Adherence to NCCN Genetic Testing Guidelines in Pancreatic Cancer and Impact on Treatment.

INTRODUCTION: National Comprehensive Cancer Network (NCCN) 2019 Guidelines recommend universal germline (GL) testing for patients (pts) with pancreatic cancer (PC), given germline mutations (gMut) can occur at a similar rate irrespective of an individual's family history of cancer. Molecular analysis of tumors in those with metastatic disease is also recommended. We aimed to determine rates of genetic testing at our institution, factors associated with testing, and outcomes of those tested. METHODS: Frequency of GL and somatic testing was examined in pts diagnosed with non-endocrine PC, with >2 visits between June 2019 and June 2021 at the Mount Sinai Health System. The clinicopathological variables and treatment outcomes were also recorded. RESULTS: A total of 149 pts met the inclusion criteria. Sixty-six pts (44%) underwent GL testing: 42 (28%) at time of diagnosis with the remainder later in treatment. The rate of GL testing increased every year: 33% (2019), 44% (2020), and 61% (2021). A family history of cancer was the only variable associated with the decision to perform GL testing. Eight pts (12% of pts tested) had pathological gMut: BRCA1 (1), BRCA2 (1), ATM (2), PALB2 (2), NTHL1 (1), both CHEK2 and APC (1). Neither gBRCA pt received a PARP inhibitor, all except one received first-line platinum. Ninety-eight pts (65.7%) had molecular tumor testing (66.7% of patients with metastases). Two pts with BRCA2 somatic mut did not have GL testing. Three pts received targeted therapies. CONCLUSION: Genetic testing based on provider discretion results in low rates of GL testing. Early results of genetic testing can have an impact on treatment decisions and trajectory of disease. Initiatives to increase testing are needed but must be feasible in real-world clinic settings.

Phase II Study of Olaparib (AZD-2281) After Standard Systemic Therapies for Disseminated Colorectal Cancer.

BACKGROUND: Effective new agents for patients with colorectal cancer (CRC) with disease progression during standard therapy regimens are needed. We hypothesized that poly ADP ribose polymerase (PARP) inhibitor therapy in patients with CRC and inefficient tumor DNA repair mechanisms, such as those with high-level microsatellite instability (MSI-H), would result in synthetic lethality. METHODS: This was an open-label phase II trial testing olaparib 400 mg p.o. b.i.d. for patients with disseminated, measurable CRC failing standard therapies with centrally confirmed tumor MSI status. The primary endpoint was the tumor response, assessed by RECIST, version 1.0. The secondary endpoints were safety/toxicity, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-three patients (20 microsatellite stable [MSS], 13 MSI-H) were enrolled. The median age for all patients was 57 years and for MSS and MSI-H patients was 51 and 61 years, respectively. All patients received at least one 28-day cycle of olaparib. No patient had a complete or partial response. Nausea (48%), fatigue (36%), and vomiting (33%) were the most commonly reported treatment-related adverse events. The median PFS for all patients was 1.84 months. No statistically significant differences were found in the median PFS or OS for the MSS group compared with the MSI-H group. CONCLUSION: Single-agent olaparib delivered after failure of standard systemic therapy did not demonstrate activity for CRC patients, regardless of microsatellite status. Future trials, testing PARP inhibitors in patients with CRC should focus on the use of DNA-damaging chemotherapy and/or radiation therapy, combined with PARP inhibitors, remembering the toxicity reported in the present study. IMPLICATIONS FOR PRACTICE: Microsatellite instability (MSI-H) colorectal tumors exhibit hypermethylation in tumor mismatch repair genes, or have mutations in one or more of these genes resulting from a germ-line defect (Lynch syndrome). PARP inhibitors such as olaparib are most effective in tumors associated with inability to repair DNA damage. However, in this trial, single agent olaparib failed to elicit responses in patients with MSI-H colorectal tumors, and in those with microsatellite-stable tumors. It is possible that by adding olaparib to radiation therapy, or to a systemic DNA damaging agent, tumor lethality could be obtained. However, the price would be increased toxicity.

Combining anti-VEGFR and anti-EGFR antibodies: Randomized phase II study of irinotecan and cetuximab with/without ramucirumab in second-line colorectal cancer:(ECOG-ACRIN E7208).

