PD-1 Blockade in Mismatch Repair-Deficient, Locally Advanced Rectal Cancer.

BACKGROUND: Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer. A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair-deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair-deficient, locally advanced rectal cancer. METHODS: We initiated a prospective phase 2 study in which single-agent dostarlimab, an anti-PD-1 monoclonal antibody, was administered every 3 weeks for 6 months in patients with mismatch repair-deficient stage II or III rectal adenocarcinoma. This treatment was to be followed by standard chemoradiotherapy and surgery. Patients who had a clinical complete response after completion of dostarlimab therapy would proceed without chemoradiotherapy and surgery. The primary end points are sustained clinical complete response 12 months after completion of dostarlimab therapy or pathological complete response after completion of dostarlimab therapy with or without chemoradiotherapy and overall response to neoadjuvant dostarlimab therapy with or without chemoradiotherapy. RESULTS: A total of 12 patients have completed treatment with dostarlimab and have undergone at least 6 months of follow-up. All 12 patients (100%; 95% confidence interval, 74 to 100) had a clinical complete response, with no evidence of tumor on magnetic resonance imaging, 18F-fluorodeoxyglucose-positron-emission tomography, endoscopic evaluation, digital rectal examination, or biopsy. At the time of this report, no patients had received chemoradiotherapy or undergone surgery, and no cases of progression or recurrence had been reported during follow-up (range, 6 to 25 months). No adverse events of grade 3 or higher have been reported. CONCLUSIONS: Mismatch repair-deficient, locally advanced rectal cancer was highly sensitive to single-agent PD-1 blockade. Longer follow-up is needed to assess the duration of response. (Funded by the Simon and Eve Colin Foundation and others; ClinicalTrials.gov number, NCT04165772.).

Top advances of the year: Ovarian cancer.

Although cure rates remain low and effective screening strategies are elusive, the recent advances in systemic therapies over the past year highlighted in this review have prolonged survival for women with ovarian cancer. In 2022, the first antibody-drug conjugate for platinum-resistant ovarian cancer received accelerated US Food and Drug Administration (FDA) approval. Confirmatory studies examining the efficacy of mirvetuximab and other antibody-drug conjugates are underway. In the upfront setting, the first data establishing an overall survival benefit from poly(ADP-ribose) polymerase inhibitor maintenance was demonstrated after a 7-year follow-up period. In contrast, long-term updates from poly(ADP-ribose) polymerase inhibitor trials in the noncurative setting reported survival detriments, and the FDA withdrew the respective indications. Several trials attempted to improve upon the standard of care for platinum-sensitive ovarian carcinoma and those with rare ovarian cancer histologies (carcinosarcoma, clear cell carcinoma) but failed to demonstrate a clinically or statistically meaningful benefit. This leaves the open question of how to further optimize systemic therapy for advanced ovarian carcinoma to improve long-term survival and cure rates.

Outcomes of Hepatic Artery-Based Therapies and Systemic Multiagent Chemotherapy in Unresectable Colorectal Liver Metastases: A Systematic Review and Meta-analysis.

