Experiences of adult cancer survivors in transitions.

PURPOSE: To understand the experiences of adult cancer survivors as they transition from the end of cancer treatment to follow-up care as a basis for developing actionable recommendations to integrate cancer care delivery and survivorship care. METHODS: A national survey was conducted in collaboration with ten Canadian provinces to identify unmet needs and experiences with follow-up for cancer survivors between 1 and 3 years post-treatment. Surveys were available in English and French and completed either on paper or on-line. Samples were drawn from provincial cancer registries and packages distributed by mail. RESULTS: A total of 40,790 survey packages were mailed out across the ten provinces and 12,929 surveys were completed by adults (age 30+ years), and 329 surveys were completed by adolescents and young adults (age 18 to 29 years) giving an overall response rate of 33.3%. For the purposes of this publication, the focus will be on the adult sample. In the adult cohort (age 30+ years), 51% of the sample were females, 60% were 65 years of age or older, and 77% had not experienced metastatic spread. Three-quarters reported their health as good/very good and 82% that their quality of life was good/very good. Overall, 87% experienced at least one physical concern, 78% experienced at least one emotional concern, and 44% experienced at least one practical concern. The average number of concerns reported for each domain ranged from 2.0 to 3.8. For those who sought help, a third experienced difficulty obtaining assistance or did not receive it. The most frequently cited reasons for not seeking help was that someone had told them what they were experiencing was normal. CONCLUSIONS: The results indicate that many adult survivors have concerns about physical, emotional, and practical issues but are not receiving help to reduce their suffering. It is imperative we take action to correct this current reality.

Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers.

Defects in epigenetic regulation play a fundamental role in the development of cancer, and epigenetic regulators have recently emerged as promising therapeutic candidates. We therefore set out to systematically interrogate epigenetic cancer dependencies by screening an epigenome-focused deep-coverage design shRNA (DECODER) library across 58 cancer cell lines. This screen identified BRM/SMARCA2, a DNA-dependent ATPase of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex, as being essential for the growth of tumor cells that harbor loss of function mutations in BRG1/SMARCA4. Depletion of BRM in BRG1-deficient cancer cells leads to a cell cycle arrest, induction of senescence, and increased levels of global H3K9me3. We further demonstrate the selective dependency of BRG1-mutant tumors on BRM in vivo. Genetic alterations of the mSWI/SNF chromatin remodeling complexes are the most frequent among chromatin regulators in cancers, with BRG1/SMARCA4 mutations occurring in ∼10-15% of lung adenocarcinomas. Our findings position BRM as an attractive therapeutic target for BRG1 mutated cancers. Because BRG1 and BRM function as mutually exclusive catalytic subunits of the mSWI/SNF complex, we propose that such synthetic lethality may be explained by paralog insufficiency, in which loss of one family member unveils critical dependence on paralogous subunits. This concept of "cancer-selective paralog dependency" may provide a more general strategy for targeting other tumor suppressor lesions/complexes with paralogous subunits.

The value of collecting population-based cancer stage data to support decision-making at organizational, regional and population levels.

The stage of a patient's cancer at diagnosis is essential to predict the prognosis and plan the treatment. Since 2008, stage data have been collected on all Ontario patients with breast, colorectal, lung and prostate cancers and are linked to other data collected by Cancer Care Ontario. Here, an analysis of such data is presented. How it can be used to assess the value of screening programs, inform resource allocation, evaluate compliance with treatment guidelines, compare survival trends and enhance the spectrum of cancer control activities across the province is demonstrated. International comparisons can also be made.

Evaluation of Factors Associated With Unmet Needs in Adult Cancer Survivors in Canada.

