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Background Immune checkpoint blockade (ICB) has improved outcomes for patients with microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) tumors. However, not all MSI-H/dMMR patients will exhibit the same ICB efficacy. Previous studies suggest that concomitant antibiotic use while receiving ICB may result in poorer outcomes. We aimed to evaluate this association in patients with MSI-H/dMMR metastatic colorectal cancer (mCRC). Materials and Methods A single-site, retrospective review of 57 patients with MSI-H/dMMR mCRC that received ICB was completed. Data collected included patient demographics, ICB information, and antibiotic use. Antibiotic exposure was considered from 90 days prior to ICB through 6 weeks after initiation. Primary endpoint was overall response rate (ORR). Results The majority of patients received pembrolizumab (27 [47%]) or nivolumab (17 [30%]) monotherapy as their ICB agent. Of the 57 patients, 19 (33.3%) had antibiotic exposure from 90 days prior to ICB initiation through 6 weeks after initiation with most (13 [68%]) having antibiotic use in the 30 days preceding ICB initiation. Similar ORRs were seen in both groups (P-value > .99). No difference was observed in OS (P-value .29) or PFS (P-value .36) between groups. Conclusion Our data show no association of lower response rates or survival in those MSI-H/dMMR patients with mCRC who receive antibiotics around the initiation of ICB. This information needs to be confirmed in a larger prospective cohort.

Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (10/2016-09/2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients; of which GAs with FDA approved genomically-matched therapy were seen in 25 (40.9%) cases. A change in therapy was recommended and implemented (primary endpoint of the study) in 25 (10.1%) and 4 (2.5%) patients of the entire study cohort, respectively. Most common reason for inability to implement the profiling-guided therapy was worsening of performance status (56.3%). Integrating GP in management of CUP is feasible but challenging due to paucity of tissue and aggressive natural history of the disease and requires innovative precision strategies.

Background We pooled data from 2 cohorts of immune checkpoint inhibitors-treated microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer patients to evaluate the prognostic value of RAS/BRAFV600E mutations and Lynch syndrome (LS). Patients and Methods Patients were defined as LS-linked if germline mutation was detected and as sporadic if loss of MLH1/PMS2 expression with BRAFV600E mutation and/or MLH1 promoter hypermethylation, or biallelic somatic MMR genes mutations were found. Progression-free survival (PFS) and overall survival (OS) were adjusted on prognostic modifiers selected on unadjusted analysis (P < .2) if limited number of events. Results Of 466 included patients, 305 (65.4%) and 161 (34.5%) received, respectively, anti-PD1 alone and anti-PD1+anti-CTLA4 in the total population, 111 (24.0%) were treated in first-line; 129 (28.8%) were BRAFV600E-mutated and 153 (32.8%) RAS-mutated. Median follow-up was 20.9 months. In adjusted analysis of the whole population (PFS/OS events = 186/133), no associations with PFS and OS were observed for BRAFV600E-mutated (PFS HR= 1.20, P = .372; OS HR = 1.06, P = .811) and RAS-mutated patients (PFS HR = 0.93, P = .712, OS HR = 0.75, P = .202). In adjusted analysis in the Lynch/sporadic status-assigned population (n = 242; PFS/OS events = 80/54), LS-liked patients had an improved PFS compared to sporadic cases (HR = 0.49, P = .036). The adjusted HR for OS was 0.56 with no significance (P = .143). No adjustment on BRAFV600E mutation was done due to collinearity. Conclusion In this cohort, RAS/BRAFV600E mutations were not associated with survival while LS conferred an improved PFS.

