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Structured Abstract Background Patients with lung cancers may have disproportionately severe COVID-19 outcomes. Understanding the patient-specific and cancer-specific features that impact severity of COVID-19 may inform optimal cancer care during this pandemic. Patients and methods We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n=102) at a single center from March 12-May 6, 2020. Thresholds of severity were defined a priori as hospitalization, ICU/intubation/DNI (a composite metric of severe disease including ICU stay, intubation and invasive mechanical ventilation, and/or transition to do not intubate [DNI]), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. HLA alleles were inferred from MSK-IMPACT (n=46) and compared to controls with lung cancer and no known non-COVID-19 (n=5166). Results COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer-deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease (Odds ratios for severe COVID-19 2.9, 95% CI 1.07-9.44 comparing the median [23.5 pack-years] to never and 3.87, 95% CI 1.35-9.68, respectively). Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. HLA supertypes were generally similar in mild or severe cases of COVID-19 compared to non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes. Conclusion COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity., Highlights • COVID-19 is associated with high burden of severity in patients with lung cancer. • Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.

Introduction: Highly aggressive thoracic neoplasms characterized by SMARCA4 (BRG1) deficiency and undifferentiated round cell or rhabdoid morphology have been recently described and proposed to represent thoracic sarcomas. However, it remains unclear whether such tumors may instead represent sarcomatoid carcinomas, and how their clinicopathologic characteristics compare with those of nonsarcomatoid SMARCA4-deficient non–small cell lung carcinomas (SD-NSCC). Methods: We identified 22 SMARCA4-deficient thoracic sarcomatoid tumors (SD-TSTs) with round cell and/or rhabdoid morphology and 45 SD-NSCCs, and comprehensively analyzed their clinicopathologic, immunohistochemical, and genomic characteristics using 341–468 gene next-generation sequencing and other molecular platforms. Results: The relationship of SD-TSTs with NSCC was supported by (1) the presence of NSCC components juxtaposed with sarcomatoid areas in five cases, (2) focal expression of NSCC lineage markers TTF1 or p40 in four additional cases, (3) smoking history in all except one patient (mean = 51 pack-years), accompanied by genomic smoking signature, and (4) high tumor mutation burden (mean = 14.2 mutations per megabase) and mutations characteristic of NSCC in a subset. Compared with SD-NSCCs, SD-TSTs exhibited considerably larger primary tumor size (p < 0.0001), worse survival (p = 0.004), and more frequent presentation at younger age (30–50 years) despite heavier smoking history. Distinctive pathologic features of SD-TSTs included consistent lack of adhesion molecule claudin-4, SMARCA2 (BRM) codeficiency, and frequent expression of stem cell markers. Conclusions: SD-TSTs represent primarily smoking-associated undifferentiated/de-differentiated carcinomas rather than primary thoracic sarcomas. Despite their histogenetic relationship with NSCC, these tumors have unique clinicopathologic characteristics, supporting their recognition as a distinct entity. Further studies are warranted to determine therapeutic approaches to this novel class of exceptionally aggressive thoracic tumors.

OBJECTIVES: Liquid biopsy for plasma circulating tumor DNA (ctDNA) next-generation sequencing (NGS) can detect ALK fusions, though data on clinical utility of this technology in the real world is limited. MATERIALS AND METHODS: Patients with lung cancer without known oncogenic drivers or who had acquired resistance to therapy (n = 736) underwent prospective plasma ctDNA NGS. A subset of this cohort (n = 497) also had tissue NGS. We evaluated ALK fusion detection, turnaround time (TAT), plasma and tissue concordance, matching to therapy, and treatment response. RESULTS: ctDNA identified an ALK fusion in 21 patients (3%) with a variety of breakpoints and fusion partners, including EML4, CLTC, and PON1, a novel ALK fusion partner. TAT for ctDNA NGS was shorter than tissue NGS (10 vs. 20 days; p