BACKGROUND: Treatment of unresectable colorectal liver metastases (UCRLM) includes locoregional and systemic therapy. A comprehensive analysis capturing long-term outcomes of these treatment options has not been performed. OBJECTIVE: A systematic review and meta-analysis was performed to calculate pooled outcomes of hepatic artery infusion with systemic chemotherapy (HAI-S), transarterial chemoembolization with systemic chemotherapy (TACE-S), transarterial radioembolization with systemic chemotherapy (TARE-S), doublet (FOLFOX, FOLFIRI), and triplet chemotherapy (FOLFOXIRI). METHODS: Outcomes included overall survival (OS), progression-free survival (PFS), rate of conversion to resection (CTR), and response rate (RR). RESULTS: A total of 32, 7, 9, and 14 publications were included in the HAI-S, TACE-S, and TARE-S chemotherapy arms. The 6/12/24/36-month OS estimates for HAI-S, TACE-S, TARE-S, FOLFOX, FOLFIRI, and FOLFOXIRI were 97%/80%/54%/35%, 100%/83%/40%/14%, 82%/61%/34%/21%, 96%/83%/53%/36%, and 96%/93%/72%/55%. Similarly, the 6/12/24/36-month PFS estimates were 74%/44%/19%/14%, 66%/20%/9%/3%, 57%/23%/10%/3%, 69%/30%/12%/7%, and 88%/55%/18%/11%. The corresponding CTR and RR rates were 31, 20%, unmeasurable (TARE-S), 35, 53; and 49, 45, 45, 50, 80%, respectively. The majority of chemotherapy studies included first-line therapy and liver-only metastases, whereas most HAI-S studies were pretreated. On subgroup analysis in first-line setting with liver-only metastases, the HAI-S arm had comparable outcomes to FOLFOXIRI and outperformed doublet chemotherapy regimens. Although triplet chemotherapy appeared to outperform other arms, high toxicity and inclusion of potentially resectable patients must be considered while interpreting results. CONCLUSIONS: HAI-S and multiagent chemotherapy are effective therapies for UCRLM. To make definitive conclusions, a randomized trial with comparable patient characteristics and line of therapy will be required. The upcoming EA2222 PUMP trial may help to address this question.

A phase 2 trial of zanidatamab in HER2-overexpressed advanced endometrial carcinoma and carcinosarcoma (ZW25-IST-2).

OBJECTIVE: HER2 overexpression is associated with decreased overall survival in metastatic endometrial cancer. Trastuzumab with chemotherapy has demonstrated efficacy for first-line management of advanced HER2+ endometrial carcinoma, but HER2-directed therapy in the recurrent setting is limited. Zanidatamab (ZW25), a humanized, bispecific antibody that simultaneously binds the 2 distinct HER2 epitopes bound by trastuzumab and pertuzumab, has demonstrated safety and activity in HER2+ tumors. Here, we report the results of a phase 2, open-label study evaluating the efficacy and safety of zanidatamab in patients with HER2+ metastatic endometrial carcinoma/carcinosarcoma who received prior treatment. METHODS: We enrolled 16 patients with HER2+ endometrial carcinoma/carcinosarcoma after progression on ≤2 lines of therapy on a single-arm phase 2 study of zanidatamab. The primary endpoint was overall response rate (ORR; complete or partial response) by Response Evaluation Criteria in Solid Tumors version 1.1. HER2 immunohistochemistry and fluorescence in situ hybridization (FISH) were performed on pretreatment samples. Intratumor HER2 genetic heterogeneity was assessed. RESULTS: This study did not meet its primary efficacy endpoint. Although a clinical benefit rate of 37.5% was observed by 24 weeks, only 1 patient achieved a partial response (ORR, 6.2%). Eight patients had HER2 intratumor heterogeneity or lacked HER2 amplification by FISH. Decreased HER2 expression on repeat pretreatment samples was observed in 3 (75%) of 4 patients evaluated. CONCLUSIONS: We observed a low response rate to zanidatamab in recurrent HER2+ endometrial carcinoma/carcinosarcoma, which may be driven by downregulation of HER2 expression. Repeat HER2 testing should be considered prior to second-line HER2-directed therapy. CLINICALTRIALS: govidentifier: NCT04513665.

Post-surgical ctDNA-based molecular residual disease detection in patients with stage I uterine malignancies.

INTRODUCTION: Among uterine malignancies, endometrial cancer (EC) is the most common cancer of the female reproductive tract. Traditionally, risk stratification in EC is determined by standard clinicopathological risk factors. Although circulating tumor DNA (ctDNA) has emerged as a prognostic biomarker in various malignancies, its clinical validity in EC remains to be established. METHODS: In this analysis of real-world data, 267 plasma samples from 101 patients with stage I EC were analyzed using a tumor-informed ctDNA assay (Signatera™ bespoke mPCR-NGS). Patients were followed post-surgically and monitored with ctDNA testing for a median of 6.8 months (range: 0.37-19.1). RESULTS: Patients who tested ctDNA-positive at both their first time point and longitudinally experienced inferior recurrence-free survival (RFS) (HR = 6.2; p = 0.0006 and HR = 15.5; p < 0.0001, respectively), and showed a recurrence rate of 58% and 52%, vs. 6% and 0%, respectively for the ctDNA-negative patients. Most ctDNA-positive patients had high-risk histologies or sarcoma, versus low-risk and high-intermediate risk (H-IR) EC. Furthermore, patients with high-risk histologies who were ctDNA-positive showed shorter RFS compared to those who tested negative (HR = 9.5; p = 0.007), and those who tested positive in the low/H-IR cohort (HR = 0.25; p = 0.04). Post-surgically, detectable ctDNA was highly prognostic of clinical outcome and remained the only significant risk factor for recurrence when adjusted for clinicopathological risk factors, such as histologic risk group, mismatch repair (MMR), and p53 status. CONCLUSION: Incorporating ctDNA monitoring along with traditional known risk factors may aid in identifying patients with stage I EC who are at highest risk of recurrence, and possibly aid in treatment stratification.

