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PURPOSE: The role of preoperative stereotactic body radiation therapy (SBRT) in pancreatic cancer is controversial, and questions regarding the optimal dose and radiation treatment field remain. To better inform future investigations of SBRT dose and radiation fields, we evaluated the patterns of failure in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC) after preoperative chemotherapy and SBRT in patients who underwent surgical resection. METHODS AND MATERIALS: We performed a single-institution retrospective review of consecutive patients treated from September 2017 to January 2022 with BR/LAPC. Patients who underwent preoperative chemotherapy and SBRT followed by surgical resection were reviewed. SBRT was delivered to a dose of 33 Gy in 5 fractions. Kaplan-Meier overall survival and progression-free survival estimates were calculated. RESULTS: In total, 18 patients (12 BRPC, 6 LAPC) were included. Median age was 69 years (range 41-84 years). Median follow-up was 30 months (range 13-59 months). Seventeen patients (94%) had a R0 resection and 13 (72%) underwent vascular reconstruction. Median overall survival and progression-free survival was 42 months (range 13-59 months) and 23 months (range 1-45 months), respectively. In total, 61% (11/18) patients experienced progression at any point during follow-up. Of the patients who experienced recurrence, 27% (3/11) experienced local progression as component of their first recurrence, whereas 100% (11/11) experienced distant progression as a component of their first recurrence. When examining all recurrences that occurred at any point in follow-up, 28% (5/18) of patients experienced local or locoregional recurrence and 61% (11/18) experienced distant progression. CONCLUSIONS: Local control and margin negative resection rates were excellent with preoperative chemotherapy and nondose-escalated SBRT in surgically resected patients with BR/LAPC. Distant recurrence was the predominant site of failure with lower incidences of isolated locoregional recurrences. Additional research is needed to determine the ideal treatment volume and patients who may benefit from dose escalation.

Colon cancer with high microsatellite instability is characterized by a high tumor mutational burden and responds well to immunotherapy. Mutations in polymerase ɛ, a DNA polymerase involved in DNA replication and repair, are also associated with an ultra-mutated phenotype. We describe a case where a patient with POLE-mutated and hypermutated recurrent colon cancer was treated with pembrolizumab. Treatment with immunotherapy in this patient also led to the clearance of circulating tumor DNA (ctDNA). ctDNA is beginning to emerge as a marker for minimal residual disease in many solid malignancies, including colon cancer. Its clearance with treatment suggests that the selection of pembrolizumab on the basis of identifying a POLE mutation on next-generation sequencing may increase disease-free survival in this patient.

Circulating tumor DNA (ctDNA) is increasingly being investigated as a tool to detect minimal residual disease in resected, stage I-III colorectal cancer. Recent ctDNA studies have indicated that detection of ctDNA following surgery for resectable colorectal cancer confers a significantly higher risk of recurrence than those with negative ctDNA postoperatively. In those with postoperative ctDNA positivity, clearance of minimal residual disease with adjuvant chemotherapy is a positive prognostic indicator. Lastly, ctDNA has demonstrated superior sensitivity to the conventional blood tumor marker carcinoembryonic antigen (CEA) and can offer median lead times of up to 11 months for radiographic detection of recurrence during the surveillance of resected, stage I-III colorectal cancer. In metastatic colorectal cancer (mCRC), there is growing evidence to suggest that plasma ctDNA can be used to monitor tumor response to conventional chemotherapy as well. The present case series demonstrated that plasma ctDNA is a predictor of tumor response to immunotherapy in patients with mCRC that are microsatellite stable or microsatellite instability high. Plasma ctDNA could serve as a dynamic marker of immunotherapy response even in colorectal tumors that were CEA non-producers. Overall, these findings add to ongoing efforts to establish the role of plasma ctDNA in monitoring response to immunotherapy in CRC.