PURPOSE Response to programmed cell death protein 1 (PD-1) blockade is often conceptualized as resulting from reinvigoration of tumor-infiltrating lymphocytes. However, recruited antitumor immunity from the periphery may also be an important contributor to response. A detailed assessment of the response dynamics of individual metastasis could provide insight to the systemic and local features that mediate response and resistance to immunotherapy. MATERIALS AND METHODS Patients with metastatic non–small-cell lung cancer (NSCLC) or mismatch repair deficiency (MMRD) carcinoma treated with PD-1 monotherapy were evaluated independently. Absolute and percent change of each target lesion were quantified at each computed tomography scan using RECIST. Patterns of progression were predefined as systemic or mixed and were correlated with clinical outcomes. RESULTS A total of 761 individual lesions from 214 patients with NSCLC and 290 lesions from 78 patients with MMRD carcinoma were examined. Individual target lesion responses aligned with best overall response of each patient (85% NSCLC and 93% MMRD lesions responded in patients with partial response/complete response). In responding patients, timing of response was uniform (73% NSCLC and 76% MMRD lesions responded synchronously), and deeper responses were associated with prolonged progression-free survival and overall survival. By contrast, at progression, mixed progression was common (45% of NSCLC and 53% of MMRD) and associated with improved survival compared with those who experienced systemic progression (NSCLC hazard ratio [HR], 0.58; P = .001; MMRD HR, 0.40; P = .07). Organ sites had differential responses, with lymph node and liver metastasis among the most and least responsive, respectively. CONCLUSION Temporal-spatial patterns of response across individual metastases tend to be uniform, favoring the role of peripheral, clonally directed antitumor immunity as a key mediator of response to PD-1 blockade. In contrast, progression is more heterogeneous, potentially revealing the clinical importance of local features and intertumoral heterogeneity.

Purpose/Objective(s) We hypothesize that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved with local therapy to progressive lesions only. This study therefore evaluated the impact of stereotactic body radiotherapy (SBRT) to sites of oligoprogression in patients with metastatic non-small-cell lung cancer (NSCLC) and breast cancer with 1-5 progressive lesions. Materials/Methods We enrolled patients with metastatic NSCLC or breast cancer who received ≥ 1 line of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of non-progressive lesions. Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤ 5 individual lesions. Stratification factors included number of progressive sites (1 vs. 2-5), prior systemic therapy (immunotherapy vs. other), primary tumor (NSCLC vs. breast), and tumor marker status (driver mutation and hormone receptor status). Patients were randomized 1:1 between SBRT to all progressive sites plus palliative standard of care (SOC) vs. palliative SOC only. Systemic therapy was per physician's discretion. The primary endpoint was progression-free survival (PFS). We used a randomized phase II design with a one-sided alpha of 0.05 and a power of 0.80, yielding a target accrual of 160 patients. PFS was compared using one-sided stratified log-rank test. One interim analysis was planned. Results From January 2019 to May 2021, 102 patients were randomized - 58 NSCLC (30 in the SBRT arm) and 44 breast (22 in each arm). Median age was 67. Most patients (75%) had > 1 site of oligoprogression and 47% had > 5 total metastatic lesions. Fifty-five (54%) patients received immunotherapy. The majority of NSCLC (86%) did not harbor an actionable driver mutation and 32% of breast cancer were triple negative. Baseline factors were balanced between arms. At a median follow-up of 51 weeks, 71 patients progressed and 30 died. Median PFS was 22 weeks in the SBRT arm vs. 10 weeks in the palliative SOC arm (p=0.005). This was driven entirely by the PFS benefit from SBRT in the NSCLC patients (44 weeks with SBRT vs. 9 weeks with SOC; p=0.004). No difference in median PFS was seen in the breast cohort (18 weeks with SBRT vs. 17 weeks with SOC; p=0.5). In multivariable Cox model inclusive of stratification factors, age, sex, lines of systemic therapy, and change of systemic therapy, the PFS benefit of SBRT remained substantial in the NSCLC cohort (Hazard Ratio: 0.38; 95% CI: 0.18-77; p=0.007). Grade ≥2 adverse events occurred in 8 patients in the SBRT arm, including 1 grade 3 pneumonitis. Conclusion Inthis pre-planned interim analysis of the first and largest randomized trial of radiotherapy for oligoprogressive metastatic NSCLC and breast cancer, we demonstrated the benefit of SBRT to sites of oligoprogression on overall PFS, meeting the primary endpoint. The mechanism of the differential benefits between NSCLC and breast cohorts merits further evaluation.

Purpose: SMARCA4 mutations are among the most common recurrent alterations in non–small cell lung cancer (NSCLC), but the relationship to other genomic abnormalities and clinical impact has not been established. Experimental Design: To characterize SMARCA4 alterations in NSCLC, we analyzed the genomic, protein expression, and clinical outcome data of patients with SMARCA4 alterations treated at Memorial Sloan Kettering. Results: In 4,813 tumors from patients with NSCLC, we identified 8% (n = 407) of patients with SMARCA4-mutant lung cancer. We describe two categories of SMARCA4 mutations: class 1 mutations (truncating mutations, fusions, and homozygous deletion) and class 2 mutations (missense mutations). Protein expression loss was associated with class 1 mutation (81% vs. 0%, P < 0.001). Both classes of mutation co-occurred more frequently with KRAS, STK11, and KEAP1 mutations compared with SMARCA4 wild-type tumors (P < 0.001). In patients with metastatic NSCLC, SMARCA4 alterations were associated with shorter overall survival, with class 1 alterations associated with shortest survival times (P < 0.001). Conversely, we found that treatment with immune checkpoint inhibitors (ICI) was associated with improved outcomes in patients with SMARCA4-mutant tumors (P = 0.01), with class 1 mutations having the best response to ICIs (P = 0.027). Conclusions: SMARCA4 alterations can be divided into two clinically relevant genomic classes associated with differential protein expression as well as distinct prognostic and treatment implications. Both classes co-occur with KEAP1, STK11, and KRAS mutations, but individually represent independent predictors of poor prognosis. Despite association with poor outcomes, SMARCA4-mutant lung cancers may be more sensitive to immunotherapy.

