Durable Response to PD1 Inhibitor Pembrolizumab in a Metastatic, Metaplastic Breast Cancer.

Metaplastic breast cancer (MBC) is a rare and aggressive subtype of breast cancer. Tumor characteristics typically feature estrogen receptor, progesterone receptor, and HER2-negative, triple-negative breast cancer (TNBC), with a poorer prognosis relative to pure invasive ductal or lobular disease. Resistance to chemotherapy often leads to local recurrence and distant metastasis. Genomic profiling has identified multiple molecular abnormalities that may translate to targetable therapies in MBC. These tumors are known to display higher PD-L1 expressivity than other subtypes of breast cancer, and disease control with pembrolizumab and chemotherapy has been documented. We identify a patient with metastatic, metaplastic TNBC, with mesenchymal components and osseous differentiation, who completed 2 years of pembrolizumab treatment and has remained without evidence of disease after 32 months of observation, while maintaining good quality of life. Future efforts should focus on immunotherapy response with respect to the various subtypes of MBC, and treatment should continue to be incorporated in clinical trials to maximize disease response.

Immune Activation and Benefit From Avelumab in EBV-Positive Gastric Cancer.

Response to immune checkpoint therapy can be associated with a high mutation burden, but other mechanisms are also likely to be important. We identified a patient with metastatic gastric cancer with meaningful clinical benefit from treatment with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab. This tumor showed no evidence of high mutation burden or mismatch repair defect but was strongly positive for presence of Epstein-Barr virus (EBV) encoded RNA. Analysis of The Cancer Genome Atlas gastric cancer data (25 EBV+, 80 microsatellite-instable [MSI], 310 microsatellite-stable [MSS]) showed that EBV-positive tumors were MSS. Two-sided Wilcoxon rank-sum tests showed that: 1) EBV-positive tumors had low mutation burden (median = 2.07 vs 3.13 in log10 scale, P < 10-12) but stronger evidence of immune infiltration (median ImmuneScore 2212 vs 1295, P < 10-4; log2 fold-change of CD8A = 1.85, P < 10-6) compared with MSI tumors, and 2) EBV-positive tumors had higher expression of immune checkpoint pathway (PD-1, CTLA-4 pathway) genes in RNA-seq data (log2 fold-changes: PD-1 = 1.85, PD-L1 = 1.93, PD-L2 = 1.50, CTLA-4 = 1.31, CD80 = 0.89, CD86 = 1.31, P < 10-4 each), and higher lymphocytic infiltration by histology (median tumor-infiltrating lymphocyte score = 3 vs 2, P < .001) compared with MSS tumors. These data suggest that EBV-positive low-mutation burden gastric cancers are a subset of MSS gastric cancers that may respond to immune checkpoint therapy.

Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma: an operational approach for clinical trials.

An operationalized workflow paradigm is presented and validated with pilot subject data. This approach is reproducible with a high concordance rate between individual readers (kappa 0.73 [confidence interval 0.59-0.87; P=<0.0001]) using a 5-point scale to assess [18F] labeled fluorodeoxyglucose metabolic activity in lymphomatous lesions. These results suggest an operationally practical 5-point scale workflow paradigm for potential use in larger clinical trials evaluating lymphoma therapeutics.

BRAF Fusion as a Novel Mechanism of Acquired Resistance to Vemurafenib in BRAFV600E Mutant Melanoma.

Purpose: Many patients with BRAFV600E mutant melanoma treated with BRAF inhibitors experience a rapid response, but ultimately develop resistance. Insight into the mechanism of resistance is critical for development of more effective treatment strategies.Experimental Design: Comprehensive genomic profiling of serial biopsies was performed in a patient with a BRAFV600E mutant metastatic melanoma who developed resistance to vemurafenib. An AGAP3-BRAF fusion gene, identified in the vemurafenib-resistant tumor, was expressed in BRAFV600E melanoma cell lines, and its effect on drug sensitivity was evaluated.Results: Clinical resistance to vemurafenib in a melanoma harboring a BRAFV600E mutation was associated with acquisition of an AGAP3-BRAF fusion gene. Expression of the AGAP3-BRAF fusion in BRAFV600E mutant melanoma cells induced vemurafenib resistance; however, these cells remained relatively sensitive to MEK inhibitors. The patient experienced clinical benefit following treatment with the combination of a BRAF and a MEK inhibitor. Rebiopsy of the tumor at a later time point, after BRAF and MEK inhibitors had been discontinued, showed loss of the AGAP3-BRAF fusion gene. Mixing experiments suggest that cells harboring both BRAFV600E and AGAP3-BRAF only have a fitness advantage over parental BRAFV600E cells during active treatment with a BRAF inhibitor.Conclusions: We report acquisition of a BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in a patient with melanoma harboring a BRAFV600E mutation. The acquisition and regression of clones harboring this fusion during the presence and absence of a BRAF inhibitor are consistent with rapidly evolving clonal dynamics in melanoma. Clin Cancer Res; 23(18); 5631-8. ©2017 AACR.

