Real-World Safety and Effectiveness of a Bevacizumab Biosimilar (ABP 215) in Metastatic Colorectal Cancer Patients in Canada.

BACKGROUND: ABP 215 is a biosimilar to the reference product, bevacizumab, and was one of the first biosimilars approved by Health Canada for the first-line treatment of metastatic colorectal cancer (mCRC). This study aimed to address gaps in real-world evidence (RWE) including patient characteristics, treatment safety (primary objective), and effectiveness (secondary objective) for first-line ABP 215 therapy in Canadian patients with mCRC. MATERIALS AND METHODS: Retrospective data were collected in 2 waves, at least 1 year (Wave 1) or 2 years (Wave 2) after commercial availability of ABP 215 at each participating site. RESULTS: A total of 75 patients from Wave 1 and 164 patients from Wave 2 treated with a minimum of 1 cycle of ABP 215 were included. At least one safety event of interest (EOI) was recorded for 34.7% of Wave 1 and 42.7% of Wave 2 patients. The median progression free survival (PFS) for Wave 1 and 2 patients were 9.47 (95% confidence interval [CI]: 6.71, 11.90) and 21.38 (95% CI: 15.82, not estimable) months, respectively. Median overall survival was not estimable for Wave 1 and was 26.45 months for Wave 2. CONCLUSION: The safety and effectiveness of ABP 215 observed in this real-world study were comparable to clinical trial findings and to other RWE with longer PFS in the current study.

Optimizing the delivery of genetic and advanced diagnostic testing in the province of Ontario: challenges and implications for laboratory technology assessment and management in decentralized healthcare systems.

AIMS: The Canadian province of Ontario provides full coverage for its residents (pop.14.8 M) for hospital-based diagnostic testing. Historical governance of the healthcare system and a legacy scheme of health technology assessment (HTA) and financing has led to a suboptimal approach of adopting advanced diagnostic technology (i.e. protein expression, cytogenetic, and molecular/genetic) for guiding therapeutic decisions. The aim of this research is to explore systemic barriers and provide guidance to improve patient and care provider experiences by reducing delays and inequity of access to testing, while benefitting laboratory innovators and maximizing system efficiency. MATERIALS AND METHODS: A mixed-methods approach including literature review, semi-structured interviews, and a multi-stakeholder forum involving patient representatives (n = 1), laboratory leaders (n = 6), physicians (n = 5), Ministry personnel (n = 4), administrators (n = 3), extra-provincial experts, and researchers (n = 7), as well as pharmaceutical (n = 5) and diagnostic companies (n = 2). The forum considered evidence of good practices in adoption, implementation, and financing laboratory services and identified barriers as well as feasible options for improving advanced diagnostic testing in Ontario. RESULTS: Overarching challenges identified included: barriers to define what is needed; need for a clear approach to adoption; and the need for more oversight and coordination. Recommendations to address these included a shift to an anticipatory system of test adoption, creating a fit-for-purpose system of health technology management that consolidates existing evaluation processes, and modernizing the governance and financing of testing so that it is managed at a care-delivery level. CONCLUSIONS: The proposals for change in Ontario highlight the role that HTA, governance, and financing of health technology play along the continuum of a health technology life cycle within a healthcare system where decision-making is highly decentralized. Resource availability and capacity were not a concern - instead, solutions require higher levels of coordination and system integration along with innovative approaches to HTA.

UV-inducible base excision repair of oxidative damaged DNA in human cells.

Methylene blue (MB) acts as a photosensitizer and after excitation by visible light (VL) produces reactive oxygen species that result in oxidatively damaged DNA. (MB + VL) produces predominantly 8-hydroxyguanine as well as other single base modifications in DNA that are repaired by base excision repair (BER). We have used a recombinant non-replicating human adenovirus, Ad5HCMVlacZ, which expresses the beta-galactosidase (beta-gal) reporter gene, to examine the role of the p53 tumor suppressor in constitutive and inducible BER of MB + VL-damaged DNA in human cells. Host cell reactivation (HCR) of beta-gal activity for MB + VL-treated Ad5HCMVlacZ was examined in normal human fibroblasts and several transformed and tumor cell lines with compromised p53 function using both non-treated cells and cells pretreated with ultraviolet light of 200-280 nm wavelength (UVC). Constitutive HCR of the MB + VL-treated reporter gene in untreated cells did not correlate with wild-type p53 expression levels, suggesting that factors other than p53 expression levels can influence constitutive BER of the reporter gene. UVC pre-treatment of the normal fibroblast strains resulted in an enhanced HCR of the MB + VL-treated reporter gene and a concomitant increase in the expression of p53, suggesting that p53 may be involved in UV-inducible BER in normal human fibroblasts. In contrast, p53 expression did not correlate with HCR values for the p53-compromised cells in UVC-pre-treated cells. In particular, the SKOV-3, LFS 087 and NF-E6 cells showed no up-regulation of p53 expression following UVC, and yet these cells showed significant enhancement of HCR following UVC pre-treatment. These results indicate that BER of MB + VL-damaged DNA is inducible in human cells by pre-UVC treatment and that the enhancement in BER may result from both p53-dependent and p53-independent mechanisms.

A case of isolated rectal recurrence of muscle invasive bladder cancer.