* Context.--Claudin-18 is expressed in some gastric cancers. Clinical trials are evaluating it as a therapeutic target. Objectives.--To evaluate claudin-18 expression in intestinal metaplasia, dysplasia, and adenocarcinoma of the distal esophagus/gastroesophageal junction and stomach and to evaluate claudin-18 expression in gastric and nongastric neuroendocrine tumors as a marker of gastric origin. Design.--Samples included gastroesophageal junction with intestinal metaplasia (n = 40), dysplasia (n = 54), and adenocarcinoma (n = 20) and stomach with intestinal metaplasia (n = 79), dysplasia (n = 43), and adenocarcinoma (n = 25). Additionally, gastric (n = 40) and nongastric (n = 322) neuroendocrine tumors were included. Claudin-18 expression was evaluated for any staining as positive and by meeting clinical trial inclusion criteria ([greater than or equal to]2+ intensity in [greater than or equal to]50% of tumor). Results.--Claudin-18 staining was not significantly different across dysplasia categories in the gastroesophageal junction (P = .11) or stomach (P = .12). The rate of positive staining was higher in gastroesophageal junction than stomach for intestinal metaplasia (37 of 40 [92.5%] versus 37 of 79 [46.8%]; P < .001) and high-grade dysplasia (33 of 38 [86.8%] versus 9 of 16 [56.3%]; P = .03). Intestinal metaplasia showed staining in 7 of 37 autoimmune gastritis samples (18.9%) compared with 30 of 42 samples without autoimmune gastritis (71.4%) (P < .001). Adenocarcinoma showed similar staining in gastroesophageal junction (15 of 20; 75.0%) and stomach (17 of 25; 68.0%) (P = .85). Eighty percent (32 of 40) of gastric neuroendocrine tumors were positive for claudin-18 expression, with 57.5% (23 of 40) meeting clinical trial inclusion criteria. Comparatively, 0.62% (2 of 322) of nongastric neuroendocrine tumors showed staining (P < .001). Conclusions.--Claudin-18 staining was similar in intestinal metaplasia, dysplasia, and adenocarcinoma. Claudin18 was negative in most cases of intestinal metaplasia in autoimmune gastritis, indicating that intestinal metaplasia in this setting may differ from other forms. Claudin-18 was sensitive and specific for gastric origin in neuroendocrine tumors. doi: 10.5858/arpa.2021-0428-OA, Gastric cancer is the fifth most common cancer and the fourth leading cause of cancer death worldwide, but gastric cancer mortality has significantly decreased during the last half century. (1) [...]

Gastroesophageal cancer is one of the most common cancers in the world, with a high rate of mortality. While there has been significant progress over the past decade, particularly with the addition of anti-HER2 therapies to platinum-based chemotherapy agents in the advanced setting, the prognosis remains poor and the treatment options for this disease entity remain limited. In this review, we discuss the current therapeutic landscape for HER2-positive gastroesphageal cancer and the seminal clinical trials that have shaped our approach to this disease entity. In addition, we highlight some of the challenges to the understanding and management of this disease, specifically discussing the breadth of molecular diversity and intratumoral heterogeneity of HER2 expression that impact the clinical efficacy and prognosis. Furthermore, we discuss the potential role of next-generation sequencing (NGS) and circulating-tumor DNA (ctDNA) as complementary tools to immunohistochemistry (IHC) and fluorescent in-situ hybridization (FISH) to guiding clinical decision making. Finally, we highlight promising clinical trials of new treatment regimens that will likely reshape the therapeutic approach to this disease entity.

