Real-world experience with cabazitaxel in patients with metastatic castration-resistant prostate cancer: a final, pooled analysis of the compassionate use programme and early access programme.

BACKGROUND: Cabazitaxel is a second-generation taxane approved for use in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel. Early access programmes were established to allow eligible patients with mCRPC access to cabazitaxel before regulatory approval. MATERIALS AND METHODS: The primary objective was to allow access to cabazitaxel before commercial availability for patients with mCRPC whose disease had progressed during or after chemotherapy with docetaxel; the secondary objective was overall safety. Patients received cabazitaxel 25 mg/m2 on Day 1 of a 21-day cycle, with daily oral 10 mg prednisone/prednisolone. G-CSF was administered per ASCO guidelines. RESULTS: In total, 1432 patients received cabazitaxel across 41 countries between 2010 and 2014 (median 6.0 treatment cycles [range 1-49]). The most frequently occurring treatment-emergent adverse events (TEAEs) possibly related to treatment were diarrhoea (33.3%), fatigue (25.4%) and anaemia (23.7%); the most frequently occurring possibly related Grade 3/4 TEAEs were neutropenia (18.7%) and febrile neutropenia (6.9%). G-CSF was administered in ≥ 1 cycle in 64% of patients (10.1% therapeutic use; 57.8% prophylactic use; 9.7% both uses). CONCLUSION: The safety profile of cabazitaxel in this pooled analysis of two cabazitaxel early access programmes was manageable and consistent with previous Phase III trials (TROPIC, PROSELICA).

Immunohistochemical and molecular analysis of human melanomas for expression of the human cancer-testis antigens NY-ESO-1 and LAGE-1.

PURPOSE: NY-ESO-1 and LAGE-1 are homologous cancer-testis antigens, which are expressed in many different cancers. It is essential to type tumors accurately to assess patient suitability for clinical trials which target these. This study evaluates typing strategies used to distinguish these two homologous but distinct antigens and to characterize and quantitate expression of each in clinical samples. EXPERIMENTAL DESIGN: We typed 120 malignant melanomas for the expression of NY-ESO-1 and LAGE-1 with immunohistochemistry, reverse transcription-PCR (RT-PCR), and quantitative real-time (qRT-PCR), which was also used to explore the relationship between NY-ESO-1 and LAGE expression. RESULTS: The two monoclonal antibodies ES121 and E978 had very similar immunohistochemistry reactivities. Both were specific for NY-ESO-1 because neither bound to homologous LAGE-1 peptides despite 84% overall amino acid homology. Of 120 melanomas tested by immunohistochemistry, NY-ESO-1 was expressed in >50% of cells in 23 melanomas (19%), between 11 and 50% cells in 15 (12.5%), <11% cells in 16 (13.5%), and negative in 66 (55%). Although specific for both antigens, the PCR methods did not provide this information about microheterogeneity. Polymorphisms in the LAGE-1 gene resulted in false negative LAGE-1 typing by qRT-PCR by inhibiting binding of oligonucleotide primers, thereby showing the exquisite specificity of qRT-PCR as a typing method. CONCLUSIONS: For NY-ESO-1 typing, immunohistochemistry compared favorably with the RT-PCR, with the added advantage of being able to characterize heterogeneity of antigen expression. Because neither mAb bound LAGE and because there was no coordinate expression LAGE and NY-ESO-1, separate typing for each is required.

Human perforin mutations and susceptibility to multiple primary cancers.

Loss-of-function mutations in the gene coding for perforin (PRF1) markedly reduce the ability of cytotoxic T lymphocytes and natural killer cells to kill target cells, causing immunosuppression and impairing immune regulation. In humans, nearly half of the cases of type 2 familial hemophagocytic lymphohistiocytosis are due to bi-allelic PRF1 mutations. The partial inactivation of PRF1 due to mutations that promote protein misfolding or the common hypomorphic allele coding for the A91V substitution have been associated with lymphoid malignancies in childhood and adolescence. To investigate whether PRF1 mutations also predispose adults to cancer, we genotyped 566 individuals diagnosed with melanoma (101), lymphoma (65), colorectal carcinoma (30) or ovarian cancer (370). The frequency of PRF1 genotypes was similar in all disease groups and 424 matched controls, indicating that the PRF1 status is not associated with an increased susceptibility to these malignancies. However, four out of 15 additional individuals diagnosed with melanoma and B-cell lymphoma during their lifetime expressed either PRF1A91V or the rare pathogenic PRF1R28C variant (p = 0.04), and developed melanoma relatively early in life. Both PRF1A91V- and PRF1R28C-expressing lymphocytes exhibited severely impaired but measurable cytotoxic function. Our results suggest that defects in human PRF1 predispose individuals to develop both melanoma and lymphoma. However, these findings require validation in larger patient cohorts.