9009 Background: The effectiveness of circulating tumor DNA (ctDNA) at matching patients to life prolonging therapy has been studied mostly in small cohorts with limited follow up. The prognostic value of ctDNA alterations, particularly those absent on tissue, is also unclear. To address these questions, we studied survival outcomes in a prospective cohort of patients (N = 1002) with non-small cell lung cancer (NSCLC). Methods: Adults with metastatic or recurrent NSCLC were eligible if they had no known driver mutation or a known driver with progression following targeted therapy. Patients were enrolled at Memorial Sloan Kettering Cancer Center (New York, NY) starting October 21, 2016; analysis here is from a snapshot November 1, 2020. All patients had ctDNA sequenced via the Resolution ctDx Lung platform. To reduce inclusion of incidental germline mutations, we excluded non-functionally significant mutations with an allele frequency 35-65% that were present in gnomAD. Patients could also receive, at their provider’s discretion, tissue sequencing with MSK-IMPACT, which filters germline and clonal hematopoietic (CH) mutations with matched white blood cell sequencing. We performed survival analyses using Cox proportional hazards models from time of diagnosis of advanced disease to death, left truncating at time of study entry. Results: Of 1002 patients, 348 (35%) were treated with targeted therapy; in 181 of these (52%) the targetable alteration was detected in ctDNA. Patients treated with targeted therapy had prolonged survival whether matched by tissue-based methods (HR 0.39, 95%CI 0.30-0.51) or ctDNA (HR 0.47, 95%CI 0.37-0.61). These benefits persisted across multiple subgroups. ctDNA alterations themselves were associated with worse survival (HR 2.2, 95%CI 1.8-2.8), in a manner that scaled with allele fraction and burden. Of 401 patients with time-matched tissue sampling, 62 (15%) had ctDNA alterations that were absent on IMPACT (“unique” ctDNA alterations). Three such patients had unique ctDNA EGFR T790M mutations leading to changes in therapy. However, unique ctDNA alterations were generally associated with worse survival than no ctDNA alterations (HR 2.5, 95%CI 1.7-3.7) and even tissue-matched ctDNA alterations (HR 1.7, 95%CI 1.1-2.4). Of 98 unique ctDNA mutations, 48 (49%) were detectable in tissue at subthreshold levels, 12 (12%) were filtered by IMPACT as CH or germline, and 38 mutations (39%) were absent even at subthreshold levels. ctDNA alteration burden correlated with radiographic disease extent. In multivariate models with radiographic disease extent and other clinical variables, ctDNA alterations were the strongest independent predictor of worse survival. Conclusions: Our results show that ctDNA may match patients to life-prolonging targeted therapy and have prognostic importance. ctDNA may provide data about a patient’s cancer missed by spatially restricted tissue sequencing. Clinical trial information: NCT01775072.

Objective To estimate rates of human papillomavirus (HPV) vaccination, factors associated with intention and belief in one's ability (self-efficacy) to receive the vaccine, and prevalence of vaccine-type HPV during the first year after an HPV-6, HPV-11, HPV-16, HPV-18 vaccine was licensed. Methods Sexually experienced females 13-26 years of age (N=409) were recruited from three primary care clinics, completed a questionnaire, and underwent cervicovaginal HPV DNA testing. Outcome measures were HPV vaccination, intention and belief in one's ability to receive the HPV vaccine in the next year, and prevalence of vaccine-type HPV. Factors independently associated with intention and belief in one's ability to receive the HPV vaccine were determined by logistic regression. Results Five percent of participants had received at least one HPV vaccine dose, 66% intended to receive the vaccine, 65% were confident they could find the time to get vaccinated, 54% believed that they could receive all three shots, and 42% believed that they could afford vaccination. Sixty-eight percent of women were HPV-positive: 9% for HPV-6, 3% for HPV-11, 17% for HPV-16, and 12% for HPV-18. Factors independently associated with intention included believing that influential people would approve of vaccination, higher perceived severity of cervical cancer or genital warts, fewer safety barriers, and pregnancy history. Factors associated with a high belief in one's ability to receive the vaccine included perceived severity of HPV, sexually transmitted disease history, insurance coverage, and fewer practical barriers to vaccination. Conclusion Interventions that aim to increase intention and belief in one's ability to receive HPV vaccines, which may lead to higher vaccination rates, should address personal beliefs about vaccination as well as systemic barriers to vaccination. Level of evidence III.

