Citations

Objectives Somatostatin receptor (SSTR) PET imaging is utilized with increasing frequency in the clinical management of neuroendocrine tumors. Incidental PET-avid CNS lesions are commonly noted and presumed to be meningiomas. However, SSTR PET lacks specificity for meningioma identification. This study aimed to clarify the role of SSTR-based imaging in the classification of incidental CNS lesions based on current clinical practice. Methods Patients who underwent both Ga-68-DOTATATE PET and brain MRI and had an incidental CNS lesion identified with a radiographic prediction of meningioma via one (discordant prediction) or both (concordant prediction) imaging modalities were retrospectively analyzed. Imaging indication, semiquantitative measures, and clinical history were recorded. Results Among 48 patients with a CNS lesion identified on both imaging modalities, most scans were performed for a history of neuroendocrine tumor (64.6%). Cases with concordant lesion-type prediction of meningioma between imaging modalities (N = 24) displayed a significantly higher SUV max (median 7.9 vs. 4.0; P = 0.008) and Krenning score (median 3.0 vs. 2.0; P = 0.005) on Ga-68-DOTATATE PET compared with cases with a discordant prediction of meningioma (N = 24). In cases with lower SUV max values, Ga-68-DOTATATE was more likely to discordantly predict meningioma without agreement by the corresponding MRI. Prior cranial radiation or use of somatostatin mimetics did not affect quantitative radiographic measures, and MRI-based tumor size was similar across groups. Conclusion Lesions with increased avidity may be more confidently predicted as meningioma in Ga-68-DOTATATE PET scans, whereas there is more discrepancy in prediction among low SUV cases.

Abstract Poorly differentiated extrapulmonary neuroendocrine carcinomas (EP NECs) are aggressive cancers characterized by a high Ki‐67 index, rapid tumor growth and poor survival, and are subdivided into small and large cell carcinoma. For small cell carcinoma of the lung, a pulmonary NEC, the combination of cytotoxic chemotherapy (CTX) and a checkpoint inhibitor (CPI) is considered standard therapy and superior to CTX alone. EP NECs are typically treated with platinum‐based regimens, some clinicians have adopted the addition of a CPI to CTX based on data from trials in patients with small cell carcinoma of the lung. In this retrospective study of EP NECs, we report 38 patients treated with standard first‐line CTX and 19 patients treated with CTX plus CPI. We did not observe any additional benefit of adding CPI to CTX in this cohort.

Abstract Introduction: Clonal hematopoiesis (CH) is defined by acquisition of somatic mutations in hematopoietic stem cells with potential for expansion over time. CH is influenced by exposures to chemotherapy/radiation & has been associated with therapy related myeloid neoplasms (tMN). Peptide receptor radionuclide therapy (PRRT) is a radionuclide therapy and is FDA approved for neuroendocrine tumors (NET). PRRT has been associated with a 2-10% risk of tMN, especially with prior exposure to alkylating agents. A prior study of 13 NET patients found CH prevalence of 64%. We carried out a prospective assessment of CH in NET patients prior to PRRT. Methods: We evaluated pre-PRRT blood samples in 37 NET patients. Genomic DNA from mononuclear cells was analyzed for CH using a custom panel targeting 229 genes to a targeted depth of >1000X. Results: After approval by Mayo Clinic IRB, 45 patients with Stage IV NET were enrolled & CH data was available for 37. Fifty-one percent of patients were female, with a median age of 68yrs (range, 34-84yrs). Types of NET included small bowel (51%), pancreatic (29%), carcinoid (8%), paraganglioma (5%), & other (5%). The median number of therapies prior to PRRT was 1 (range, 0-4) & included somatostatin analogues (SSA)-81%, alkylating agents-30%, & prior radiation-13%. Thirty-six of 37 patients had variants identified, 5 of which were presumed germline (DDX41, CDKN2B, CHEK2, POT1, ERBB2), & 17 (45.9%) had pathogenic variants meeting the operational definition of CH (DNMT3A, TET2, PPM1D, TP53, SF3B1, ASXL1). The median number of pathogenic variants per patient was 1 (range, 0-2), & 6 patients had >1. In patients >60yrs old, 46% had pathogenic variants & 3 patients with pathogenic variants (TET2, TP53, DNMT3A) were <60 years old. The most common pathogenic variants were in epigenetic regulators, DNMT3A (37.5%) & TET2 (16.7%) with a median VAF of 2.8% (range, 0.70-50%). Eight patients (47%) with pathogenic CH had grade 1 cytopenias at baseline, compared to 10 patients (50%) without pathogenic CH. One patient had grade 3/4 cytopenia at baseline & had a missense variant in TP53 (VAF 50%) & history of exposure to anthracyclines, alkylating agents, platinum & radiation. The patient developed MDS before receiving PRRT. Pathogenic CH variants were more common in patients with previous exposure to radiation (p=0.008) or SSA (p=0.005). Two patients had PPM1D variants, both with a history of prior radiation, one with a history of prior alkylating treatment. Conclusion: To our knowledge this is the largest prospective evaluation of CH in NET. We identified CH to be present in 46% of patients & DNMT3A mutations were most common. This establishes the clonal landscape with mutations involving epigenetic regulators, DNA damage repair, transcription & splicing factors. Prospective longitudinal evaluation will evaluate the association between CH, cytopenias and tMN. Citation Format: Yael Kusne, Terra Lasho, Zaid Elsabbagh, Abhishek Mangaonkar, Rachel Eiring, Timothy Hobday, Jason Starr, Tanios Bekaii-Saab, Thorvardur Halfdanarson, Mrinal Patnaik, Mohamad Sonbol. Prevalence of clonal hematopoiesis in neuroendocrine tumor patients prior to lutetium 177 dotatate therapy (Lu177): A prospective trial of 36 patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5928.