BackgroundChemotherapy has long been shown to confer a survival benefit in patients with metastatic esophageal cancer. However, not all patients with metastatic disease receive chemotherapy.AimTo evaluate a large cancer database of metastatic esophageal cancer cases to identify predictors of receipt to chemotherapy and survival.MethodsWe interrogated the National Cancer Database (NCDB) between 2004-2015 and included patients with M1 disease who had received or did not receive chemotherapy. A logistic regression model was used to examine the associations between chemotherapy and potential confounders and a Cox proportional hazards model was employed to examine the effect of chemotherapy on overall survival (OS). Propensity score analyses were further performed to balance measurable confounders between patients treated with and without chemotherapy.ResultsA total of 29182 patients met criteria for inclusion in this analysis, with 21911 (75%) receiving chemotherapy and 7271 (25%) not receiving chemotherapy. The median follow-up was 69.45 mo. The median OS for patients receiving chemotherapy was 9.53 mo (9.33-9.72) vs 2.43 mo (2.27-2.60) with no chemotherapy. Year of diagnosis 2010-2014 [odds ratio (OR): 1.29, 95% confidence interval (CI): 1.17-1.43, P value < 0.001], median income > $46000 (OR: 1.49, 95%CI: 1.27-1.75, P value < 0.001), and node-positivity (OR: 1.35, 95%CI: 1.20-1.52, P < 0.001) were independent predictors of receiving chemotherapy, while female gender (OR: 0.86, 95%CI: 0.76-0.98, P = 0.019), black race (OR: 0.76, 95%CI: 0.67-0.93, P = 0.005), uninsured status (OR: 0.41, 95%CI: 0.33-0.52, P < 0.001), and high Charlson Comorbidity Index (CCI) (OR for CCI ≥ 2: 0.61, 95%CI: 0.50-0.74, P < 0.001) predicted for lower odds of receiving chemotherapy. Modeling the effect of chemotherapy on OS using a time-dependent coefficient showed that chemotherapy was associated with improved OS up to 10 mo, after which there is no significant effect on OS. Moreover, uninsured status [hazard ratio (HR): 1.20, 95%CI: 1.09-1.31, P < 0.001], being from the geographic Midwest (HR: 1.07, 95%CI: 1.01-1.14, P = 0.032), high CCI (HR for CCI ≥ 2: 1.16, 95%CI: 1.07-1.26, P < 0.001), and higher tumor grade (HR for grade 3 vs grade 1: 1.28, 95%CI: 1.14-1.44, P < 0.001) and higher T stage (HR for T1 vs T4: 0.89, 95%CI: 0.84-0.95, P < 0.001) were independent predictors of worse OS on multivariable analyses.ConclusionIn this large, retrospective NCDB analysis, we identified several socioeconomic and clinicopathologic predictors for receiving chemotherapy and OS in patients with metastatic esophageal cancer. The benefit of chemotherapy on OS is time-dependent and favors early initiation. Focused outreach in lower income and underinsured patients is critical as receipt of chemotherapy is associated with improved OS.

Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual disease, there are now ongoing, phase III randomized clinical trials to evaluate their role in the management paradigm of CRC. In this review, we highlight landmark studies that have formed the basis for ongoing studies on the clinically applicability of plasma ctDNA assays in resected, stage I-III CRC and metastatic CRC. We discuss clinical settings by which ctDNA may have the most immediate impact in routine clinical practice. These include the potential for ctDNA to (1) guide surveillance and intensification or de-intensification strategies of adjuvant therapy in resected, stage I-III CRC, (2) predict treatment response to neoadjuvant therapy in locally advanced rectal cancer inclusive of total neoadjuvant therapy (TNT), and (3) predict response to systemic and surgical therapies in metastatic disease. We end by considering clinical variables that can influence our ability to reliably interpret ctDNA dynamics in the clinic.

Early-onset colorectal cancer has been on the rise in Western populations. Here, we compare patient characteristics between those with early- (

Immunotherapy has been established as a standard in select molecular subgroups of treatment-refractory advanced gastric cancer. However, its role in resectable gastric cancer where perioperative systemic therapy is the standard remains unclear. We present a case of a man who was diagnosed with resectable gastric cancer that was microsatellite stable but programmed death-ligand 1 (PD-L1) and Epstein-Barr Virus (EBV)-positive. Given extenuating circumstances of the SARS-CoV-2 pandemic, preferences to limit exposure to the healthcare setting, and the unique tumor molecular features, neoadjuvant pembrolizumab and capecitabine was pursued after multidisciplinary discussion. He was able to achieve a complete response to this neoadjuvant regimen with no further signs of radiographic or pathologic disease on follow-up. We highlight a dramatic response to this novel approach that represents among the first cases to support a potentially viable neoadjuvant chemoimmunotherapy strategy to resectable gastric cancer. In select patients, perioperative immunotherapy-based therapy may constitute a promising strategy in resectable gastric cancer and warrants further investigation.