Background Cancer of unknown primary (CUP) presenting as bone‐predominant (BCUP) or lymph node‐only disease (LNCUP) represents two clinically distinct subsets of nonvisceral CUP. These present a diagnostic challenge with a large differential of putative primary cancers and defy the “one‐treatment‐fits‐all” approach. Materials and Methods We identified patients with BCUP (n = 29) and LNCUP (n = 63) using a prospectively collected CUP database and tumor registry of patients seen at MD Anderson Cancer Center between 2001 to 2017. Clinicopathological characteristics, treatments, and outcomes were abstracted. A control group of non‐BCUP/LNCUP cases (n = 443) from the database was used for comparison. Kaplan‐Meier method was used to estimate overall survival and compared using log‐rank test. Results In this cohort, 64% and 60% patients had disseminated disease at diagnosis and 39% and 23% had Culine poor‐risk disease in BCUP and LNCUP, respectively. Median overall survival (OS) for BCUP was 14.5 months and for LNCUP was 32.6 months. For BCUP, gemcitabine plus platinum was the most common initial chemotherapy (54%). For LNCUP, carboplatin plus paclitaxel was the most common initial chemotherapy (38%). Radiation was given to 74% of patients with BCUP and 37% of those with LNCUP. On multivariate analysis, poor‐risk Culine group (hazard ratio [HR], 1.76; p < .001) and high neutrophil‐to‐lymphocyte ratio (HR, 2.38, p < .001) were associated with worse OS. Conclusion BCUP and LNCUP are rare subsets within CUP with varying prognosis. Poor‐risk Culine group and high neutrophil‐to‐lymphocyte ratio are associated with poor survival. Select patients with limited metastases can have long‐term survival with aggressive multimodality treatment. Careful clinicopathological review can facilitate chances of site‐directed therapy. Implications for Practice Cancer of unknown primary (CUP) rarely presents as bone‐predominant (BCUP) or lymph node‐only (LNCUP) disease. This article describes a cohort of each and compares with a larger CUP cohort. Patients with BCUP have unique issues with fractures and pain, often receiving radiation. Overall survival of 14.5 months was similar to a larger CUP comparison cohort. Patients with LNCUP had improved overall survival at 32.6 months, with longer survival in patients without disseminated disease. Culine poor‐risk group and neutrophil‐to‐lymphocyte ratio were associated with worse overall survival. Tips regarding diagnosis and management of these rare malignant subsets are provided., Considering the limited understanding of bone‐predominant or lymph‐node‐only cancers of unknown primary, this article describes the clinical features and outcome data of these two unique conditions.

Background Proportionate female representation in health research is necessary for scientific rigor and health equity. We aimed to assess the representation of women in clinical trials leading to U.S. Food and Drug Administration (FDA) cancer drug approvals. Materials and Methods Trials supporting FDA cancer drug approvals between July 2008 and June 2018 were sourced from PubMed and ClinicalTrials.gov. The ratio of female to male trial enrollment was compared with cancer incidence and mortality in the U.S. using International Agency for Research on Cancer data. Reproductive tract and breast cancers were excluded. Odds ratios (ORs) and 95% confidence intervals (CIs) comparing trial enrollment with population incidence and mortality were calculated. Results A total of 186 trials leading to 170 FDA cancer drug approvals showed slight female underrepresentation compared with overall cancer incidence in the U.S. (OR, 0.97; 95% CI, 0.95–0.98, p < .0001). Female enrollment for drugs approved between 2008–2013 and 2014–2018 was unchanged (OR, 1.02; 95% CI, 0.99–1.05, p = .25). There was slight female underrepresentation in hematological trials (OR, 0.95; 95% CI, 0.91–0.998; p = .040 for leukemia; OR, 0.95; 95% CI, 0.90–0.997; p = .040 for lymphoma) and significant female underrepresentation in colorectal (OR, 0.72; 95% CI, 0.69–0.76; p < .0001), pancreas (OR, 0.85; 95% CI, 0.78–0.93; p = .0004), lung (OR, 0.77; 95% CI, 0.75–0.80; p < .0001), kidney (OR, 0.63; 95% CI, 0.60–0.67; p < .0001), and thyroid cancer trials (OR, 0.26; 95% CI, 0.23–0.28; p < .0001) compared with U.S. incidence. Conclusion Female underrepresentation has persisted within solid organ tumor trials but is less notable in hematologic trials. Additional work is required to identify drivers of such disparity. Implications for Practice Adequate gender representation in clinical trials is a matter of health equity. This study demonstrates that women remain underrepresented in trials across hematological and solid organ trials compared with cancer incidence and mortality in women, with the disparity worse in a number of solid organ tumor types. There are thus still significant improvements to be made regarding adequate representation of women in trials. Studies exploring the reasons for ongoing disparity in gender representation are warranted to help clinicians to rectify this.