We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

Importance Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) shows frequent and durable responses to programmed cell death 1 blockade. While most of these tumors are sporadic and observed in older patients, first-line pembrolizumab data are limited to findings from the KEYNOTE-177 trial (A Phase III Study of Pembrolizumab [MK-3475] vs Chemotherapy in Microsatellite Instability-High [MSI-H] or Mismatch Repair Deficient [dMMR] Stage IV Colorectal Carcinoma). Objective To investigate outcome with first-line pembrolizumab monotherapy in mostly older patients with dMMR mCRC at a multisite clinical practice. Design, Setting, and Participants This cohort study included consecutive patients with dMMR mCRC who received pembrolizumab monotherapy between April 1, 2015, and January 1, 2022, at Mayo Clinic sites and the Mayo Clinic Health System. Patients were identified from review of electronic health records at the sites, which included the evaluation of digitized radiologic imaging studies. Intervention Patients with dMMR mCRC received first-line pembrolizumab, 200 mg, every 3 weeks. Main Outcomes and Measures The primary study end point was progression-free survival (PFS), which was analyzed using the Kaplan-Meier method and a multivariable stepwise Cox proportional hazards regression model. Clinicopathological features, including metastatic site and molecular data ( BRAF V600E and KRAS ), were also analyzed along with tumor response rate, which was determined using Response Evaluation Criteria in Solid Tumors, version 1.1. Results The study cohort included 41 patients (median [IQR] age at treatment initiation, 81 [76-86] years; 29 females [71%]) with dMMR mCRC. Of these patients, 30 (79%) had the BRAF V600E variant and 32 (80%) were classified as having sporadic tumors. Median (range) follow-up was 23 (3-89) months. Median (IQR) number of treatment cycles was 9 (4-20). Overall response rate was 49% (20 of 41 patients), including 13 patients (32%) with complete responses and 7 (17%) with partial responses. Median (IQR) PFS was 21 (95% CI, 6-39) months. Liver as a site of metastasis was associated with significantly poorer PFS vs nonliver metastasis (adjusted hazard ratio, 3.40; 95% CI, 1.27-9.13; adjusted P = .01). Complete and partial responses were observed in 3 patients (21%) with liver metastasis vs 17 patients (63%) with nonliver metastases. Treatment-related grade 3 or 4 adverse events were observed in 8 patients (20%), 2 of whom discontinued therapy; there was 1 treatment-related death. Conclusions and Relevance This cohort study found a clinically significant prolongation of survival in older patients with dMMR mCRC who were treated with first-line pembrolizumab in routine clinical practice. Furthermore, liver vs nonliver metastasis was associated with poorer survival in this patient population, which suggests that the metastatic site has implications for survival outcome.