INTRODUCTION: Early studies showed promise of combined anti-EGFR plus anti-VEGF antibodies for advanced colorectal cancer (CRC), yet this was later rejected as toxic and ineffective in studies not selected for RAS status. We studied advanced KRAS wild-type CRC, as second-line treatment, using irinotecan-cetuximab (IC) with or without the anti-VEGFR antibody, ramucirumab (ICR). METHODS: Patients with one prior regimen including fluoropyrimidine, oxaliplatin and bevacizumab, with KRAS wild-type tumors, were stratified by ECOG PS, time since last chemotherapy and progression on oxaliplatin, to IC (180 and 500 mg/2 q2w), vs modified ICR (mICR) (150 and 400 mg/m2 plus 6 mg/kg respectively). 102 patients were compared for progression-free survival (PFS) as primary endpoint (85% power for 70% improvement in median PFS from 4.5 to 7.65 months). RESULTS: Of the 102 enrolled, 44 treated with IC and 45 with mICR were evaluable. Median PFS was 6.0 vs 9.2 months respectively (HR 0.75, p = .07, significant by study design for p < .128). Response rate was 23% vs 36% (p = .27) and disease-control rate (DCR) was 52% vs 73% (p = .05). Grade ≥3 toxicity was not equivalent. Overall survival was not significantly different at ∼19 months. CONCLUSION: Previous phase 3 trials without RAS genotyping, rejected combining anti-EGFR and anti-VEGF drugs. In this randomized multi-center phase 2 study for KRAS wild type CRC (all previously bevacizumab-treated) the addition of ramucirumab, to irinotecan and cetuximab improved PFS and DCR, showing the combination is feasible and effective here. Further phase 3 trials with appropriate patient-selection are required. (NCT01079780).

Association of Antibiotic Receipt With Survival Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma Receiving Chemotherapy.

Importance: The prognosis for patients with metastatic pancreatic ductal adenocarcinoma (PDAC) is dismal, due in part to chemoresistance. Bacteria-mediated mechanisms of chemoresistance suggest a potential role for antibiotics in modulating response to chemotherapy. Objective: To evaluate whether use of peritreatment antibiotics is associated with survival among patients with metastatic PDAC treated with first-line gemcitabine or fluorouracil chemotherapy. Design, Setting, and Participants: Using the population-based Surveillance, Epidemiology, and End Results-Medicare linked database, this retrospective cohort study analyzed data for patients diagnosed with PDAC between January 1, 2007, and December 31, 2017. Data analysis was conducted between September 1, 2021, and January 15, 2023. The population-based sample included 3850 patients with primary metastatic PDAC treated with first-line gemcitabine or fluorouracil chemotherapy. Patients who received antibiotics were matched based on propensity scores to patients who did not receive antibiotics. Exposures: Receipt of 5 or more days of oral antibiotics or 1 injectable antibiotic in the month before or after beginning first-line chemotherapy. Main Outcomes and Measures: Overall survival and cancer-specific survival. The end of follow-up was December 31, 2019, for overall survival and December 31, 2018, for cancer-specific survival. Results: Of the 3850 patients treated with first-line gemcitabine (3150 [81.8%]) or fluorouracil (700 [18.2%]), 2178 (56.6%) received antibiotics. The mean (SD) age at diagnosis was 74.2 (5.8) years and patients were predominantly women (2102 [54.6%]), White (3396 [88.2%]), and from metropolitan areas (3393 [88.1%]) in the northeastern or western US (2952 [76.7%]). In total, 1672 propensity-matched pairs were analyzed. Antibiotic receipt was associated with an 11% improvement in overall survival (hazard ratio [HR], 0.89; 95% CI, 0.83-0.96; P = .003) and a 16% improvement in cancer-specific survival (HR, 0.84; 95% CI, 0.77-0.92; P < .001) among patients treated with gemcitabine. In contrast, there was no association between antibiotic receipt and overall survival (HR, 1.08; 95% CI, 0.90-1.29; P = .41) or cancer-specific survival (HR, 1.12; 95% CI, 0.90-1.36; P = .29) among patients treated with fluorouracil. In a subgroup of gemcitabine-treated patients who received antibiotics, nonpenicillin ß-lactams were associated with an 11% survival benefit (HR, 0.89; 95% CI, 0.81-0.97; P = .01). Conclusions and Relevance: In this cohort study, receipt of perichemotherapy antibiotics was associated with improved survival among patients treated with gemcitabine, but not fluorouracil, suggesting that antibiotics may modulate bacteria-mediated gemcitabine resistance and have the potential to improve PDAC outcomes.