Ductal carcinoma in situ (DCIS) is a preinvasive breast lesion accounting for approximately 30% of all newly detected breast cancers in the US. DCIS has been separated into two groups by architecture (comedo versus noncomedo) and nuclear grade. The expression of biological markers in DCIS, however, would reflect the true biologic potential of the lesion. Patients with estrogen receptor (ER)-negative, human epidermal growth factor-2 (HER-2)-positive DCIS pose a treatment challenge. They are not candidates for tamoxifen; trastuzumab has an undetermined role in DCIS. In this report, we present a case of a 45-year-old woman diagnosed with invasive breast cancer and ER-negative/HER-2-positive DCIS who developed recurrence and progression of DCIS as manifested by a new palpable mass while receiving trastuzumab as part of adjuvant treatment for invasive breast cancer. The potential clinical implications are discussed.

Background CEA is expressed in >90% of pancreatic cancers (PC) and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help bypass tolerance. We conducted a pilot randomized phase I trial in PC patients to determine the peptide dose required to induce an optimal CD8+ T cell response. Methods Patients with a PS 0-1, HLA-A2+ and CEA-expressing, previously-treated PC were randomized to receive 10 μg (arm A), 100 μg (arm B) or 1000 μg (arm C) of CEA peptide emulsified in Montanide and GM-CSF, given every 2 weeks until disease progression. Results Sixty-six patients were screened and 19 enrolled of whom 14 received at least 3 doses of the vaccine and thus evaluated for the primary immunologic endpoint. A median of 4 cycles (range 1-81) was delivered. Median and mean peak IFN-γ T cell response by ELISPOT (spots per 104 CD8+ cells, Arm A/B/C) was 11/52/271 (A vs. C, p = 0.028) for medians and 37/148/248 (A vs. C, p = 0.032) for means. T cell responses developed or increased in 20%/60%/100% of pts in Arms A/B/C. Seven of the 19 patients remain alive at a minimum 32 months from trial initiation, including three with unresectable disease. Conclusions The T cell response in this randomized phase I trial was dose-dependent with the 1 mg CEA peptide dose eliciting the most robust T cell responses. A signal of clinical benefit was observed and no significant toxicity was noted. Further evaluation of 1 mg CEA peptide with stronger adjuvants, and/or combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts. Trial registration ClinicalTrials.gov NCT00203892

A 70-year-old woman presented to our clinic in 2007 after an evaluation for dysphagia revealed a poorly differentiated adenocarcinoma of the gastroesophogeal junction. Workup for metastatic disease was negative at presentation. She had a complete response to treatment, which was completed in November 2007. She continued to follow up regularly until 2011 when she presented again with neurologic symptoms and was found to have an isolated brain metastasis. She underwent resection of the lesion, and pathology was consistent with her originally diagnosed gastric cancer. The patient received adjuvant radiation therapy, however, unfortunately had rapid progression of disease 1 month later and was transitioned to hospice. Here, we report a rare case of late recurrence of gastric cancer with isolated brain metastasis with a review of literature.

252 Background: Heparin induced thrombocytopenia (HIT) is a devastating thrombotic complication of heparin therapy and occurs in 0.2 to 5% of patients receiving heparin products and is a clinicopathologic diagnosis. The American Society of Hematology Guidelines, recommend the use of the “4Ts” scoring system to determine the pre-test probability of suspected cases. Also, a presumptive clinical diagnosis of HIT must be followed by immediate cessation of all forms of heparin and initiation of alternate anticoagulation. Proper diagnosis and treatment can be difficult for medical and surgical clinicians, with implications for morbidity, mortality, patient safety, and cost. The Objective of this study was to assess the incidence and appropriateness of HIT testing at our institution before and after an educational session for clinicians. We hypothesized that our intervention would provide better quality care of patients with suspected HIT. Methods: First, a retrospective chart review was conducted for a 3-month period, in which we collected baseline patient and HIT-testing data. Next, an “in-service” type lecture was delivered on seven occasions to various hospitalist groups. Follow-up data for an additional 3-month period was collected after these sessions. Results: See Table. Conclusions: In this single-center study, our educational interventions were successful in reducing inappropriate HIT testing, and encouraging consultation with hematology colleagues. Future studies are needed to evaluate the utility of online teaching modules, electronic order sets,and applicability to other medical centers. [Table: see text]