BRCA1 or 2 mutations result in higher cancer risk for breast cancer (BC) and epithelial ovarian cancer (EOC) for carriers than exists in the general population. Optimal breast imaging surveillance in these patients has not been well defined. An Institutional Review Board-approved, multi-institutional retrospective chart review was performed. Patients diagnosed with BRCA-associated EOC between 1990-2015 were identified; demographic and clinical data were collected and analyzed. 192 BRCA mutation-positive patients with EOC were identified. 16/192 (8.3%) women were diagnosed with BC following EOC, at a median of 50 (range 5-327) months following EOC diagnosis and median age 59.5 (45-84) years. Breast cancer was most commonly detected on mammogram 7/16 (44%) or clinical exam 7/16 (44%). 2/16 (12.5%) had occult BC found during risk-reducing mastectomy. 14 (88%) had early-stage (0-2) disease. At mean follow-up of 8.1 years, 6 (37.5%) patients with BC following EOC had died due to EOC. The risk of BC diagnosis following EOC in BRCA mutation carriers is low; most of these BCs are early stage and diagnosed with mammography or physical exam. Overall, survival in BRCA mutation carriers is dominated by EOC-related mortality. Breast cancer surveillance in BRCA mutation carriers following EOC should prioritize nonsurgical strategies.

BackgroundPalliative therapy has been associated with improved overall survival (OS) in several tumor types. Not all patients with metastatic esophageal cancer receive palliative chemotherapy, and the roles of other palliative therapies in these patients are limited.AimTo investigate the impact of other palliative therapies in patients with metastatic esophageal cancer not receiving chemotherapy.MethodsThe National Cancer Database was used to identify patients between 2004-2015. Patients with M1 disease who declined chemotherapy and had known palliative therapy status [palliative therapies were defined as surgery, radiotherapy (RT), pain management, or any combination thereof] were included. Cases with unknown chemotherapy, RT, or nonprimary surgery status were excluded. Kaplan-Meier estimates of OS were calculated. Cox proportional hazards regression models were employed to examine factors influencing survival.ResultsAmong 140234 esophageal cancer cases, we identified 1493 patients who did not receive chemotherapy and had complete data. Median age was 70 years, most (66.3%) had a Charlson Comorbidity Index (CCI) of 0, and 37.1% were treated at an academic center. The majority (72.7%) did not receive other palliative therapies. On both univariate and multivariable analyses, there was no difference in OS between those receiving other palliative therapy (median 2.83 mo, 95%CI: 2.53-3.12) vs no palliative therapy (2.37 no, 95%CI: 2.2-2.56; multivariable P = 0.290). On univariate, but not multivariable analysis, treatment at an academic center was predictive of improved OS [Hazard ratio (HR) 0.90, 95%CI: 0.80-1.00; P = 0.047]. On multivariable analysis, female sex (HR 0.81, 95%CI: 0.71-0.92) and non-black, other race compared to white race (HR 0.72, 95%CI: 0.56-0.93) were associated with reduced mortality, while South geographic region relative to West region (HR 1.23, 95%CI: 1.04-1.46) and CCI of 1 relative to CCI of 0 (HR 1.17, 95%CI: 1.03-1.32) were associated with increased mortality. Higher histologic grade and T-stage were also associated with worse OS (P < 0.05).ConclusionPalliative therapies other than chemotherapy conferred a numerically higher, but not statistically significant difference in OS among patients with metastatic esophageal cancer not receiving chemotherapy. Quality of life metrics, inpatient status, and subgroup analyses are important for examining the role of palliative therapies other than chemotherapy in metastatic esophageal cancer and future studies are warranted.

Patients with colorectal cancer (CRC) have benefited significantly from advances in multimodal treatment with significant improvements in long-term survival. More patients are currently being treated with surgical resection or ablation following neoadjuvant or adjuvant chemotherapy. However, several cytotoxic agents that are administered routinely have been linked to liver toxicities that impair liver function and regeneration. Recognition of chemotherapy-related liver toxicity emphasizes the importance of multidisciplinary planning to optimize care. This review aims to summarize current data on multimodal treatment concepts for CRC, provide an overview of liver damage caused by commonly administered chemotherapeutic agents, and evaluate currently suggested protective agents.