Approach to Resectable Gastric Cancer: Evolving Paradigm of Neoadjuvant and Adjuvant Treatment.

OPINION STATEMENT: Recent therapeutic advances have prolonged survival in patients with metastatic gastric cancer, though the prognosis for patients with locally advanced resectable gastric cancer remains poor. Long-term survival after resection of locally advanced gastric adenocarcinoma is dependent on early eradication of micrometastatic disease and optimal surgical resection. Preoperative therapy with a docetaxel-containing three-drug regimen has recently been shown to be superior to an anthracycline-containing three-drug regimen or two-drug therapy with a fluoropyrimidine and platinum. Chemoradiation is not essential and is reserved for patients with suboptimal resection. Emerging research strategies include introduction of pre- and postoperative checkpoint blockade and biomarker-directed therapy.

Immunotherapy for the treatment of colorectal cancer.

Immune checkpoint inhibition (ICI) has transformed the management of metastatic colorectal cancer (mCRC) with mismatch-repair deficiency (dMMR) and microsatellite instability (MSI-H), though this constitutes on average less than 5% of mCRC, and ICI is ineffective in preserved MMR/microsatellite stable disease (pMMR/MSS). Here we review the efficacy of ICI in dMMR/MSI-H mCRC, poor response to ICI in pMMR/MSS mCRC, role for ICI in locally advanced disease, biomarkers of response, novel immunotherapies, and future directions in targeting resistance mechanisms.

Intestinal Blautia Is Associated with Reduced Death from Graft-versus-Host Disease.

The relationship between intestinal microbiota composition and acute graft-versus-host disease (GVHD) after allogeneic blood/marrow transplantation (allo-BMT) is not well understood. Intestinal bacteria have long been thought to contribute to GVHD pathophysiology, but recent animal studies in nontransplant settings have found that anti-inflammatory effects are mediated by certain subpopulations of intestinal commensals. Hypothesizing that a more nuanced relationship may exist between the intestinal bacteria and GVHD, we evaluated the fecal bacterial composition of 64 patients 12 days after BMT. We found that increased bacterial diversity was associated with reduced GVHD-related mortality. Furthermore, harboring increased amounts of bacteria belonging to the genus Blautia was associated with reduced GVHD lethality in this cohort and was confirmed in another independent cohort of 51 patients from the same institution. Blautia abundance was also associated with improved overall survival. We evaluated the abundance of Blautia with respect to clinical factors and found that loss of Blautia was associated with treatment with antibiotics that inhibit anaerobic bacteria and receiving total parenteral nutrition for longer durations. We conclude that increased abundance of commensal bacteria belonging to the Blautia genus is associated with reduced lethal GVHD and improved overall survival.

18F-BMS-986229 PET to Assess Programmed-Death Ligand 1 Status in Gastroesophageal Cancer.