Postoperative intraperitoneal 5-fluoro-2'-deoxyuridine added to chemoradiation in patients curatively resected (R0) for locally advanced gastric and gastroesophageal junction adenocarcinoma.

PURPOSE: Chemoradiation after surgery for locally advanced gastric cancer improves overall and relapse-free survival compared with observation. However, locoregional recurrences remain high. Accordingly, we instituted this pilot/feasibility study, including intraperitoneal 5-fluoro-2'-deoxyuridine (IP FUDR) as part of the treatment. METHODS: Gastric/gastroesophageal junction adenocarcinoma stage Ib-IV (M0) patients who underwent R(0) resection were eligible and had IP catheters inserted at time of surgery. IP FUDR (3 g/dose/day) was given during study days 1-3 and 15-17 before combined 5-fluorouracil, leucovorin, and external beam radiation (45 Gy). Endpoints included toxicity, completion rate, locoregional recurrence, and survival. RESULTS: Twenty-eight patients (22 men) were enrolled from 2002-2006 at two institutions; their median age was 59.5 years. After R(0) resection, a median 22 (range, 8-102) lymph nodes were examined, and 22 patients had positive nodes. AJCC stages were IB (n = 8), II (n = 10), IIIA (n = 5), IIIB (n = 1), and IV (n = 4). Full-dose IP FUDR and chemoradiation treatment was completed in 20 and 25 patients, respectively. At nearly 4-year median follow-up, 11 patients were disease-free, 5 were alive with disease, 7 were dead of disease, and 1 was dead from other cause; 4 have been lost to follow-up. Recurrences were local in one, intra-abdominal in six, distant in two, multiple sites in two, and unknown in one. The median relapse-free survival is 65.3 months, and the median overall survival has not yet been reached. CONCLUSIONS: IP FUDR before chemoradiation after R(0) gastric cancer resection is well tolerated without compromising completion of postoperative adjuvant treatment. Larger randomized trials studying IP FUDR as part of gastric cancer multidisciplinary treatment are needed to prove efficacy in reducing regional recurrence and improving survival.

Prescreening to Increase Therapeutic Oncology Trial Enrollment at the Largest Public Hospital in the United States.

PURPOSE: The recruitment of underserved patients into therapeutic oncology trials is imperative. The National Institutes of Health mandates the inclusion of minorities in clinical research, although their participation remains under-represented. Institutions have used data mining to match patients to clinical trials. In a public health care system, such expensive tools are unavailable. METHODS: The NYU Clinical Trials Office implemented a quality improvement program at Bellevue Hospital Cancer Center to increase therapeutic trial enrollment. Patients are screened through the electronic medical record, tumor board conferences, and the cancer registry. Our analysis evaluated two variables: number of patients identified and those enrolled into clinical trials. RESULTS: Two years before the program, there were 31 patients enrolled. For a period of 24 months (July 2017 to July 2019), we identified 255 patients, of whom 143 (56.1%) were enrolled. Of those enrolled, 121 (84.6%) received treatment, and 22 (15%) were screen failures. Fifty-five (38.5%) were referred to NYU Perlmutter Cancer Center for therapy. Of the total enrollees, 64% were female, 56% were non-White, and overall median age was 55 years (range: 33-88 years). Our participants spoke 16 different languages, and 57% were non-English-speaking. We enrolled patients into eight different disease categories, with 38% recruited to breast cancer trials. Eighty-three percent of our patients reside in low-income areas, with 62% in both low-income and Health Professional Shortage Areas. CONCLUSION: Prescreening at Bellevue has led to a 4.6-fold increase in patient enrollment to clinical trials. Future research into using prescreening programs at public institutions may improve access to clinical trials for underserved populations.

BTLA+CD200+ B cells dictate the divergent immune landscape and immunotherapeutic resistance in metastatic vs. primary pancreatic cancer.

Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCIIloIL10+ macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24+CD44-CD40- B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1hiIL18hi tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy-responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease.

Effectiveness of image-guided radiotherapy for locally advanced rectal cancer.