We present the case of a 53-year-old man with a 25-pack/year smoking history and a 6-month history of gross hematuria, who presented with a pT3a, N0, M0, muscle invasive bladder cancer (MIBC). He declined neoadjuvant chemotherapy, but received post-cystectomy adjuvant chemotherapy. Six months post-adjuvant chemotherapy, he presented with abdominal pain and a large bowel obstruction, and was found to have an isolated rectal recurrence of MIBC. This case illustrates 2 important issues: (1) patients with a smoking history and symptoms of hematuria need to be carefully evaluated to rule out urothelial cancer; and (2) in patients with muscle invasive disease, local pelvic recurrence is common and close surveillance for recurrence needs to be implemented.

Hypoxia disrupts the Fanconi anemia pathway and sensitizes cells to chemotherapy through regulation of UBE2T.

BACKGROUND AND PURPOSE: Hypoxia is a common feature of the microenvironment of solid tumors which has been shown to promote malignancy and poor patient outcome through multiple mechanisms. The association of hypoxia with more aggressive disease may be due in part to recently identified links between hypoxia and genetic instability. For example, hypoxia has been demonstrated to impede DNA repair by down-regulating the homologous recombination protein RAD51. Here we investigated hypoxic regulation of UBE2T, a ubiquitin ligase required in the Fanconi anemia (FA) DNA repair pathway. MATERIALS AND METHODS: We analysed UBE2T expression by microarray, quantitative PCR and western blot analysis in a panel of cancer cell lines as a function of oxygen concentration. The importance of this regulation was assessed by measuring cell survival in response to DNA damaging agents under normoxia or hypoxia. Finally, HIF dependency was determined using knockdown cell lines and RCC4 cells which constitutively express HIF1α. RESULTS: Hypoxia results in rapid and potent reductions in mRNA levels of UBE2T in a panel of cancer cell lines. Reduced UBE2T mRNA expression is HIF independent and was not due to changes in mRNA or protein stability, but rather reflected reduced promoter activity. Exposure of tumor cells to hypoxia greatly increased their sensitivity to treatment with the interstrand crosslinking (ICL) agent mitomycin C. CONCLUSIONS: Exposure to hypoxic conditions down-regulates UBE2T expression which correlates with an increased sensitivity to crosslinking agents consistent with a defective Fanconi anemia pathway. This pathway can potentially be exploited to target hypoxic cells in tumors.

Depletion of poly(ADP-ribose) polymerase-1 reduces host cell reactivation of a UV-damaged adenovirus-encoded reporter gene in human dermal fibroblasts.

In response to ultraviolet radiation (UV), mammalian cells rapidly activate a nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP), and we recently showed that one of the causes for PARP-activation is UV-induced direct DNA photolesions which are repaired by nucleotide excision repair process (NER). To determine whether PARP can play a role in NER, we stably depleted PARP in NER-proficient human skin fibroblasts GM637 by DNA vector-based RNAi. In these cells, we examined host cell reactivation (HCR) of UVB or UVC-irradiated recombinant adenovirus AdCA35lacZ, encoding a beta-galactosidase (beta-gal) reporter gene. The depletion of PARP decreased the HCR of UVB- or UVC-damaged reporter gene to a similar extent, indicating the role of PARP in NER. Moreover, PARP-depletion reduced the HCR capacity of the NER-competent GM637 cells to a level closer to that in the XP-C and CS-B cell lines, which are deficient in the lesion recognition steps of the global genome repair (GGR) and transcription-coupled repair (TCR) sub-pathways of NER, respectively. In order to identify the potential role of PARP in these two sub-pathways of NER from that of its known role in base excision repair (BER) of UVB-induced oxidant damage, we depleted PARP from XP-C and CS-B cells and examined HCR of the reporter gene damaged by UVB, UVC or photoactivated methylene blue, the latter causing predominantly 8-oxo-2'-deoxyguanosine damage that is repaired by BER. Interestingly, a decreased HCR due to PARP-depletion was observed in both the NER-deficient cell lines in response to virus damaged by these three agents, albeit with different kinetics from 12 to 44h after infection. The role of PARP in NER was highlighted by a decreased clonogenic survival of UV-irradiated NER-competent GM637 cells depleted of PARP. Our results, while confirming the role of PARP in base excision repair, suggest a novel role of PARP in both the GGR and TCR sub-pathways of NER.

Deficient base excision repair of oxidative DNA damage induced by methylene blue plus visible light in xeroderma pigmentosum group C fibroblasts.

Methylene blue plus visible light (MB+VL) results in oxidative DNA damage, producing predominantly 7,8-dihydroxy-8-oxoguanine and other single base modifications that are repaired by base excision repair (BER). AdCA17 is non-replicating recombinant human adenovirus that infects human cells and expresses the beta-galactosidase (beta-gal) reporter gene. We have examined host cell reactivation (HCR) of beta-gal activity for (MB+VL)-treated AdCA17 in cells from patients with xeoroderma pigmentosum from complementation group C (XP-C). HCR was substantially reduced in an SV40 transformed XP-C fibroblast compared to two SV40-transformed normal cells and in three XP-C primary fibroblast strains compared to four normal strains for both untreated and UVC-treated cells. These results indicate an involvement of the XPC gene in BER of MB+VL-induced oxidative DNA damage. In addition, pre-UVC-treatment of both normal and XP-C fibroblasts resulted in enhanced HCR of the MB+VL-treated reporter gene giving evidence for a UVC-inducible and XPC-independent BER pathway in human cells.