Anti-programmed death 1 (PD-1) inhibitors are the standard of care for advanced gastroesophageal cancer. Although recommendations and approval by regulatory agencies are often based on programmed death ligand 1 (PD-L1) expression, pathologic assessments of PD-L1 status have several limitations. Single-site biopsies do not adequately capture disease heterogeneity within individual tumor lesions or among several lesions within the same patient, the PD-L1 combined positive score is a dynamic biomarker subject to evolution throughout a patient's disease course, and repeated biopsies are invasive and not always feasible. Methods: This was a prospective pilot study of the PD-L1-targeting radiotracer, 18F-BMS-986229, with PET imaging (PD-L1 PET) in patients with gastroesophageal cancer. Patients were administered the 18F-BMS-986229 radiotracer intravenously at a dose of 370 MBq over 1-2 min and underwent whole-body PET/CT imaging 60 min later. The primary objective of this study was to evaluate the safety and feasibility of 18F-BMS-986229. The trial is registered with ClinicalTrials.gov (NCT04161781). Results: Between February 3, 2020, and February 2, 2022, 10 patients with gastroesophageal adenocarcinoma underwent PD-L1 PET. There were no adverse events associated with the 18F-BMS-986229 tracer, and imaging did not result in treatment delays; the primary endpoint was achieved. Radiographic evaluation of PD-L1 expression was concordant with pathologic assessment in 88% of biopsied lesions, and 18F-BMS-986229 uptake on PET imaging correlated with pathologic evaluation by the combined positive score (Spearman rank correlation coefficient, 0.64). Seventy-one percent of patients with 18F-BMS-986229 accumulation on PET imaging also had lesions without 18F-BMS-986229 uptake, highlighting the intrapatient heterogeneity of PD-L1 expression. Patients treated with frontline programmed death 1 inhibitors who had 18F-BMS-986229 accumulation in any lesions on PET imaging had longer progression-free survival than patients without tracer accumulation in any lesions (median progression-free survival, 28.4 vs. 9.9 mo), though the small sample size prevents any definitive conclusions. Conclusion: PD-L1 PET imaging was safe, feasible, and concordant with pathologic evaluation and offers a potential noninvasive tool to assess PD-L1 expression.

Clinical and molecular characteristics of early-onset vs average-onset esophagogastric cancer.

BACKGROUND: The rate of esophagogastric cancer is rising among individuals under 50 years of age. It remains unknown whether early-onset esophagogastric cancer represents a unique entity. This study investigated the clinical and molecular characteristics of early-onset and average-onset esophagogastric cancer . METHODS: We reviewed the Memorial Sloan Kettering Cancer Center gastric, esophageal, and gastroesophageal junction cancer database. Associations between baseline characteristics and tumor and germline molecular alterations were compared between those with early-onset and average-onset esophagogastric cancer using Fisher exact tests and the Benjamini-Hochberg method for multiple-hypothesis correction. RESULTS: We included 1123 patients with early-onset esophagogastric cancer (n = 219; median age = 43 years [range = 18-49 years]) and average-onset esophagogastric cancer (n = 904; median age = 67 years [range = 50-94 years]) treated between 2005 and 2018. The early-onset group had more women (39% vs 28%, P = .002). Patients with early-onset esophagogastric cancer were more likely to have a gastric primary site (64% vs 44%, P < .0001). The signet ring cell and/or diffuse type was 3 times more common in the early-onset esophagogastric cancer group (31% vs 9%, P < .0001). Early-onsite tumors were more frequently genomically stable (31% vs 18%, P = .0002) and unlikely to be microsatellite instability high (2% vs 7%, P = .003). After restricting to adenocarcinoma and signet ring cell and/or diffuse type carcinomas, we observed no difference in stage (P = .40) or overall survival from stage IV diagnosis (median = 22.7 vs 22.1 months, P = .78). CONCLUSIONS: Our study supported a preponderance of gastric primary disease sites, signet ring histology, and genomically stable molecular subtypes in early-onset esophagogastric cancer. Our findings highlight the need for further research to define the underlying pathogenesis and strategies for early detection and prevention.

Immune-Related Colitis Is Associated with Fecal Microbial Dysbiosis and Can Be Mitigated by Fecal Microbiota Transplantation.