2561 Background: CEA is expressed in >90% of PC and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help bypass tolerance. We conducted a pilot randomized phase I trial in PC pts to determine the appropriate CEA-vac peptide dose required to induce an optimal cytotoxic T lymphocyte (CTL) response. Methods: Eligible pts, PS 0-1, expressed HLA-A2 and had CEA-expressing, histologically-confirmed, previously-treated PC. Randomization: 10 μg (arm A), 100 μg (arm B) or 1000 μg (arm C). CEA-vac was given Q 2 weeks until disease progression (amended 4/09 to a 24 dose maximum). Results: From 2/06-9/09 66 pts were screened for HLA-A2; 19 pts randomized to Arms A/B/C 5/8/6 are evaluable for toxicity; 14 pts (5/5/4) who received at least 3 doses of CEA-vac are evaluable for the primary immunologic endpoint. Median age: 60 (range 27-86), female: 68%, PS 0: 58%. Disease stage: metastatic (M) 74%, locally advanced (LA) 5%, resected (R) 21%. Cycles: median 4 (range 1-81). Mean CTL response by ELISPOT (spots per 104 CD8+ cells, Arm A/B/C): 37/126/248. (A vs. C, p=0.037). CTL responses developed in 20%/60%/100% of pts in Arms A/B/C. 1 LA pt in Arm C had a complete radiologic response, a strong CTL response, and remains alive at 71 mo. 1 M pt in Arm B had SD for 11 mo, a strong CTL response, and is alive at 39 mo. Toxicity: no grade 3/4 toxicities, 58% grade 1/2 skin toxicity. Conclusions: CTL response was dose-dependent in this randomized phase I trial; the 1 mg peptide dose elicited the most robust CTL response. Clinical activity was demonstrated at the higher doses. Further evaluation of 1 mg CEA-vac with stronger adjuvants, combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts. Supported by UCCCSG P30CA14599.

21101 Background: Tumor angiogenesis and vascularization are essential for the growth and metastasis of tumors. VEGF-C expression and peritumoral lymphocyte density (PLD) are markers of angiogenesis. They have been correlated with poor prognosis in female breast cancer (FBC). The purpose of this study is to characterize VEGF-C expression and PLD in MBC and correlate with FBC specimens. Method: We reviewed records of patients diagnosed with MBC and FBC at the Cincinnati VAMC, from 1989 to 2006. Pathology slides were retrieved. We used VEGF-C (Host Rabbit, PAD: Z-CVC7) . Imunohistochemical stains of VEGF-C were given scores of 0 to 3+ based on nuclear stains. PLD was analyzed based on the number of lymphocyte cells surrounding the tumor; score of 0 to 3+. Slides were reviewed independently by two pathologists. Results: We found nine MBC cases and selected 9 FBC cases. Mean age was 72 in the male patients and 62 in the females. Stages of disease were distributed as follows in MBC versus FBC, 11% versus 22% stage 0, 23% versus 23% stage I, 44% versus 44% stage II, and 22% versus 11% stage IV. Ductal carcinoma was the predominant histology in 88% of FBC and 88% MBC. Other histological types included papillary (1 MBC) and lobular (1 FBC). Among the invasive MBC tumors , 75 % were ER+/PR +, 13% ER+/PR-, and 12% ER -/PR- , compared to 72 % ER+/PR+, 14% ER+/PR-, and 14% ER-/PR- in FBC. Eight out of the 9 MBC cases (89%) stained positive for VEGF-C expression, compared to one FBC case (11%). The 1 male breast intraductal carcinoma was positive for VEGF-C expression, compared to none of the two intraductal FBC. PLD was more intense in male than female tumors : score 0 or 1+: 44% in MBC versus 67% in FBC , score 2+: 22% in MBC Versus 22% in FBC, and score 3+: 22% in MBC versus 11% in FBC. VEGF-C expression did not seem to correlate with ER/PR status. The median survival for patients with MBC was 4.5 years and for patients with FBC 6.9 years. Conclusion: VEGF-C expression and PLD were more pronounced in MBC versus FBC. This finding may correlate with more aggressive behavior of breast tumor cells in male patients, more intense angiogenic reaction and lower median survival. Further studies are warranted to further elucidate the role of angiogenesis in male breast cancer and explore potential antiangiogenic therapeutic modalities. No significant financial relationships to disclose.