BACKGROUND: Image-guided radiotherapy (IGRT) combines precise target visualization with optimal delivery of radiation dose to spare normal tissue from radiation and may potentially reduce side-effects and long-term treatment complications. We have assessed the effectiveness of IGRT for locally advanced rectal cancer. METHODS: A retrospective review of 22 patients with locally advanced rectal cancer who underwent preoperative chemoradiation was conducted. RESULTS: Nineteen patients (median age, 69 years) underwent surgical resection after chemoradiation. All 19 patients achieved complete resection with negative margins. Seven patients (32%) had no residual tumor in the surgical specimen. One patient had grade 4 gastrointestinal toxicity and hematological toxicity probably related to inadvertent overdosing of capecitabine. The median survival for the whole group-patients who had pCR and those who did not have pCR-was 14, 17, and 15 months, respectively. CONCLUSIONS: Image-guided radiotherapy provided effective treatment for locally advanced rectal cancer with minimal toxicity and should be investigated in future prospective trials.

Advances in the pharmacotherapeutic management of esophageal squamous cell carcinoma.

INTRODUCTION: Esophageal squamous cancer remains an important cause of mortality worldwide with two new immunotherapy drugs recently approved for metastatic disease. AREAS COVERED: The authors review the epidemiology and genomics of esophageal squamous cell carcinoma. They also examine prior trials involving targeted agents under investigation as well immunotherapies that have been approved and novel combinations. EXPERT OPINION: Great advances have been made in characterizing the molecular changes in esophageal carcinoma. However, relatively few drugs have shown benefit in this disease. Targeted therapies have not shown to improve survival although many of these trials did not explore potential biomarkers. Pembrolizumab and nivolumab are now approved for esophageal squamous carcinoma but much more data are needed to understand how these agents may be used in non-metastatic settings. Novel treatments are still required as overall prognosis remains poor.

SSAT State-of-the-Art Conference: Advancements in the Microbiome.

The microbiome plays a major role in human physiology by influencing obesity, inducing inflammation, and impacting cancer therapies. During the 60th Annual Meeting of the Society of the Alimentary Tract (SSAT) at the State-of-the-Art Conference, experts in the field discussed the influence of the microbiome. This paper is a summary of the influence of the microbiome on obesity, inflammatory bowel disease, pancreatic cancer, cancer therapies, and gastrointestinal optimization. This review shows how the microbiome plays an important role in the development of diseases and surgical complications. Future studies are needed in targeting the gut microbiome to develop individualized therapies.

Ipilumumab for hepatocellular cancer in a liver transplant recipient, with durable response, tolerance and without allograft rejection.

Organ transplant recipients are not routinely included in clinical trials, and as a result there is a paucity of data to guide clinicians in the treatment of malignancies in this unique patient population. This is a case report and focused review of the treatment of hepatocellular carcinoma in patients with orthotopic liver transplants. We describe a single patient's treatment over a period of 4 years from the time of diagnosis to submission of this case report. We submit evidence that the anti-CTLA-4 antibody ipilimumab can produce a durable response, with a tolerable adverse event profile and without associated allograft rejection.

Pharmacotherapy for metastatic esophageal cancer: where do we need to improve?

INTRODUCTION: Esophageal cancer is a heterogeneous cancer comprised of differing cells of origin, molecular changes, and immune microenvironments. To date, most advances have been made in chemotherapy regimens where a one-size-fits-all approach is used. As a result, there remains a lack of tailored treatment options for such a heterogeneous cancer. This paper highlights the current standard of care treatment options as well as active areas of clinical research. AREAS COVERED: The authors review the key trials that have led to current standard of care treatment including pivotal chemotherapy and targeted therapy trials. The authors then discuss the current approved uses and future directions for immunotherapy. EXPERT OPINION: Current treatment options lack tailored treatment strategies based on the tumor's biology. To date, approved targeted approaches only include HER2-directed and anti-VEGFR2 therapies. Furthermore, while immunotherapy treatment response is often durable, few clear predictive biomarkers for response have been identified. Future research should focus on characterizing additional molecular targets for therapeutic intervention and predictive biomarkers for immunotherapy, as well as combination approaches of immunotherapy with other therapeutic modalities to increase response rate. Ultimately, the field should strive to develop personalized treatment options based on a tumor's molecular profile, microenvironment, and neo-antigen expression.

Harnessing the Microbiome for Pancreatic Cancer Immunotherapy.

Late-stage pancreatic cancer harbors a fibrotic and immune-excluded tumor microenvironment that impedes immunotherapy success. A key to unlocking pancreatic cancer immunotherapy may be treating early-stage pancreatic cancer, when peripancreatic inflammation promoted by the microbiome potentiates oncogenic signaling and suppresses innate and adaptive immunity. Hence, understanding the role of microbiota in pancreatic cancer initiation, progression, and immunosuppression is crucial. We propose that not only are microbiota targets for immunomodulation in this disease, but also that microbiome profiling has a potential role in pancreatic cancer screening. Furthermore, combining microbiome profiling with liquid and tissue biopsy may validate the early pancreatic cancer treatment approach of microbiome modulation and immunotherapy.