Immune checkpoint inhibition (CPI) for metastatic colorectal cancer (mCRC) with deficient mismatch repair (dMMR) demonstrates high clinical activity that appears durable, but the impact of CPI on pathological tumor response is unknown. In this retrospective analysis, our objective was to assess pathological response and clinical outcomes in dMMR mCRC patients treated with CPI prior to surgical resection of primary and/or metastatic tumor. Among 121 advanced dMMR mCRC patients treated with CPI at 2 institutions between November 2016 and December 2018, 14 underwent surgery. Pathologic complete response was noted in the resected specimens of 13 patients despite the presence of residual tumor on preoperative imaging in 12 of those patients. With median follow-up of 9 months, no patients have had disease relapse or progression. For this small retrospective study, the data suggest that residual radiographic tumor may not require systematic resection following response to anti-PD1–based therapy. However, larger prospective studies are warranted.

Colorectal cancer (CRC) remains a leading cause of cancer-related deaths in the United States. Although immunotherapy has dramatically changed the landscape of treatment for many advanced cancers, the benefit in CRC has thus far been limited to patients with microsatellite instability high (MSI-H):DNA mismatch repair–deficient (dMMR) tumors. Recent studies in the refractory CRC setting have led to US Food and Drug Administration approvals for pembrolizumab as well as nivolumab (with or without ipilimumab) for tumors harboring an MSI-H:dMMR molecular profile. Several randomized controlled trials are underway to move immunotherapy into the frontline for metastatic cancer (with or without chemotherapy) and the adjuvant setting. Awareness of these studies is critical given the relatively low incidence (approximately 3%–5%) of MSI-H:dMMR in advanced or metastatic CRC to support study completion, because the results could be potentially practice changing. The real challenge in this disease is related to demonstrating the benefit of immunotherapy for the vast majority of patients with CRC not harboring MSI-H:dMMR. Given the rapid pace of scientific changes, this article provides a narrative review regarding the current landscape of immunotherapy for CRC. Particular attention is paid to the currently available data that inform today’s clinical practice along with upcoming randomized controlled trials that may soon dramatically change the treatment landscape for CRC.

Currently, treatment of small bowel adenocarcinoma (SBA) mirrors that of colorectal cancer (CRC). Recent genomic data have demonstrated SBA to be a genetically unique entity, suggesting that therapies not traditionally utilized in CRC should be explored. In order to further characterize the activity of taxanes in this rare cancer, we completed a single-center retrospective study. Twenty patients were found to have been treated with taxane-based regimens (monotherapy in 3, combination therapy in 17). Median time to progression was 3.8 months (95% confidence interval [CI] 2.9–4.6), and median overall survival was 10.7 months (95% CI: 3.1–18.3). The results of this study demonstrate clinical activity from taxane-based therapy in advanced SBA and support further clinical trial investigation.