The role of palliative surgery in the management of acute complications in patients with disseminated malignancy remains controversial given the complexity of assessing acute surgical risk and long-term oncologic outcome. With the emergence of checkpoint blockade immunotherapy, there appears to be an increasing role for historically palliative procedures as a bridge to systemic immunotherapy. This is especially evident in advanced microsatellite instability-high (MSI-H) colorectal cancer where malignant obstruction and fistula formation are more common and where immunotherapy with checkpoint blockade (anti-PD-1/PD-L1, anti-CTLA-4) has a high response rate with potential for favorable oncologic outcomes. We present a series of three patients with MSI-H metastatic colorectal cancer complicated by malignant bowel obstruction and fistula formation, who having progressed on standard chemotherapy, underwent palliative intervention as a bridge to immune checkpoint blockade with durable and clinically meaningful anti-cancer responses. These cases highlight the need to re-evaluate the role of historically palliative operations in the setting of disease progression for immunotherapy-responsive tumors.

Peritoneal metastases from colon cancer are a particularly challenging disease process given the limited response to systemic chemotherapy. In patients with isolated peritoneal metastases, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy offers a potential treatment option to these patients with limited peritoneal metastases as long as a complete cytoreduction is achieved. Decision about a patient's candidacy for this treatment modality should be undertaken by a multidisciplinary group at expert centers. [ABSTRACT FROM AUTHOR]

ImportanceBRCA mutation carriers are at increased risk of developing breast cancer. However, the incidence of breast cancer after a diagnosis of epithelial ovarian cancer (EOC), one of the tubal/peritoneal cancers collectively referred to as pelvic serous carcinomas, is not well known. Optimal breast cancer surveillance and detection for these patients have also not been well characterized.ObjectivesTo determine the incidence of breast cancer after a diagnosis of EOC and to evaluate the need for breast cancer surveillance for these patients.Design, setting, and participantsA retrospective database review of 364 patients who underwent BRCA mutation testing for EOC (stages I-IV) between 1998 and 2012 at an academic medical center with gynecologic and breast cancer centers.Main outcomes and measuresIncidence of breast cancer and methods of surveillance.ResultsOf 364 patients, 135 (37.1%) were found to carry a germline BRCA1 or BRCA2 mutation. The mean age of patients at diagnosis of EOC was 49.5 years (range, 28-89 years). Of the 135 patients, 12 (8.9%) developed breast cancer. The median time from diagnosis of EOC to diagnosis of breast cancer was 50.5 months. Annual mammography was performed for 80 patients (59.3%), with annual magnetic resonance imaging of the breasts performed for 60 patients (44.4%). Thirteen patients (9.6%) underwent a bilateral prophylactic mastectomy at a median of 23 months following EOC diagnosis. Breast cancer was most commonly diagnosed by mammography for 7 of the 12 patients (58.3%), 3 (25.0%) of whom had a palpable mass and 2 (16.7%) of whom had incidental breast cancer detected during a prophylactic mastectomy. Seven patients with breast cancer (58.3%) underwent a bilateral mastectomy. All patients had early-stage breast cancer (stages 0-II). Four patients (33.3%) received adjuvant chemotherapy. At a median follow-up of 6.3 years, 4 of the 12 patients (33.3%) died of recurrent EOC after a diagnosis of breast cancer. The overall 10-year survival rate for the entire cohort of 135 patients was 17.0%.Conclusions and relevanceThe risk of metachronous breast cancer is low in patients with known BRCA mutations and EOC. A majority of these cases of breast cancer at an early stage are detected by use of mammography. Despite the small number of patients in our study, these results suggest that optimal breast cancer surveillance for patients with BRCA-associated EOC needs to be reevaluated given the low incidence of breast cancer among these high-risk patients. Confirmation of our findings from larger studies seems to be indicated.