Importance: Understanding the challenges faced by an increasing number of cancer survivors can guide the development and implementation of effective survivorship care models. Objective: To identify the physical, emotional, and practical concerns and associated unmet needs reported by cancer survivors. Design, Setting, and Participants: This cross-sectional survey study obtained data from the Experiences of Cancer Patients in Transitions Study of the Canadian Partnership Against Cancer, in collaboration with cancer agencies in the 10 Canadian provinces, that was disseminated in 2016. This analysis included only adult survivors aged 30 years or older who underwent chemotherapy, radiation therapy, surgical treatment, or a combination of these therapies for breast, prostate, colorectal, melanoma, or hematological cancer within the past 1 to 3 years. Data synthesis and quality assessment were conducted in 2017. Data analysis was completed in July 2019. Main Outcomes and Measures: The outcomes were the (1) quantification of the magnitude and multiplicity of the physical, emotional, and practical concerns of adult survivors of breast, colorectal, prostate, melanoma, or hematological cancer; (2) exploration of the magnitude of associated unmet needs; and (3) identification of patient-, treatment-, and cancer-specific factors associated with the reporting of unmet needs. Results: Overall, 10 717 adult respondents were included (5660 [53%] female and 6367 [60%] aged ≥65 years). The median number of concerns per respondent was 6 (interquartile range [IQR], 3-10). Among respondents with concerns, help was sought for a median of 2 (IQR, 0-4) concerns. Unmet needs were reported for a median of 4 (IQR, 2-7) concerns. Emotional concerns were reported by 8330 respondents (78%), physical concerns by 9236 respondents (86%), and practical concerns by 4668 respondents (44%). At least 1 unmet need was reported by 7033 survivors (84%) with emotional concerns, 7475 (81%) with physical concerns, and 3459 (74%) with practical concerns. Age, sex, annual income, marital status, geographic location, language, and treatment type were significant factors associated with unmet needs. Survivors of melanoma cancer had a significantly higher likelihood of reporting unmet emotional needs (odds ratio [OR], 1.75; 95% CI, 1.17-2.61; P = .01), whereas survivors of prostate (OR, 0.60; 95% CI, 0.43-0.84; P < .001) and hematological (OR, 0.70; 95% CI, 0.50-0.99; P = .04) cancers were significantly less likely to report unmet needs for physical concerns when compared with breast cancer survivors. Involvement of the general practitioner combined with the oncologist in providing care was associated with a significantly lower likelihood of reporting unmet emotional (OR, 0.78; 95% CI, 0.62-1.00; P = .05) and practical (OR, 0.72; 95% CI, 0.55-0.94; P = .01) needs. Conclusions and Relevance: The extent of unmet needs among cancer survivors found in this study suggests the need for enhancements in survivorship care, including better awareness of the realities of survivorship, earlier interventions for emerging concerns among survivors, and greater integration of cancer programs and primary care for more seamless transitions.

Precision Targeted Therapy with BLU-667 for RET-Driven Cancers.

The receptor tyrosine kinase rearranged during transfection (RET) is an oncogenic driver activated in multiple cancers, including non-small cell lung cancer (NSCLC), medullary thyroid cancer (MTC), and papillary thyroid cancer. No approved therapies have been designed to target RET; treatment has been limited to multikinase inhibitors (MKI), which can have significant off-target toxicities and limited efficacy. BLU-667 is a highly potent and selective RET inhibitor designed to overcome these limitations. In vitro, BLU-667 demonstrated ≥10-fold increased potency over approved MKIs against oncogenic RET variants and resistance mutants. In vivo, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various RET mutations and fusions without inhibiting VEGFR2. In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with RET-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.Significance: Patients with RET-driven cancers derive limited benefit from available MKIs. BLU-667 is a potent and selective RET inhibitor that induces tumor regression in cancer models with RET mutations and fusions. BLU-667 attenuated RET signaling and produced durable clinical responses in patients with RET-altered tumors, clinically validating selective RET targeting. Cancer Discov; 8(7); 836-49. ©2018 AACR.See related commentary by Iams and Lovly, p. 797This article is highlighted in the In This Issue feature, p. 781.

The replication fork block protein Fob1 functions as a negative regulator of the FEAR network.

BACKGROUND: The protein phosphatase Cdc14 is a key regulator of exit from mitosis in budding yeast. Its activation during anaphase is characterized by dissociation from its inhibitor Cfi1/Net1 in the nucleolus and is controlled by two regulatory networks. The Cdc14 early anaphase release (FEAR) network promotes activation of the phosphatase during early anaphase, whereas the mitotic exit network (MEN) activates Cdc14 during late stages of anaphase. RESULTS: Here we investigate how the FEAR network component Spo12 regulates Cdc14 activation. We identify the replication fork block protein Fob1 as a Spo12-interacting factor. Inactivation of FOB1 leads to premature release of Cdc14 from the nucleolus in metaphase-arrested cells. Conversely, high levels of FOB1 delay the release of Cdc14 from the nucleolus. Fob1 associates with Cfi1/Net1, and consistent with this observation, we find that the bulk of Cdc14 localizes to the Fob1 binding region within the rDNA repeats. Finally, we show that Spo12 phosphorylation is cell cycle regulated and affects its binding to Fob1. CONCLUSIONS: Fob1 functions as a negative regulator of the FEAR network. We propose that Fob1 helps to prevent the dissociation of Cdc14 from Cfi1/Net1 prior to anaphase and that Spo12 activation during early anaphase promotes the release of Cdc14 from its inhibitor by antagonizing Fob1 function.

