Improving Rates of Germline BRCA Mutation Testing for Patients With Ovarian Cancer in Vancouver Island, British Columbia, Canada.

PURPOSE: Despite more than a decade of endorsement from multiple international cancer authorities advocating all women with ovarian cancer be offered germline breast cancer (BRCA) gene testing, British Columbia Cancer Victoria was not meeting this target. A quality improvement project was undertaken with the aim of increasing completed BRCA testing rates for all eligible patients seen at British Columbia Cancer Victoria to > 90% by 1 year from April 2016. METHODS: A current state analysis was completed, and multiple change ideas were developed, including education of medical oncologists, referral process update, initiating a group consenting seminar, and engagement of a nurse practitioner to lead the seminar. We used a retrospective chart audit from December 2014 to February 2018. On April 15, 2016, we initiated our Plan, Do, Study, Act (PDSA) cycles and completed them on February 28, 2018. We evaluated sustainability through an additional retrospective chart audit from January 2021 to August 2021. RESULTS: Patients with completed germline BRCA genetic testing climbed from an average of 58%-89% per month. Before our project, patients waited on average 243 days (± 214) for their genetic test results. After implementation, patients received results within 118 days (± 98). This was sustained with an average of 83% of patients per month having completed germline BRCA testing almost 3 years after project completion. CONCLUSION: Our quality improvement initiative resulted in a sustained increase in germline BRCA test completion for eligible patients with ovarian cancer.

Real-world experience managing unresectable or metastatic small cell carcinoma of the prostate.

INTRODUCTION: Unresectable and metastatic small cell carcinoma of the prostate (SCPC) is a rare and aggressive disease that is under-represented in clinical trials. We carried out a retrospective chart review of metastatic or unresectable SCPC patients at British Columbia (BC) Cancer centers, studying diagnosis and treatment patterns. METHODS: Drug-dispensing records from the six BC Cancer centers were obtained from 2002-2017. For each patient, information was collected on baseline information prior to therapy and for each line of treatment. Treatments at each line were compared regarding time to progression and overall survival by Kaplan-Meier curves. RESULTS: Forty-one patients received treatment; 65.6% had metastatic disease and 61% had pure small cell carcinoma. Median time from treatment to death was 10 months (95% confidence interval [CI] 6-16). Patients with initially prostate-confined disease had a better median overall survival (mOS) of 21 months (95% CI 13-34) compared to those with initially locally advanced (mOS 19 months, 95% CI 5-37) and metastatic disease (mOS 8 months, 95% CI 6-10) (log-rank p=0.0364). All patients received either cisplatin- or carboplatin-based combination chemotherapy as the first-line treatment and 36.7% received second-line therapy. Time to second-line therapy was eight months for those who presented with metastatic SCPC, compared to 13 months for those with initial non-metastatic SCPC. CONCLUSIONS: This single-province, multi-institution cohort reports data on unresectable and metastatic SCPC and highlights the poor prognosis of this rare disease entity.

Exercise Recommendation for People With Bone Metastases: Expert Consensus for Health Care Providers and Exercise Professionals.

PURPOSE: Exercise has been underutilized in people with advanced or incurable cancer despite the potential to improve physical function and reduce psychosocial morbidity, especially for people with bone metastases because of concerns over skeletal complications. The International Bone Metastases Exercise Working Group (IBMEWG) was formed to develop best practice recommendations for exercise programming for people with bone metastases on the basis of published research, clinical experience, and expert opinion. METHODS: The IBMEWG undertook sequential steps to inform the recommendations: (1) modified Delphi survey, (2) systematic review, (3) cross-sectional survey to physicians and nurse practitioners, (4) in-person meeting of IBMEWG to review evidence from steps 1-3 to develop draft recommendations, and (5) stakeholder engagement. RESULTS: Recommendations emerged from the contributing evidence and IBMEWG discussion for pre-exercise screening, exercise testing, exercise prescription, and monitoring of exercise response. Identification of individuals who are potentially at higher risk of exercise-related skeletal complication is a complex interplay of these factors: (1) lesion-related, (2) cancer and cancer treatment-related, and (3) the person-related. Exercise assessment and prescription requires consideration of the location and presentation of bone lesion(s) and should be delivered by qualified exercise professionals with oncology education and exercise prescription experience. Emphasis on postural alignment, controlled movement, and proper technique is essential. CONCLUSION: Ultimately, the perceived risk of skeletal complications should be weighed against potential health benefits on the basis of consultation between the person, health care team, and exercise professionals. These recommendations provide an initial framework to improve the integration of exercise programming into clinical care for people with bone metastases.