Impact of tumor board recommendations on treatment outcome for locally advanced head and neck cancer.

BACKGROUND/AIMS: To identify physician selection factors in the treatment of locally advanced head and neck cancer and how treatment outcome is affected by Tumor Board recommendations. METHODS: A retrospective analysis of 213 patients treated for locally advanced head and neck cancer in a single institution was performed. All treatments followed Tumor Board recommendations: 115 patients had chemotherapy and radiation, and 98 patients received postoperative radiation. Patient characteristics, treatment toxicity, locoregional control and survival between these two treatment groups were compared. Patient survival was compared with survival data reported in randomized studies of locally advanced head and neck cancer. RESULTS: There were no differences in comorbidity factors, and T or N stages between the two groups. A statistically significant number of patients with oropharyngeal and oral cavity tumors had chemoradiation and postoperative radiation, respectively (p < 0.0001). Grade 3-4 toxicities during treatment were 48 and 87% for the postoperative radiation and chemoradiation groups, respectively (p = 0.0001). There were no differences in survival, locoregional recurrences and distant metastases between the two groups. Patient survival was comparable to survival rates reported by randomized studies of locally advanced head and neck cancer. CONCLUSION: Disease sites remained the key determining factor for treatment selection. Multidisciplinary approaches provided optimal treatment outcome for locally advanced head and neck cancer, with overall survival in these patients being comparable to that reported in randomized clinical trials.

Can we downstage locally advanced pancreatic cancer to resectable? A phase I/II study of induction oxaliplatin and 5-FU chemoradiation.

BACKGROUND: Half of patients with pancreatic adenocarcinoma (PC) present with regionally advanced disease. This includes borderline resectable and locally advanced unresectable tumors as defined by current NCCN guidelines for resectability. Chemoradiation (CH-RT) is used in this setting in attempt to control local disease, and possibly downstage to resectable disease. We report a phase I/II trial of a combination of 5FU/Oxaliplatin with concurrent radiation in patients presenting with borderline resectable and locally advanced unresectable pancreatic cancer. METHODS: Patients with biopsy-proven borderline resectable or locally advanced unresectable PC were eligible. Chemotherapy included continuous infusion 5FU (200 mg/m2) daily and oxaliplatin weekly for 5 weeks in dose escalation cohorts, ranging from 30 to 60 mg/m2. Concurrent radiation therapy consisted of 4,500 cGy in 25 fractions (180 cGy/fx/d) followed by a comedown to the tumor and margins for an additional 540 cGy ×3 (total dose 5,040 cGy in 28 fractions). Following completion of CH-RT, patients deemed resectable underwent surgery; those who remained unresectable for cure but did not progress (SD, stable disease) received mFOLFOX6 ×6 cycles. Survival was calculated using Kaplan-Meier analysis. End-points of the phase II portion were resectability and overall survival. RESULTS: Overall, 24 subjects (15 men and 9 women, mean age 64.5 years) were enrolled between June 2004 and December 2009 and received CH-RT. Seventeen patients were enrolled in the Phase I component of the study, fifteen of whom completed neoadjuvant therapy. Reasons for not completing treatment included grade 3 toxicities (1 patient) and withdrawal of consent (1 patient). The highest dose of oxaliplatin (60 mg/m2) was well tolerated and it was used as the recommended phase II dose. An additional 7 patients were treated in the phase II portion, 5 of whom completed CH-RT; the remaining 2 patients did not complete treatment because of grade 3 toxicities. Overall, 4/24 did not complete CH-RT. Grade 4 toxicities related to initial CH-RT were observed during phase I (n=2, pulmonary embolism and lymphopenia) and phase II (n=3, fatigue, leukopenia and thrombocytopenia). Following restaging after completion of CH-RT, 4 patients had progressed (PD); 9 patients had SD and received additional chemotherapy with mFOLFOX6 (one of them had a dramatic response after two cycles and underwent curative resection); the remaining 7 patients (29.2%) were noted to have a response and were explored: 2 had PD, 4 had SD, still unresectable, and 1 patient was resected for cure with negative margins. Overall 2 patients (8.3%) in the study received curative resection following neoadjuvant therapy. Median overall survival for the entire study population was 11.4 months. Overall survival for the two resected patients was 41.7 and 21.6 months. CONCLUSIONS: Combined modality treatment for borderline resectable and locally advanced unresectable pancreatic cancer with oxaliplatin, 5FU and radiation was reasonably well tolerated. The majority of patients remained unresectable. Survival data with this regimen were comparable to others for locally advanced pancreas cancer, suggesting the need for more novel approaches.