Analysis of Protein-Protein Interactions Between MEN Components.

The isolation of protein complexes is a powerful method to elucidate how signaling networks are regulated. Co-immunoprecipitation (co-IP) is a widely used procedure to detect and characterize the physical association of pathway components that has frequently been used to reveal mechanisms of pathway regulation. This chapter outlines the roles of protein-protein interactions in signal transduction and the regulatory functions such assemblies impart to cells. The principles behind co-IPs are discussed and best practices for conducting and interpreting co-IPs experiments are outlined. Finally, protocols are presented for detecting protein-protein interactions in cycling cells and in cells progressing through a synchronized cell cycle.

Targeting cancer with kinase inhibitors.

Kinase inhibitors have played an increasingly prominent role in the treatment of cancer and other diseases. Currently, more than 25 oncology drugs that target kinases have been approved, and numerous additional therapeutics are in various stages of clinical evaluation. In this Review, we provide an in-depth analysis of activation mechanisms for kinases in cancer, highlight recent successes in drug discovery, and demonstrate the clinical impact of selective kinase inhibitors. We also describe the substantial progress that has been made in designing next-generation inhibitors to circumvent on-target resistance mechanisms, as well as ongoing strategies for combining kinase inhibitors in the clinic. Last, there are numerous prospects for the discovery of novel kinase targets, and we explore cancer immunotherapy as a new and promising research area for studying kinase biology.

Rates of breast cancer surgery in Canada from 2007/08 to 2009/10: retrospective cohort study.

BACKGROUND: Surgery is a common and important component of breast cancer treatment. We assessed the rates of breast cancer surgery across Canada from 2007/08 to 2009/10. METHODS: We used hospital and day surgery data from the Canadian Institute for Health Information to assemble a cohort of women who had undergone breast cancer surgery. We identified the index surgical procedure and subsequent surgical procedures performed within 1 year for each woman included in the analysis. We calculated the crude mastectomy rate for each province, and we calculated the adjusted mastectomy rate for select jurisdictions using a logistic regression model fitted using age, neighbourhood income quintile and travel time. RESULTS: In total, 57 840 women underwent breast cancer surgery during the study period. Among women with unilateral invasive breast cancer, the crude mastectomy rate was 39%. Adjusted rates for mastectomy varied widely by province (26%-69%). The rate of re-excision within 1 year for women who had breast-conserving surgery as their index procedure was 23% and varied by province in terms of frequency and type (mastectomy or repeat breast-conserving surgery). Among women who underwent mastectomy for unilateral invasive breast cancer, 6% also underwent contralateral prophylactic mastectomy, and 7% had immediate breast reconstruction following surgery. Of mastectomy procedures, 20% were performed as day surgery; for breast-conserving surgery, 70% were performed as day surgery. INTERPRETATION: There is substantial interprovincial variation in surgical care for breast cancer in Canada. Further research is needed to better understand such variation, and continued monitoring should be the focus of quality initiatives.

Pharmacological and genomic profiling identifies NF-κB-targeted treatment strategies for mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive malignancy that is characterized by poor prognosis. Large-scale pharmacological profiling across more than 100 hematological cell line models identified a subset of MCL cell lines that are highly sensitive to the B cell receptor (BCR) signaling inhibitors ibrutinib and sotrastaurin. Sensitive MCL models exhibited chronic activation of the BCR-driven classical nuclear factor-κB (NF-κB) pathway, whereas insensitive cell lines displayed activation of the alternative NF-κB pathway. Transcriptome sequencing revealed genetic lesions in alternative NF-κB pathway signaling components in ibrutinib-insensitive cell lines, and sequencing of 165 samples from patients with MCL identified recurrent mutations in TRAF2 or BIRC3 in 15% of these individuals. Although they are associated with insensitivity to ibrutinib, lesions in the alternative NF-κB pathway conferred dependence on the protein kinase NIK (also called mitogen-activated protein 3 kinase 14 or MAP3K14) both in vitro and in vivo. Thus, NIK is a new therapeutic target for MCL treatment, particularly for lymphomas that are refractory to BCR pathway inhibitors. Our findings reveal a pattern of mutually exclusive activation of the BCR-NF-κB or NIK-NF-κB pathways in MCL and provide critical insights into patient stratification strategies for NF-κB pathway-targeted agents.