Background. Appendiceal adenocarcinomas (AAs) are rare and this has limited their molecular understanding. The purpose of our study was to characterize the molecular profile of AA and explore the role of targeted therapy against cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR). Patients and Methods. We performed a retrospective review of 607 patients with AA at a single institution. A total of 149 patients underwent molecular testing for at least one of the following: activating mutations in KRAS, BRAF, cKIT, EGFR, or PI3K; protein expression of c-KIT or COX-2; or microsatellite instability (MSI) status by immunohistochemistry. Kaplan-Meier product limit method and log-rank test were used to estimate overall survival (OS) and to determine associations among OS, COX-2 expression, KRAS mutations, and other characteristics. Results. Age, grade, stage, signet ring cells, mucinous histology, and completeness of cytoreduction score correlated with survival outcomes. COX-2 expression, KRAS, PI3K, and BRAF mutations were seen in 61%, 55%, 17%, and 4% of patients, respectively. High MSI was seen in 6% of patients. KRAS mutation was strongly associated with well differentiated or moderately differentiated AA (p < .01). COX-2 expression (p = .33) and the presence of KRAS mutation (p = .91) had no impact on OS. The use of celecoxib in patients whose tumors expressed COX-2 (p = .84) and the use of cetuximab or panitumumab in patients with KRAS wild-type tumors (p = .83) also had no impact on OS. Conclusion. In this cohort, we demonstrated that COX-2 expression and KRAS mutations were frequently seen in AA, although neither exhibited any prognostic significance. MSI was infrequent in AA. Targeted therapy against COX-2 and EGFR appeared to provide no clinical benefit. Well and moderately differentiated AA were molecularly distinct from poorly differentiated AA.

Several critical issues need to be considered in interpreting the results of the single-center observational study of the FOLFOX regimen in appendiceal pseudomyxoma peritonei (PMP) reported by Pietrantonio et al. [1]. Clinical behavior of mucinous appendiceal neoplasms is variable and highly dependent on histological grade [2]. Currently, multiple histopathological grading systems exist [3–5]. Although the authors’ eligibility criteria describe inclusion of borderline mucinous tumors and well-differentiated appendiceal adenocarcinomas, the grading is reported as either low (n = 12) or high (n = 8). Because no reference grading system is provided, the meaning of high and low grade is unclear. According to the American Joint Committee on Cancer’s AJCC Cancer Staging Manual, 7th edition, high-grade mucinous appendiceal adenocarcinomas are defined as moderate to poorly differentiated tumors [6], and that is inconsistent with the inclusion criteria. Eligible patients were either unresectable (n = 6) or had relapsed following initial cytoreductive surgery (CRS; n = 14). It was reported that 2 of the 6 initially unresectable cases underwent cytoreductive surgery, but the rate of repeat CRS in the 14 patients who had initially relapsed following a complete CRS was not reported. Because repeated CRS in appendiceal PMP represents a proven approach [7, 8] the rate of a second CRS should be reported. Because both PFS and overall survival times are not censored at the time of a second CRS, the reported time-to-event analyses may best reflect an anticancer approach of chemotherapy followed by repeated CRS [9]. Low-grade mucinous appendiceal neoplasms are known to have an indolent disease course; therefore, the presence of 7 cases with >20% growth at 3 months (progressive disease) is highly unusual for this disease type. Furthermore, the >30% shrinkage seen in 4 of these patients is unusual in the context of a median of 8 cycles (∼4 months) and a maximum of 12 (∼6 months). As a center that has conducted extensive research in appendiceal neoplasms, we disagree with the statement that a “decrease in the amount of mucus was invariably observed” and feel that the magnitude of radiographic change reported over a 3- to 6-month period for low-grade mucinous appendiceal neoplasms is not an accurate reflection of the disease biology under study. Prior reports documenting radiographic responses have all included more aggressive and higher grade appendiceal neoplasms and are not reflective of the population in this report [10, 11]. In part, we believe that the findings reported reflect the intrinsic challenges of both separating mucinous from more serous peritoneal accumulations and measuring geographically shaped mucinous implants that shift between scans. This latter point is amplified by the limitation of measuring only two peritoneal areas, as per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. Prospective controlled studies are needed to clarify the role of chemotherapy in PMP. A clinical trial ({"type":"clinical-trial","attrs":{"text":"NCT01946854","term_id":"NCT01946854"}}NCT01946854) for unresectable low-grade mucinous appendiceal adenocarcinomas with PMP is ongoing at MD Anderson. In that trial, patients are randomized to either 6 months of chemotherapy followed by 6 months of observation or 6 months of observation followed by 6 months of chemotherapy. Within this study, a modified peritoneal RECIST measurement in which five locations are measured is being investigated. Because each patient serves as his or her own control, we hope this study will better clarify the true rate of radiographic change for this biologically unique tumor type.