The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression.

We found that the cancerous pancreas harbors a markedly more abundant microbiome compared with normal pancreas in both mice and humans, and select bacteria are differentially increased in the tumorous pancreas compared with gut. Ablation of the microbiome protects against preinvasive and invasive pancreatic ductal adenocarcinoma (PDA), whereas transfer of bacteria from PDA-bearing hosts, but not controls, reverses tumor protection. Bacterial ablation was associated with immunogenic reprogramming of the PDA tumor microenvironment, including a reduction in myeloid-derived suppressor cells and an increase in M1 macrophage differentiation, promoting TH1 differentiation of CD4+ T cells and CD8+ T-cell activation. Bacterial ablation also enabled efficacy for checkpoint-targeted immunotherapy by upregulating PD-1 expression. Mechanistically, the PDA microbiome generated a tolerogenic immune program by differentially activating select Toll-like receptors in monocytic cells. These data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of PDA and that the microbiome has potential as a therapeutic target in the modulation of disease progression.Significance: We found that a distinct and abundant microbiome drives suppressive monocytic cellular differentiation in pancreatic cancer via selective Toll-like receptor ligation leading to T-cell anergy. Targeting the microbiome protects against oncogenesis, reverses intratumoral immune tolerance, and enables efficacy for checkpoint-based immunotherapy. These data have implications for understanding immune suppression in pancreatic cancer and its reversal in the clinic. Cancer Discov; 8(4); 403-16. ©2018 AACR.See related commentary by Riquelme et al., p. 386This article is highlighted in the In This Issue feature, p. 371.

RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity.

Update on clinical data with regimens inhibiting angiogenesis and epidermal growth factor receptor for patients with newly diagnosed metastatic colorectal cancer.

As a result of the development of novel chemotherapeutic drugs and targeted biologic agents, the treatment of colon cancer has changed significantly over the past 10 years. Today, we have more active agents to use in colon cancer than ever before. The better understanding underlying the pathogenesis of this disease at the molecular level has allowed us to take advantage of 2 key pathways, the angiogenic and epidermal growth factor (EGF) signaling pathways. The combination of traditional chemotherapy drugs with agents that inhibit these pathways has led to a significant improvement in survival. At present, patients with metastatic colon cancer routinely achieve a median survival time > 2 years. The numerous agents available have made the choice of initial treatment more difficult for a newly diagnosed patient. Herein, we review the 2 main molecular targets of biologic therapy in colon cancer and examine the clinical evidence for regimens that inhibit angiogenesis and EGF receptor alone or in combination for newly diagnosed metastatic colorectal cancer.

Controversies in the treatment of local and locally advanced gastric and esophageal cancers.

Despite overall progress in the therapy of local and locally advanced esophageal, gastroesophageal junction, and gastric adenocarcinomas, death as a result of these tumors remains a common outcome. Most randomized phase III trials on which level-one evidence has been built have included the heterogeneous histologies and locations associated with these tumors. However, the different etiologies, molecular biology, and recurrence patterns associated with gastroesophageal malignancies suggest the need to split rather than lump. Biologic and response differences exist between squamous and adenocarcinomas, as well as diffuse and intestinal histologies. This may be a cause behind conflicting outcomes in similar trials. The accepted standard of chemoradiotherapy for locally advanced esophageal and gastroesophageal junction cancers is based on a few positive trials, with the best chemotherapy and total dose of radiation remaining controversial. In the West, the staging evaluations of locally advanced gastric cancer are not uniform. Yet, these evaluations will inform the results of preoperative and perioperative treatments. Although postoperative chemoradiotherapy for gastric cancer has been an accepted treatment option for the last decade, more recent studies have called into question the need for radiotherapy. In perioperative strategies, it has yet to be determined whether histologic or molecular changes in the operative specimen should inform postoperative treatment. An appropriate place for targeted therapy needs to be found in preoperative and postoperative treatment regimens. Finally, because so much is lost when trials are forced to close for lack of accrual, it is imperative to build multidisciplinary consensus before they are launched.