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.

Shared clonality in distinctive lesions of lymphomatoid papulosis and mycosis fungoides occurring in the same patients suggests a common origin.

Lymphomatoid papulosis (LyP) lies within the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders. Approximately 10% to 15% of patients with LyP develop other lymphomas, most commonly mycosis fungoides (MF), suggesting a biological relationship between these distinctive diseases. Here, we describe the clinical and histopathologic features of 11 patients who had both LyP and MF, including a total of 30 biopsy specimens (14 LyP and 16 MF). Clinically, LyP lesions were characterized by clustered papules undergoing spontaneous regression and were classified as type A (n = 11), type C (n = 2), or type D (n = 1). All cases of MF were characterized clinically by patch/plaque disease, were stage I or II at the time of diagnosis, and consisted of a CD4-predominant epidermotropic T-cell infiltrate. We used polymerase chain reaction-based methods to assess the TCR-ß chain (TCRB) and TCR-γ chain (TCRG) in both LyP and MF lesions of all patients. Monoclonal TCR gene rearrangements were detected in 13 LyP lesions from 10 of 11 patients and in 14 MF lesions from 10 of 11 patients. All 10 patients in whom their skin lesions carried monoclonal TCR gene rearrangements exhibited overlapping clones in both their LyP and MF lesions; additional non-overlapping clones were identified in 3 LyP lesions from 2 patients and 1 MF lesion from another patient. The demonstration of shared monoclonal T-cell receptor gene rearrangements in LyP and MF lesions in almost all patients suggests a common origin between these distinctive clinicopathological diseases.

Primary cutaneous carcinosarcoma: insights into its clonal origin and mutational pattern expression analysis through next-generation sequencing.

Primary cutaneous carcinosarcoma is a rare biphenotypic neoplasm exhibiting both epithelial and sarcomatous elements. Even though its origin and biological aspects remain poorly understood, it has been postulated that this tumor may arise from progenitor cells, which subsequently differentiate into distinct tumor components. We have investigated the histological and immunohistochemical staining patterns of a cutaneous carcinosarcoma case, as well as its ultrastructural aspects. In addition, sarcomatous and epithelial tumor components were separated by laser capture microdissection and subjected to targeted, high-depth, next-generation sequencing of a 46-cancer gene panel to asses the gene mutational pattern amongst both components. There were transitional cells at the epithelial/mesenchymal transition that labeled with putative progenitor cell markers (K19, c-kit, CD34 and Bcl-2). There was shared reactivity to antibodies directed against the progenitor cell marker EpCAM (epithelial cell adhesion molecule) in both components. Ultrastructurally, individual cells were demonstrated to have overlapping features of epithelial and mesenchymal differentiation. The mutational analysis revealed point mutations in exon 5 of TP53, which were identical in both the epithelial and sarcomatous components, and which were concordant with p53 expression at a tissue level. The aforementioned histological, ultrastructural, immunohistochemical and mutational pattern is strongly suggestive of a common clonal origin to the distinct elements of this tumor.