641 Background: Tumors of neuroendocrine origin are a rare, heterogenous group of neoplasms. Neuroendocrine neoplasms (NENs) are categorized by site of origin, differentiation status, and by grade (Ki-67 expression and/or mitotic rate), with prognostic variability accordingly. These tumors frequently metastasize to bone, with reported incidence between 6-12% by older SSTR imaging. Our study evaluates patients with well-differentiated tumors of neuroendocrine origin to determine the incidence of osseous metastases when evaluated with higher-sensitivity Ga68 DOTATATE PET scans. The study characterizes the clinical features. Methods: This study was performed at a single, 3-site, US tertiary-care institution. IRB approval was obtained. An automated data extraction tool was used to mine the electronic medical record by searching all positron emission tomography (PET) studies for keywords. Identified scans had to include a combination of the following keywords: “Dotatate” AND “met*” or “lesion” AND “bone” or “osse*” or “skel*”. The individual medical records from the generated report were reviewed to include only patients with 1) well-differentiated NETs of GI and pancreatic origin, lung carcinoid, paraganglioma/pheochromocytoma, or other/unknown primary site, and 2) patients with confirmed osseous metastatic disease. Patient data was entered into a database and evaluated in aggregate. Results: 1,948 PET scans of 1,473 patients were extracted from the EMR, from which 424 patients were identified for inclusion; scans were performed between 5/2018 and 5/2021. Calculated incidence of bone metastasis by Ga68 DOTATATE PET was 28.8%. Median age of included population was 61 years (range 14-92), 49.5% being male. Site of origin was 47.2% bowel NET, 18.9% pancreatic NET, 10.8% lung carcinoid, 10.6% paraganglioma/pheochromocytoma, 2.1% other site, and 10.4% unknown primary. Majority of patients were asymptomatic (64.0%), had sclerotic appearance (76.7%), Krenning 4 (71.4%), and >3 sites (68.3%) of osseous disease. 94.6% of the population had disease of the axial skeleton; 65.6% appendicular. Only 57 patients (13.4%) with osseous disease suffered a fracture, despite metastases at high-risk sites. Fracture occurred at disproportionately low rates in NETs originating in bowel (22.8% of fractures), with proportionately higher rates among pancreatic NETS and paragangliomas/pheochromocytomas (31.6% and 22.8%, respectively). Fractures occurred at proportionately higher rates in higher-grade disease compared to low-grade. Conclusions: Osseous metastatic disease in well-differentiated NENs is evident at much higher rates when imaging with Ga68 DOTATATE PET compared with previously reported data. Nevertheless, fracture occurred at a low rate, suggesting that these patients are at a relatively low risk for skeletal-related events.

57 Background: Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) or microsatellite instability-high (MSI-H) show frequent and durable responses to programmed cell death -1 (PD-1) blockade. While the majority of these tumors are sporadics and observed in elderly patients, first-line data are limited to the KEYNOTE-177 study. Here, we report a consecutive series of elderly patients with dMMR mCRC treated with pembrolizumab in routine clinical practice that includes analysis of clinical outcome based on metastatic site. Methods: Patients with dMMR mCRC received first-line pembrolizumab (200 mg every 3 weeks) (N = 41) at Mayo Clinic and Mayo Clinic Health System (2015-2022). Clinicopathological features including metastatic site and molecular data ( BRAFV600E, KRAS) were analyzed in relationship to tumor response rate (RECIST version 1.1). Furthermore, these variables were also analyzed in relationship to patient progression-free survival (PFS) using Kaplan-Meier methodology and multivariable stepwise Cox regression. Results: Among patients with dMMR mCRC, 29/41 (70.7%) were female, 30 (78.9%) harbored BRAFV600E, and 32 (80%) were sporadic. Median age at start of treatment was 80.6 years (IQR of 75.9, 85.9) and median number of treatment cycles was 9 (IQR: 4, 20). At a median follow-up of 23 months (range, 3.0 to 88.5), patient median PFS was 21.3 months (95% CI: 6.4, 38.5). An overall response was observed in 48.8% (20 of 41) of patients including 13 (31.7%) complete (CR) and 7 (17.1%) partial responses (PR). The median duration of response was 42.2 months (95%CI: 8.6, NR). Patients with metastases that included liver had significantly poorer PFS compared to those with non-liver metastases (HRadj 3.40 (95%CI: 1.27-9.13); Padj= 0. 01). In this regard, responses (CR, PR) to pembrolizumab were observed in 3 (21.4%) patients with liver metastasis compared to 17 (62.9%) of those with non-liver metastases. Treatment-related grade 3 or 4 adverse events were observed in 9 (22.0%) patients of whom two discontinued therapy, and there was one treatment-related death. Conclusions: First-line therapy with pembrolizumab for dMMR mCRC significantly prolonged survival in an elderly patient population with manageable toxicity in routine clinical practice. Moreover, the survival benefit of pembrolizumab was significantly attenuated in patients with liver vs non-liver metastases.

