ATM Deficiency Sensitizes Mantle Cell Lymphoma Cells to Poly(ADP-Ribose) Polymerase-1 Inhibitors

Poly(ADP-ribose) polymerase-1 (PARP-1) inhibition is toxic to cells with mutations in the breast and ovarian cancer susceptibility genes BRCA1 or BRCA2, a concept termed synthetic lethality. However, whether this approach is applicable to other human cancers with defects in other DNA repair genes has yet to be determined. The ataxia telangiectasia mutated (ATM) gene is altered in several human cancers including mantle cell lymphoma (MCL). Here, we characterize a panel of MCL cell lines for ATM status and function and investigate the potential for synthetic lethality in MCL in the presence of small-molecule inhibitors of PARP-1. We show that Granta-519 and UPN2 cells have low levels of ATM protein, are defective in DNA damage-induced ATM-dependent signaling, are radiation sensitive, and have cell cycle checkpoint defects: all characteristics of defective ATM function. Significantly, Granta-519 and UPN2 cells were more sensitive to PARP-1 inhibition than were the ATM-proficient MCL cell lines examined. Furthermore, the PARP-1 inhibitor olaparib (known previously as AZD2281/KU-0059436) significantly decreased tumor growth and increased overall survival in mice bearing s.c. xenografts of ATM-deficient Granta-519 cells while producing only a modest effect on overall survival of mice bearing xenografts of the ATM-proficient cell line, Z138. Thus, PARP inhibitors have therapeutic potential in the treatment of MCL, and the concept of synthetic lethality extends to human cancers with ATM alterations

Crizotinib Inhibition of ROS1-Positive Tumours in Advanced Non-Small-Cell Lung Cancer: A Canadian Perspective

The ROS1 kinase is an oncogenic driver in non-small-cell lung cancer (NSCLC). Fusion events involving the ROS1 gene are found in 1%–2% of NSCLC patients and lead to deregulation of a tyrosine kinase–mediated multi-use intracellular signalling pathway, which then promotes the growth, proliferation, and progression of tumour cells. ROS1 fusion is a distinct molecular subtype of NSCLC, found independently of other recognized driver mutations, and it is predominantly identified in younger patients (<50 years of age), women, never-smokers, and patients with adenocarcinoma histology. Targeted inhibition of the aberrant ROS1 kinase with crizotinib is associated with increased progression-free survival (PFS) and improved quality-of-life measures. As the sole approved treatment for ROS1-rearranged NSCLC, crizotinib has been demonstrated, through a variety of clinical trials and retrospective analyses, to be a safe, effective, well-tolerated, and appropriate treatment for patients having the ROS1 rearrangement. Canadian physicians endorse current guidelines which recommend that all patients with nonsquamous advanced NSCLC, regardless of clinical characteristics, be tested for ROS1 rearrangement. Future integration of multigene testing panels into the standard of care could allow for efficient and cost-effective comprehensive testing of all patients with advanced nsclc. If a ROS1 rearrangement is found, treatment with crizotinib, preferably in the first-line setting, constitutes the standard of care, with other treatment options being investigated, as appropriate, should resistance to crizotinib develop

Canadian Perspectives: Update on Inhibition of ALK-Positive Tumours in Advanced Non-Small-Cell Lung Cancer

Background: Inhibition of the anaplastic lymphoma kinase (ALK) oncogenic driver in advanced non-small-cell lung carcinoma (NSCLS) improves survival. In 2015, Canadian thoracic oncology specialists published a consensus guideline about the identification and treatment of ALK-positive patients, recommending use of the ALK inhibitor crizotinib in the first line. New scientific literature warrants a consensus update. Methods: Clinical trials of ALK inhibitor were reviewed to assess benefits, risks, and implications relative to current Canadian guidance in patients with ALK-positive NSCLS. Results: Randomized phase III trials have demonstrated clinical benefit for single-agent alectinib and ceritinib used in treatment-naïve patients and as second-line therapy after crizotinib. Phase II trials have demonstrated activity for single-agent brigatinib and lorlatinib in further lines of therapy. Improved responses in brain metastases were observed for all second- and next/third-generation ALK tyrosine kinase inhibitors in patients progressing on crizotinib. Canadian recommendations are therefore revised as follows: (1) Patients with advanced nonsquamous NSCLS have to be tested for the presence of an ALK rearrangement. (2) Treatment-naïve patients with ALK-positive disease should initially be offered single-agent alectinib or ceritinib, or both sequentially. (3) Crizotinib-refractory patients should be treated with single-agent alectinib or ceritinib, or both sequentially. (4) Further treatments could include single-agent brigatinib or lorlatinib, or both sequentially. (5) Patients progressing on ALK tyrosine kinase inhibitors should be considered for pemetrexed-based chemotherapy. (6) Other systemic therapies should be exhausted before immunotherapy is considered. Summary: Multiple lines of ALK inhibition are now recommended for patients with advanced NSCLS with an ALK rearrangement

A Catalyst for Transforming Health Systems and Person-Centred Care: Canadian National Position Statement on Patient-Reported Outcomes

Background: Patient-reported outcomes (pros) are essential to capture the patient’s perspective and to influence care. Although pros and pro measures are known to have many important benefits, they are not consistently being used and there is there no Canadian pros oversight. The Position Statement presented here is the first step toward supporting the implementation of pros in the Canadian health care setting. Methods: The Canadian pros National Steering Committee drafted position statements, which were submitted for stakeholder feedback before, during, and after the first National Canadian Patient Reported Outcomes (canpros) scientific conference, 14–15 November 2019 in Calgary, Alberta. In addition to the stakeholder feedback cycle, a patient advocate group submitted a section to capture the patient voice. Results: The canpros Position Statement is an outcome of the 2019 canpros scientific conference, with an oncology focus. The Position Statement is categorized into 6 sections covering 4 theme areas: Patient and Families, Health Policy, Clinical Implementation, and Research. The patient voice perfectly mirrors the recommendations that the experts reached by consensus and provides an overriding impetus for the use of pros in health care. Conclusions: Although our vision of pros transforming the health care system to be more patient-centred is still aspirational, the Position Statement presented here takes a first step toward providing recommendations in key areas to align Canadian efforts. The Position Statement is directed toward a health policy audience; future iterations will target other audiences, including researchers, clinicians, and patients. Our intent is that future versions will broaden the focus to include chronic diseases beyond cancer