Understanding Immune Tolerance of Cancer: Re-Purposing Insights from Fetal Allografts and Microbes.

Cancer cells seem to exploit mechanisms that evolve as part of physiological tolerance, which is a complementary and often beneficial form of defense. The study of physiological systems of tolerance can therefore provide insights into the development of a state of host tolerance of cancer, and how to break it. Analysis of these models has the potential to improve our understanding of existing immunological therapeutic targets, and help to identify future targets and rational therapeutic combinations. The treatment of cancer with immune checkpoint inhibitors aims to reverse the progression to tolerance of cancer, and achieve an immunogenic, rather than tolerogenic, homeostasis. Broadening the efficacy and durability of checkpoint inhibitors focuses on reversing tolerance and stimulating immunogenicity in the cancer, host, and environment. Two examples of important physiological states of tolerance that may inform tolerance of cancer are microbial infection and placental reproduction. These states of tolerance result from bilateral shaping of host and non-self, akin to immunoediting in cancer, and offer reliable models to study the immune tolerance paradigm.

"Standard Care" in Cancer Clinical Trials: An Analysis of Care Provided to Women in the Control Arms of Breast Cancer Clinical Trials.

Background: For trials to validly evaluate new treatments, comparison against the best existing alternative treatment is essential. We reviewed the care provided to women in control arms of breast cancer clinical trials to estimate the proportion consistent with the standard of care as defined in clinical guidelines. Methods: We analyzed phase III randomized controlled breast cancer trials comparing drug treatments with "standard care," enrolling between 2004 and 2014, and registered on ClinicalTrials.gov Our primary outcome was the proportion of trials in which treatment in the control arm was consistent with concurrent NCCN Guidelines. A secondary analysis assessed trials recruiting outside the United States that provided control group therapy not consistent with NCCN Guidelines, comparing them with the German Gynecological Oncology Group (AGO) guidelines. We assessed associations between the primary outcome and a priori selected trial characteristics. Results: This study included 210 trials that recruited 229,182 women worldwide; 29% of trials (60/210) did not provide control group treatment that was consistent with NCCN Guidelines. For trials not recruiting in the United States, results were similar; in 21% of trials, control arm treatment was inconsistent with both AGO and NCCN Guidelines. Factors significantly associated with offering control arm treatment that were inconsistent with guidelines were time period (later trials were less likely to be consistent), breast cancer stage and type (trials in early-stage breast cancer and estrogen receptor-negative disease were less likely consistent), and recruitment in ≥4 countries and recruitment outside the United States. Conclusions: To ensure that clinical trials achieve their goal of obtaining the best information to guide patient treatment, the question of how investigators chose and describe "standard care" for control arm participants warrants further investigation.

Oligometastatic colorectal adenocarcinoma to the spleen and ovaries.

In the context of colorectal cancer, splenic and ovarian metastases are rare outside of widely disseminated disease. Growing evidence suggests that 'oligometastatic' or limited metastatic disease can be treated surgically with good oncological outcomes. Splenic and ovarian metastases are not well represented in studies of oligometastatic colorectal cancer, resulting in uncertainty in the best management for these patients. We present the case of a 78-year-old woman diagnosed with oligometastatic colorectal cancer to bilateral ovaries and spleen, 5 years after resection of a primary colon cancer. The patient was treated with a bilateral salpingo-oopherectomy and subsequent open splenectomy. We discuss the role of surgery and peri-operative chemotherapy in the management of oligometastatic colorectal cancer involving atypical sites.

Rate of cancer progression as a predictive marker of efficacy of immunotherapy; an analysis in metastatic non-small-cell lung cancer.

Aim: To explore the value of rate of cancer progression (ROP) prior to starting PD-1 inhibitors as a predictive and prognostic biomarker. Materials & methods: Retrospective data of patients with metastatic non-small-cell lung cancer treated with second-line PD-1 inhibitors were collected. Patients were divided into two groups: slow and rapid based on their ROP. Results: A total of 73 patients were eligible. Progression-free survival (PFS) was significantly shorter in rapid ROP, compared with slow (1.7 vs 4.8 months; HR: 2.42; 95% CI: 1.36-4.30; p = 0.008), as was the overall survival (OS; 5.6 vs 18.7 months; HR: 2.30; 95% CI: 1.13-4.69; p = 0.02). Overall response rate (40 vs 17%) was numerically higher in slow ROP than rapid (p = 0.19). PFS/OS did not correlate with the best response to their last chemotherapy or time to progression from previous line of therapy. Presence of a targetable mutation negatively correlated with PFS/OS. Conclusion: ROP prior to starting PD-1 inhibitors correlates with survival. PFS/OS were shorter in rapid ROP.

Immunotherapy in Non-Small Cell Lung Cancer: Shifting Prognostic Paradigms.

Immune checkpoint inhibitors have shown efficacy in the treatment of non-small cell lung cancer (NSCLC) in the adjuvant, first- and subsequent-line settings. In metastatic disease, they provide hope of durable response where “best-case” scenario has long been inadequate. This progress has highlighted the immunogenic nature of NSCLC and invigorated research into immunotherapy in the field. In this review we consider the foundations of immunotherapy in NSCLC, canvass the current research and summarise the evidence guiding clinical practice.

EGFR-Co-Mutated Advanced NSCLC and Response to EGFR Tyrosine Kinase Inhibitors.

OBJECTIVES: The evolution of EGFR tyrosine kinase inhibitors (TKIs) has changed the landscape of disease for a subset of patients with NSCLC. Most patients with an EGFR mutation respond to these drugs; however, a proportion show limited or no tumor response. We explored the impact of co-mutation (double or multiple mutation), compared with a single mutation, of the EGFR gene on response to TKIs in a series of patients with metastatic NSCLC. METHODS: We retrospectively analyzed the mutation profiles of nonsquamous NSCLC tested at Royal Prince Alfred Hospital between 2012 and 2015 by MassArray using the OncoCarta v1.0 panel. Patients with metastatic disease whose tumors had sensitizing EGFR mutation(s) were included. The primary end point was progression-free survival (PFS). We used the Kaplan-Meier method for PFS and overall survival; the log rank test was used to compare groups with and without co-mutation. Multivariable analysis was done for PFS; response rate was assessed using chi-square and logistic regression analysis. RESULTS: A total of 62 patients were included, and of these, eight (12.9%) had a co-mutation. The median PFS and overall survival times were 11.5 and 26.3 months, respectively. Patients with EGFR co-mutation had a significantly shorter median PFS than those with a single mutation (5.7 months versus 12.3 months, p = 0.02). The response rate to TKIs was significantly worse in those with co-mutation compared with in those without co-mutation (38% versus 89%, p < 0.001). CONCLUSIONS: Taking into account the small number of patients in this study, PFS in patients with EGFR co-mutation appeared significantly shorter, and response rate significantly lower, than in patients with a single mutation. Data from multipanel testing may identify subgroups of patients who are likely to respond poorly to standard treatment. Clarification of these subgroups may improve patient care.