Colitis induced by treatment with immune-checkpoint inhibitors (ICI), termed irColitis, is a substantial cause of morbidity complicating cancer treatment. We hypothesized that abnormal fecal microbiome features would be present at the time of irColitis onset and that restoring the microbiome with fecal transplant from a healthy donor would mitigate disease severity. Herein, we present fecal microbiota profiles from 18 patients with irColitis from a single center, 5 of whom were treated with healthy-donor fecal microbial transplantation (FMT). Although fecal samples collected at onset of irColitis had comparable α-diversity to that of comparator groups with gastrointestinal symptoms, irColitis was characterized by fecal microbial dysbiosis. Abundances of Proteobacteria were associated with irColitis in multivariable analyses. Five patients with irColitis refractory to steroids and biologic anti-inflammatory agents received healthy-donor FMT, with initial clinical improvement in irColitis symptoms observed in four of five patients. Two subsequently exhibited recurrence of irColitis symptoms following courses of antibiotics. Both received a second "salvage" FMT that was, again, followed by clinical improvement of irColitis. In summary, we observed distinct microbial community changes that were present at the time of irColitis onset. FMT was followed by clinical improvements in several cases of steroid- and biologic-agent-refractory irColitis. Strategies to restore or prevent microbiome dysbiosis in the context of immunotherapy toxicities should be further explored in prospective clinical trials.

Noninvasive Assessment of Human Epidermal Growth Factor Receptor 2 (HER2) in Esophagogastric Cancer Using 89Zr-Trastuzumab PET: A Pilot Study.

Variations in human epidermal growth factor receptor 2 (HER2) expression between the primary tumor and metastases may contribute to drug resistance in HER2-positive (HER2+) metastatic esophagogastric cancer (mEGC). 89Zr-trastuzumab PET (HER2 PET) holds promise for noninvasive assessment of variations in HER2 expression and target engagement. The aim of this study was to describe HER2 PET findings in patients with mEGC. Methods: Patients with HER2+ mEGC were imaged with HER2 PET, 18F-FDG PET, and CT. Lesions were annotated using measurements (on CT) and maximum SUVs (on HER2 PET). Correlation of visualized disease burden among imaging modalities with clinical and pathologic characteristics was performed. Results: Thirty-three patients with HER2+ mEGC were imaged with HER2 PET and CT (12% esophageal, 64% gastroesophageal junction, and 24% gastric adenocarcinoma), 26 of whom were also imaged with 18F-FDG PET. More lesions were identified on 18F-FDG PET (median, 7 [range, 1-14]) than HER2 PET (median, 4 [range, 0-11]). Of the 8 lesions identified on HER2 but not on 18F-FDG PET, 3 (38%) were in bone and 1 was in the brain. Of the 68 lesions identified on 18F-FDG but not on HER2 PET, 4 (6%) were in bone and the remainder were in the lymph nodes (35, 51%) and liver (16, 24%). Of the 33 total patients, 23 (70%) were HER2 imaging-positive (≥50% of tumor load positive). Only 10 patients had 100% of the tumor load positive; 2 had 0% positive. When only patients receiving HER2-directed therapy as first-line treatment were considered (n = 13), median progression-free survival (PFS) therapy was not significantly different between HER2 imaging-positive and -negative patients. Median PFS for patients with at least 1 intense or very intense lesion (SUV ≥ 10) was 16 (95% CI: 11-not reached) mo (n = 7), compared with 12 (95% CI: 6.3-not reached) mo for patients without an intense or very intense lesion (n = 6) (P = 0.35). Conclusion: HER2 PET may identify heterogeneity of HER2 expression and allow assessment of lesions throughout the entire body. A potential application of HER2 PET is noninvasive evaluation of HER2 status including assessment of intrapatient disease heterogeneity not captured by standard imaging or single-site biopsies.

Practical Considerations in Diagnosing and Managing Early-Onset GI Cancers.

The incidence of early-onset (EO) GI cancers occurring in individuals younger than age 50 years has been rising at an alarming rate over the past two decades. Although this rise in incidence among young patients correlates with increased rates of obesity, changes in diet, and alterations in the environment, the effects of these environmental factors on carcinogenesis, metastasis, and treatment response are unknown. Although several unique clinical trends exist among EO-GI cancers and their average-onset GI cancer counterparts, GI cancers are molecularly indistinct between younger and older patients, and no data support distinct treatment paradigms for patients with EO disease. The majority of EO-GI cancers are not explained by germline changes. There remains a critical need for further research to understand the pathogenesis and optimal management of EO-GI cancers. In addition, current screening strategies are not adequate to identify EO-GI cancers, and early biomarkers are needed. Specialized centers, with a focus on psychosocial aspects of cancer management, can address the unique care needs of patients with EO-GI cancers.

