and survival of patients with non-small cell lung (NSCLC), breast, and colorectal cancer. Disparities in cancer outcomes exist in counties with high levels of poverty, defined as ≥20% of residents below the federal poverty level. Despite this well-established association, little is known about how the duration of poverty impacts cancer care and outcomes. One measure of poverty duration is that of "persistent poverty," defined as counties in high poverty since 1980. In this retrospective cohort study, patients with NSCLC, breast and colorectal cancer were identified from SEER (2012-2016). County-level poverty was obtained from the American Community Survey (1980-2015). Outcomes included advanced stage at diagnosis (stage III-IV), resection of localized disease (stage I-II) and cancer-specific survival. Hierarchical generalized linear models and accelerated failure time models with Weibull distribution were used, adjusted for patient-level covariates and region. Overall, 522,514 patients were identified, of which 5.1% were in persistent poverty. Patients in persistent poverty were more likely to present with advanced disease [NSCLC odds ratio (OR): 1.12, 95% confidence interval (CI): 1.06-1.18; breast OR: 1.09, 95% CI: 1.02-1.17; colorectal OR: 1.00, 95% CI: 0.94-1.06], less likely to undergo surgery (NSCLC OR: 0.81, 95% CI: 0.73-0.90; breast OR: 0.82, 95% CI: 0.72-0.94; colorectal OR: 0.84, 95% CI: 0.70-1.00) and had increased cancer-specific mortality (NSCLC HR: 1.09, 95% CI: 1.06-1.13; breast HR: 1.18, 95% CI: 1.05-1.32; colorectal HR: 1.09, 95% CI: 1.03-1.17) as compared with those without poverty. These differences were observed to a lesser magnitude in counties with current, but not persistent, poverty and disappeared in counties no longer in poverty. The duration of poverty has a direct impact on cancer-specific outcomes, with the greatest effect seen in persistent poverty and resolution of disparities when a county is no longer in poverty. Policy focused on directing resources to communities in persistent poverty may represent a possible strategy to reduce disparities in cancer care and outcomes.

Development and Characterization of an Anti-Cancer Monoclonal Antibody for Treatment of Human Carcinomas

Simple SummaryCancers can grow and spread to different parts of the body. The aim of immunotherapy is to stimulate the immune system to eliminate cancer cells in a selective manner. Tumor-targeting monoclonal antibodies (mAb) can be used as immunotherapy to stimulate innate antitumor immunity. In this review, we have described the development and characterization of an anti-cancers mAb NEO-201. NEO-201 is an IgG1 humanized mAb that binds specifically to tumor-associated variants of CEACAM-5 and CEACAM-6 expressed by colon, ovarian, pancreatic, non-small cell lung, head and neck, cervical, uterine and breast cancers, but is not reactive against most normal tissues. The peculiarity of NEO-201 is its ability to counteract tumor growth through different mechanisms. NEO-201 engages components of immune system to kill tumor cells expressing its target via antibody-dependent cell-mediated cytotoxicity and complement dependent cytotoxicity. NEO-201 can also indirectly enhance anti-cancer activity through the blockade of the interaction between CEACAM-5 expressed on tumor cells and CEACAM-1 expressed on natural killer cells to reverse CEACAM-1-dependent inhibition of NK cytotoxicity or through its binding to human regulatory T cells. The specificity of NEO-201 in recognizing suppressive regulatory T cells provides the basis for combination cancer immunotherapy with checkpoint inhibitors targeting the PD-1/PD-L1 pathway.NEO-201 is an IgG1 humanized monoclonal antibody (mAb) that binds to tumor-associated variants of carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-5 and CEACAM-6. NEO-201 reacts to colon, ovarian, pancreatic, non-small cell lung, head and neck, cervical, uterine and breast cancers, but is not reactive against most normal tissues. NEO-201 can kill tumor cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement dependent cytotoxicity (CDC) to directly kill tumor cells expressing its target. We explored indirect mechanisms of its action that may enhance immune tumor killing. NEO-201 can block the interaction between CEACAM-5 expressed on tumor cells and CEACAM-1 expressed on natural killer (NK) cells to reverse CEACAM-1-dependent inhibition of NK cytotoxicity. Previous studies have demonstrated safety/tolerability in non-human primates, and in a first in human phase 1 clinical trial at the National Cancer Institute (NCI). In addition, preclinical studies have demonstrated that NEO-201 can bind to human regulatory T (Treg) cells. The specificity of NEO-201 in recognizing suppressive Treg cells provides the basis for combination cancer immunotherapy with checkpoint inhibitors targeting the PD-1/PD-L1 pathway.