Regulation of Spo12 phosphorylation and its essential role in the FEAR network.

BACKGROUND: In budding yeast, the protein phosphatase Cdc14 coordinates late mitotic events and triggers exit from mitosis. During early anaphase, Cdc14 is activated by the FEAR network, but how signaling through the FEAR network occurs is poorly understood. RESULTS: We find that the FEAR network component Spo12 is phosphorylated on S118. This phosphorylation is essential for Spo12 function and is restricted to early anaphase, when the FEAR network is active. The anaphase-specific phosphorylation of Spo12 requires mitotic CDKs and depends on the FEAR network components Separase and Slk19. Furthermore, we find that CDC14 is required to maintain Spo12 in the dephosphorylated state prior to anaphase. CONCLUSIONS: Our results show that anaphase-specific phosphorylation of Spo12 is essential for FEAR network function and raise the interesting possibility that Cdc14 itself helps to prevent the FEAR network from being prematurely activated.

Mitotic CDKs control the metaphase-anaphase transition and trigger spindle elongation.

Mitotic cyclin-dependent kinases (CDKs) control entry into mitosis, but their role during mitotic progression is less well understood. Here we characterize the functions of CDK activity associated with the mitotic cyclins Clb1, Clb2, and Clb3. We show that Clb-CDKs are important for the activation of the ubiquitin ligase Anaphase-Promoting Complex/Cyclosome (APC/C)-Cdc20 that triggers the metaphase-anaphase transition. Furthermore, we define an essential role for Clb-CDK activity in anaphase spindle elongation. Thus, mitotic CDKs serve not only to initiate M phase, but are also needed continuously throughout mitosis to trigger key mitotic events such as APC/C activation and anaphase spindle elongation.

The Polo-like kinase Cdc5 interacts with FEAR network components and Cdc14.

Exit from mitosis in Saccharomyces cerevisiae is triggered by activation of the phosphatase Cdc14. Throughout interphase and early mitosis, Cdc14 is sequestered in the nucleolus by its inhibitor Cfi1/Net1. In anaphase, the Cdc Fourteen Early Anaphase Release (FEAR) network and the Mitotic Exit Network (MEN) coordinately trigger the release of Cdc14 from the nucleolus. Here we show that the FEAR network component Cdc5 physically associates with two other members of the pathway, the Separase Esp1 and the Esp1-binding protein Slk19. Furthermore, we find that Cdc5 physically interacts with Cdc14 and that this association is mediated by Cdc5's Polo-box domain, a phospho-serine/phosphothreonine binding domain. Finally, we present evidence that the Cdc5-Cdc14 association is direct, further supporting the central role of Cdc5 in Cdc14 localization.

APC/C-Cdh1-mediated degradation of the Polo kinase Cdc5 promotes the return of Cdc14 into the nucleolus.

In the budding yeast Saccharomyces cerevisiae, the protein phosphatase Cdc14 triggers exit from mitosis by promoting the inactivation of cyclin-dependent kinases (CDKs). Cdc14's activity is controlled by Cfi1/Net1, which holds and inhibits the phosphatase in the nucleolus from G1 until metaphase. During anaphase, two regulatory networks, the Cdc14 Early Anaphase Release (FEAR) network and the Mitotic Exit Network (MEN), promote the dissociation of Cdc14 from its inhibitor, allowing the phosphatase to reach its targets throughout the cell. The molecular circuits that trigger the return of Cdc14 into the nucleolus after the completion of exit from mitosis are not known. Here we show that activation of a ubiquitin ligase known as the Anaphase-Promoting Complex or Cyclosome (APC/C) bound to the specificity factor Cdh1 triggers the degradation of the Polo kinase Cdc5, a key factor in releasing Cdc14 from its inhibitor in the nucleolus.