Caveolin-1 temporal modulation enhances antibody drug efficacy in heterogeneous gastric cancer.

Resistance mechanisms and heterogeneity in HER2-positive gastric cancers (GC) limit Trastuzumab benefit in 32% of patients, and other targeted therapies have failed in clinical trials. Using patient samples, patient-derived xenografts (PDXs), partially humanized biological models, and HER2-targeted imaging technologies we demonstrate the role of caveolin-1 (CAV1) as a complementary biomarker in GC selection for Trastuzumab therapy. In retrospective analyses of samples from patients enrolled on Trastuzumab trials, the CAV1-high profile associates with low membrane HER2 density and low patient survival. We show a negative correlation between CAV1 tumoral protein levels - a major protein of cholesterol-rich membrane domains - and Trastuzumab-drug conjugate TDM1 tumor uptake. Finally, CAV1 depletion using knockdown or pharmacologic approaches (statins) increases antibody drug efficacy in tumors with incomplete HER2 membranous reactivity. In support of these findings, background statin use in patients associates with enhanced antibody efficacy. Together, this work provides preclinical justification and clinical evidence that require prospective investigation of antibody drugs combined with statins to delay drug resistance in tumors.

How we treat mature B-cell neoplasms (indolent B-cell lymphomas).

Mature B cell neoplasms, previously indolent non-Hodgkin lymphomas (iNHLs), are a heterogeneous group of malignancies sharing similar disease courses and treatment paradigms. Most patients with iNHL have an excellent prognosis, and in many, treatment can be deferred for years. However, some patients will have an accelerated course and may experience transformation into aggressive lymphomas. In this review, we focus on management concepts shared across iNHLs, as well as histology-specific strategies. We address open questions in the field, including the influence of genomics and molecular pathway alterations on treatment decisions. In addition, we review the management of uncommon clinical entities including nodular lymphocyte-predominant Hodgkin lymphoma, hairy cell leukemia, splenic lymphoma and primary lymphoma of extranodal sites. Finally, we include a perspective on novel targeted therapies, antibodies, antibody-drug conjugates, bispecific T cell engagers and chimeric antigen receptor T cell therapy.

Preoperative cholangitis is an independent risk factor for mortality in patients after pancreatoduodenectomy for pancreatic cancer.

OBJECTIVES: Preoperative biliary stenting is required for patients with obstructive jaundice from pancreatic adenocarcinoma who are receiving neoadjuvant chemotherapy. While in most patients this approach results in durable biliary drainage, some patients develop cholangitis during neoadjuvant treatment. Further, several studies have shown that preoperative cholangitis in patients with hepatobiliary malignancies can result in substantially unfavorable outcomes. The aim of this study was to evaluate the impact of preoperative cholangitis in patients who underwent pancreaticoduodenectomy after completing neoadjuvant chemotherapy. METHODS: Participants: all adult patients (n = 449) diagnosed with pancreatic adenocarcinoma from January 1st, 2013 to March 31st, 2018 who pursued treatment at the Massachusetts General Hospital were screened. Of these 449 patients, 97 met final inclusion criteria of receiving neoadjuvant chemotherapy with intent to pursue curative surgery. Data were collected via retrospective chart review including baseline characteristics, survival, episodes of preoperative cholangitis, and surgical complications. RESULTS: In patients completing successful pancreaticoduodenectomy surgery, preoperative cholangitis is associated with increased mortality (HR 2.67, 95% CI:1.16-6.13). This finding is independent of postoperative outcomes or tumor recurrence rate. The presence of cholangitis did not impact completion of neoadjuvant chemotherapy (92% vs 85%, p = 0.5) or ability to proceed to surgery (76% vs 75%, p = 1.0). Preoperative cholangitis was not associated with postoperative morbidity (42.1% vs 45.1%, p = 1.0). CONCLUSIONS: One episode of cholangitis during neoadjuvant chemotherapy is associated with increased mortality following successful pancreaticoduodenectomy, independent of immediate postoperative outcomes or tumor recurrence. Preoperative cholangitis does not affect ability to pursue neoadjuvant chemotherapy or complete successful surgery. Patients who develop cholangitis during the neoadjuvant chemotherapy treatment phase may reflect a distinct phenotype of patients with PDAC with a complex and more challenging clinical course.