499 Background: The impact of socioeconomic status on gastrointestinal (GI) cancer mortality in the United States (US) is not well-established. We hypothesized that socially vulnerable populations have disproportionately higher mortality rates. Hence, we assessed the association of the social vulnerability index (SVI) with GI cancer mortality across US counties. Methods: Social vulnerability indices were obtained from the agency for toxic substances and disease registry (ATSDR) from 2014-2018 to compute percentile ranking scores (PRS: ranging from 0-1) for each US county. PRS were further categorized into quartiles (Q: 1st: 0-0.25 [least vulnerable]; 4th:0.75-1.00 [most vulnerable]). The wide-ranging online data for epidemiological research (WONDER) database was queried to abstract county-level age-adjusted mortality rates (AAMR) per 100,000 person-years (PY) for populations diagnosed with GI cancers. AAMRs were then linked with quartile rankings. Rate ratios (RR) of AAMRs between 4th and 1st Q were subsequently estimated with 95% confidence intervals using population-weighted, Poisson regression. Results: A total of 3142 counties were included in this analysis. The AAMR for overall deaths (OD) and premature deaths (PD; defined as death at age <65) in the GI cancer population was 53.8 and 17.7 per 100,000 PY. A gradient increase in GI cancer-related mortality was observed from 1st Q to 4th Q (OD: 49.2 vs 59.3; PD: 14.1 vs 21.3). This stepwise increase in AAMR over the quartiles was consistent across gender, different racial/ethnic subgroups, and rural/urban categories of counties. The AAMRs for OD were significantly higher in the 4th Q as compared to the 1st Q for gastric (RR: 1.67 [95% CI, 1.51-1.86]), hepatocellular including intrahepatic biliary (1.52 [1.45-1.61]), colorectal (1.21 [1.16-1.26]) and biliary (1.17 [1.06-1.28]) cancer. Similarly, significantly higher AAMRs for PD were observed in 4th Q vs1st Q for gastric (1.81 [1.60-2.05]), hepatocellular including intrahepatic biliary (1.78 [1.58-2.00]), biliary (1.64 [1.35-1.99]), colorectal (1.29 [1.21-1.39]) and pancreatic (1.16 [1.07-1.25]) cancer. However, no significant differences were observed for esophageal and small intestinal cancers. Men with gastric (1.58 [1.41-1.78]) and hepatocellular cancer (1.54 [1.43-1.66]), non-Hispanic Black population (1.54 [1.31-1.80]) with hepatocellular cancer, and Hispanic population with colorectal cancer (1.50 [1.31-1.72]) were observed to have higher overall mortality in the 4th Q compared to the 1st Q. The findings were similar for premature mortality. Conclusions: Population-level data suggests that the US counties with higher socio-economic adversities may be at an increased risk of GI cancer-related mortality. Investigations using patient-level data are required to probe the impact of socioeconomic vulnerabilities on cancer-related mortality.

23 Background: Identification of factors associated with enrollment disparities in clinical trials can narrow cancer care inequities. Funding source can influence minority representation in clinical trials. Therefore, we aimed to assess the impact of funding sources on enrollment disparities in colorectal (CRC) clinical trials. Methods: CRC phase II/III randomized controlled trial (RCTs) identified through MEDLINE and EMBASE from each database’s inception through 2022 were considered eligible. Trial level enrollment incidence ratios (EIR) were computed; defined as the ratio of trial proportions of a gender, age, or racial/ethnic subgroup category and the global incidence in the corresponding gender/age subgroup (from the global burden of disease database), or the US-population-based incidence in the corresponding racial/ethnic subgroup (from SEER 21 database). EIRs were then meta-analyzed using a random-effects model for each funding source category (US- government, industry, others). Temporal trends were analyzed using a univariate meta-regression. Results: Using data from 287 RCTs, women were significantly under-represented in the industry sponsored trials (EIR: 0.85 [95% CI: 0.83 - 0.88]) but not in US-government sponsored trials (0.92 [0.84-1.00]). A total of 87 RCTs reported age proportions; older adults (above 65 years) were significantly under-represented in the industry sponsored (0.84 [0.74-0.96]) and as well as in US-government sponsored CRC trials (0.52 [0.44-0.61]). Only 56 and 15 trials reported race and ethnicity, respectively. Limited data on racial/ethnic enrollment revealed significant under-representation of Black (0.45 [0.36 -0.57]) and Hispanic (0.45 [0.31-0.66]) patients across industry sponsored CRC trials. In contrast, no significant disparity was observed in the inclusion of Asian race in the industry sponsored trials. The number of US-government sponsored trials reporting racial/ethnic subgroups were small ( < 10) which precluded any meaningful statistics. Trends show that the representation of women has improved ( P: 0.02) while the representation of Black ( P: 0.007) and Hispanic patients ( P: 0.04) has worsened over the last three decades in industry sponsored CRC trials. Conclusions: The reporting of race/ethnicity is suboptimal in CRC trials especially in those sponsored by US government. Older adults may be under-represented regardless of funding source. Women, Blacks and Hispanics may be under-represented in industry sponsored CRC clinical trials. While representation of women appears to be improving, representation of Black and Hispanic patients has worsened in industry sponsored CRC clinical trials over the last three decades.