Immune activation and response to pembrolizumab in POLE-mutant endometrial cancer.

Antibodies that target the immune checkpoint receptor programmed cell death protein 1 (PD-1) have resulted in prolonged and beneficial responses toward a variety of human cancers. However, anti-PD-1 therapy in some patients provides no benefit and/or results in adverse side effects. The factors that determine whether patients will be drug sensitive or resistant are not fully understood; therefore, genomic assessment of exceptional responders can provide important insight into patient response. Here, we identified a patient with endometrial cancer who had an exceptional response to the anti-PD-1 antibody pembrolizumab. Clinical grade targeted genomic profiling of a pretreatment tumor sample from this individual identified a mutation in DNA polymerase epsilon (POLE) that associated with an ultramutator phenotype. Analysis of The Cancer Genome Atlas (TCGA) revealed that the presence of POLE mutation associates with high mutational burden and elevated expression of several immune checkpoint genes. Together, these data suggest that cancers harboring POLE mutations are good candidates for immune checkpoint inhibitor therapy.

Detection of pars injury by SPECT in patients younger than age 10 with low back pain.

BACKGROUND: Evaluation of extension-based low back pain in young athletes with suspected pars injury may include a referral for skeletal single photon emission computed tomography (SPECT). However, the diagnostic yield of this technique in children with low back pain before the age of 10 years remains uncertain. We examined a series of consecutive SPECT scans to address this question. MATERIALS AND METHODS: A retrospective review of department databases revealed 107 consecutive skeletal Tc-99m MDP SPECT scans performed between January 1, 2007 and December 31, 2009 in children less than 10 years of age. Of these, 72 studies were performed for a referral diagnosis of back pain. There were 43 girls (44 studies) and 28 boys (28 studies). The mean age was 7.2 years (range, 1.9 to 9.9 y). All SPECT scans were reviewed and positive findings documented. In addition, all available anatomic imaging, imaging reports (computed tomography, magnetic resonance, and x-ray) and clinical notes were reviewed, and results were compared with those of SPECT studies. RESULTS: Of the 72 SPECT studies, 35 (49%) identified a focal area in the spine of abnormal increased uptake, with 17 in the region of the pars interarticularis. With additional imaging, 1 case was demonstrated not to be a pars injury (computed tomography showed a transverse process fracture) and 2 patients with negative SPECT scans were shown to have pars injuries that SPECT scan had not detected, for a total of 18 pars injuries (25%) in this cohort. Reported participation in gymnastics or football was related to pars injury (odds ratio 4.3, P=0.04). CONCLUSIONS: Pars injury was found in 25% of children referred for SPECT scan with back pain below 10 years of age. SPECT scan was highly sensitive for this injury as well as in identifying other potential sites of pathology, and should be considered in the workup of persistent low back pain in young children. LEVEL OF EVIDENCE: Level II, diagnostic study.

Amyloid plaque imaging agent [C-11]-6-OH-BTA-1: biodistribution and radiation dosimetry in baboon.

BACKGROUND: The amyloid neuritic plaque is considered to be a toxic collection of amyloid-ss protein found in brain tissue in Alzheimer's disease. A neutral analogue of the amyloid-binding thioflavin-T (BTA), has been radiolabeled as [C-11]-6-OH-BTA-1. It crosses the blood brain barrier, and is a promising tracer for imaging plaques in vivo using positron emission tomography. We now report the biodistribution and dosimetry of [C-11]-6-OH-BTA-1 in baboons. METHODS: Four 2-hour whole body studies were acquired in an ECAT ACCEL camera in two baboons after the bolus injection of [C-11]-6-OH-BTA-1. After 3.5 minute transmission scans performed per bed position prior to injection, emission scans were collected in 2-D mode over five bed positions. Regions of interest (ROI) were drawn around the brain, left and right lungs, heart, liver, gall bladder, left and right kidneys, spleen and urinary bladder. Since no fluid was removed from the baboons, total body radioactivity was calculated using the injected dose and a calibration factor determined from a cylinder phantom. The area under the curve (AUC) for each ROI was determined by trapezoidal integration of the first few points with subsequent points fit by a decreasing monoexponential. The AUC was then divided by counts in the total body, and resulting residence times were entered into the MIRDOSE3 program. RESULTS: The animals tolerated the procedure well. The ligand was eliminated via the hepatobiliary and renal systems. In the adult male and female reference the gallbladder received the highest estimated radiation dose and was the critical organ (3.9E-02 mGy/MBq and 4.3E-02 mGy/MBq respectively). CONCLUSION: In the United States, the absorbed dose to the gallbladder would limit [C-11]-6-OH-BTA-1 administered with the approval of a Radioactive Drug Research Committee (RDRC) to a single injection of 1295 MBq (35 mCi) in the adult male, and 1314 MBq (35 mCi) in the adult female.