A case of intraplacental gestational choriocarcinoma; characterised by the methylation pattern of the early placenta and an absence of driver mutations.

BACKGROUND: Gestational choriocarcinoma is a rare malignancy believed to arise from the trophoblast cells of the placenta. Despite the frequently aggressive clinical nature, choriocarcinoma has been routinely curable with cytotoxic chemotherapy for over 50 years. To date little is known regarding the route to oncogenesis in this malignancy. METHODS: In a case of intraplacental choriocarcinoma, we have performed detailed genetic studies including microsatellite analysis, whole genome sequencing (WGS) and methylation analysis of the tumour and surrounding mature placenta. RESULTS: The results of the WGS sequencing indicated a very low level of mutation and the absence of any driver mutations or oncogene activity in the tumour. The methylation analysis identified a distinctly different profile in the tumour from that of the mature placenta. Comparison with a panel of reference methylation profiles from different stages of placental development indicated that the tumour segregated with the first trimester samples. CONCLUSIONS: These findings suggest that gestational choriocarcinoma is likely to arise as a result of aberrations of methylation during development, rather than from DNA mutations. The results support the hypothesis that gestational choriocarcinoma arises from a normally transient early trophoblast cell. At this point in development this cell naturally has a phenotype of rapid division, tissue invasion and sensitivity to DNA damaging chemotherapy that is very similar to that of the mature choriocarcinoma cell.

Therapeutic Implication of Genomic Landscape of Adult Metastatic Sarcoma.

PURPOSE: This study investigated therapeutic potential of integrated genome and transcriptome profiling of metastatic sarcoma, a rare but extremely heterogeneous group of aggressive mesenchymal malignancies with few systemic therapeutic options. METHODS: Forty-three adult patients with advanced or metastatic non-GI stromal tumor sarcomas of various histology subtypes who were enrolled in the Personalized OncoGenomics program at BC Cancer were included in this study. Fresh tumor tissues along with blood samples underwent whole-genome and transcriptome sequencing. RESULTS: The most frequent genomic alterations in this cohort are large-scale structural variation and somatic copy number variation. Outlier RNA expression as well as somatic copy number variations, structural variations, and small mutations together suggest the presence of one or more potential therapeutic targets in the majority of patients in our cohort. Point mutations or deletions in known targetable cancer genes are rare; for example, tuberous sclerosis complex 2 provides a rationale for targeting the mammalian target of rapamycin pathway, resulting in a few patients with exceptional clinical benefit from everolimus. In addition, we observed recurrent 17p11-12 amplifications, which seem to be a sarcoma-specific event. This may suggest that this region harbors an oncogene(s) that is significant for sarcoma tumorigenesis. Furthermore, some sarcoma tumors carrying a distinct mutational signature suggestive of homologous recombination deficiency seem to demonstrate sensitivity to double-strand DNA-damaging agents. CONCLUSION: Integrated large-scale genomic analysis may provide insights into potential therapeutic targets as well as novel biologic features of metastatic sarcomas that could fuel future experimental and clinical research and help design biomarker-driven basket clinical trials for novel therapeutic strategies.

Immune Modulation by Androgen Deprivation and Radiation Therapy: Implications for Prostate Cancer Immunotherapy.

Prostate cancer patients often receive androgen deprivation therapy (ADT) in combination with radiation therapy (RT). Recent evidence suggests that both ADT and RT have immune modulatory properties. First, ADT can cause infiltration of lymphocytes into the prostate, although it remains unclear whether the influx of lymphocytes is beneficial, particularly with the advent of new classes of androgen blockers. Second, in rare cases, radiation can elicit immune responses that mediate regression of metastatic lesions lying outside the field of radiation, a phenomenon known as the abscopal response. In light of these findings, there is emerging interest in exploiting any potential synergy between ADT, RT, and immunotherapy. Here, we provide a comprehensive review of the rationale behind combining immunotherapy with ADT and RT for the treatment of prostate cancer, including an examination of the current clinical trials that employ this combination. The reported outcomes of several trials demonstrate the promise of this combination strategy; however, further scrutiny is needed to elucidate how these standard therapies interact with immune modulators. In addition, we discuss the importance of synchronizing immune modulation relative to ADT and RT, and provide insight into elements that may impact the ability to achieve maximum synergy between these treatments.