Oncologic immunomodulatory agents in patients with cancer and COVID-19.

Corticosteroids, anti-CD20 agents, immunotherapies, and cytotoxic chemotherapy are commonly used in the treatment of patients with cancer. It is unclear how these agents affect patients with cancer who are infected with SARS-CoV-2. We retrospectively investigated associations between SARS-CoV-2-associated respiratory failure or death with receipt of the aforementioned medications and with pre-COVID-19 neutropenia. The study included all cancer patients diagnosed with SARS-CoV-2 at Memorial Sloan Kettering Cancer Center until June 2, 2020 (N = 820). We controlled for cancer-related characteristics known to predispose to worse COVID-19 as well as level of respiratory support during corticosteroid administration. Corticosteroid administration was associated with worse outcomes prior to use of supplemental oxygen; no statistically significant difference was observed in sicker cohorts. In patients with metastatic thoracic cancer, 9 of 25 (36%) and 10 of 31 (32%) had respiratory failure or death among those who did and did not receive immunotherapy, respectively. Seven of 23 (30%) and 52 of 187 (28%) patients with hematologic cancer had respiratory failure or death among those who did and did not receive anti-CD20 therapy, respectively. Chemotherapy itself was not associated with worse outcomes, but pre-COVID-19 neutropenia was associated with worse COVID-19 course. Relative prevalence of chemotherapy-associated neutropenia in previous studies may account for different conclusions regarding the risks of chemotherapy in patients with COVID-19. In the absence of prospective studies and evidence-based guidelines, our data may aid providers looking to assess the risks and benefits of these agents in caring for cancer patients in the COVID-19 era.

A Comprehensive Comparison of Early-Onset and Average-Onset Colorectal Cancers.

BACKGROUND: The causative factors for the recent increase in early-onset colorectal cancer (EO-CRC) incidence are unknown. We sought to determine if early-onset disease is clinically or genomically distinct from average-onset colorectal cancer (AO-CRC). METHODS: Clinical, histopathologic, and genomic characteristics of EO-CRC patients (2014-2019), divided into age 35 years and younger and 36-49 years at diagnosis, were compared with AO-CRC (50 years and older). Patients with mismatch repair deficient tumors, CRC-related hereditary syndromes, and inflammatory bowel disease were excluded from all but the germline analysis. All statistical tests were 2-sided. RESULTS: In total, 759 patients with EO-CRC (35 years, n = 151; 36-49 years, n = 608) and AO-CRC (n = 687) were included. Left-sided tumors (35 years and younger = 80.8%; 36-49 years = 83.7%; AO = 63.9%; P < .001 for both comparisons), rectal bleeding (35 years and younger = 41.1%; 36-49 years = 41.0%; AO = 25.9%; P = .001 and P < .001, respectively), and abdominal pain (35 years and younger = 37.1%; 36-49 years = 34.0%; AO = 26.8%; P = .01 and P = .005, respectively) were more common in EO-CRC. Among microsatellite stable tumors, we found no differences in histopathologic tumor characteristics. Initially, differences in TP53 and Receptor Tyrosine Kinase signaling pathway (RTK-RAS)alterations were noted by age. However, on multivariate analysis including somatic gene analysis and tumor sidedness, no statistically significant differences at the gene or pathway level were demonstrated. Among advanced microsatellite stable CRCs, chemotherapy response and survival were equivalent by age cohorts. Pathogenic germline variants were identified in 23.3% of patients 35 years and younger vs 14.1% of AO-CRC (P = .01). CONCLUSIONS: EO-CRCs are more commonly left-sided and present with rectal bleeding and abdominal pain but are otherwise clinically and genomically indistinguishable from AO-CRCs. Aggressive treatment regimens based solely on the age at CRC diagnosis are not warranted.