Pericardial effusion and tamponade following interferon alpha treatment for locally advanced melanoma.

Regional Metastatic Melanoma has a relatively high mortality rate. Adjuvant interferon-alpha (IFN-α) has been shown to improve disease-free survival, post-resection. Cardiotoxicity associated with IFN-α use has been described previously in the literature, but here we describe the first case of pericardial effusion with cardiac tamponade secondary to IFN-α 2b treatment of melanoma. Clinicians should be aware of this potentially lethal complication and the possible acuity of its onset.

Compendium of unpublished phase III trials in oncology: characteristics and impact on clinical practice.

PURPOSE: Many phase III trials presented at annual meetings of the American Society of Clinical Oncology (ASCO) remain unpublished. The results of these unpublished trials, if more generally known, might have an impact on clinical practice. METHODS: Abstracts of large phase III trials evaluating systemic cancer treatment were identified from conference proceedings of the 1989 to 2003 ASCO annual meetings. PubMed, Medline, and Embase were searched for corresponding publications. A compendium of unpublished phase III trials was assembled. Clinical significance of nonpublication was determined by disease site-specific oncology experts from two academic cancer centers in Canada. RESULTS: A total of 709 phase III trials were identified of which 66 (9.3%) remain without a subsequent publication at a minimum of 6.5 years of follow-up and 94 (13%) were published after a delay of ≥ 5 years from their initial presentation. Of the unpublished trials, 48% were presented as oral sessions at an ASCO meeting, and 71% of the abstracts reported negative results. The experts judged that 70% of the unpublished trials addressed an important question and 59% might have had clinical impact if their results had been published promptly. CONCLUSION: A substantial number of cancer clinical trials with potential influence on clinical practice remain unpublished and many other trials are published after a substantial delay. Nonpublication of clinical trials breaks an implicit contract with participants, institutional review boards, and sponsors.

Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma.

Bcl family members Bcl-2, Bcl-x(L), and Mcl-1, are frequently expressed and implicated in the survival of myeloma cells. Obatoclax (GX015-070) is a novel, small-molecule antagonist of the BH3-binding groove of the Bcl family of proteins. We show that GX015-070 inhibits the binding of Bak to Mcl-1, up-regulates Bim, induces cytochrome c release, and activates capase-3 in human myeloma cell lines (HMCLs), confirming the predicted mechanism of action. Consequently, GX015-070 potently inhibited the viability of 15 of 16 HMCLs (mean IC(50) of 246 nM), including those resistant to melphalan and dexamethasone. In combination studies, GX015-070 enhanced the antimyeloma activity induced by melphalan, dexamethasone, or bortezomib. Sensitivity to GX015-070 correlated with the absence or near absence of Bcl-x(L). Coculture with interleukin-6 or adherence to bone marrow stroma conferred modest resistance; however, it did not overcome GX015-070-induced cytotoxicity. Of importance, GX015-070 as a single agent induced potent cytotoxic responses against patient-derived tumor cells. GX015-070 inhibited normal bone marrow-derived colony formation; however, cytotoxicity to human blood lymphocytes was not observed. Taken together, these studies describe a novel BH3 mimic with selectivity for Mcl-1, and support the therapeutic application of GX015-070 for diverse neoplasias including multiple myeloma.

Ran modulates spindle assembly by regulating a subset of TPX2 and Kid activities including Aurora A activation.

Ran, a GTPase in the Ras superfamily, is proposed to be a spatial regulator of microtubule spindle assembly by maintaining key spindle assembly factors in an active state close to chromatin. RanGTP is hypothesized to maintain the spindle assembly factors in the active state by binding to importin beta, part of the nuclear transport receptor complex, thereby preventing the inhibitory binding of the nuclear transport receptors to spindle assembly factors. To directly test this hypothesis, two putative downstream targets of the Ran spindle assembly pathway, TPX2, a protein required for correct spindle assembly and Kid, a chromokinesin involved in chromosome arm orientation on the spindle, were analyzed to determine if their direct binding to nuclear transport receptors inhibited their function. In the amino-terminal domain of TPX2 we identified nuclear targeting information, microtubule-binding and Aurora A binding activities. Nuclear transport receptor binding to TPX2 inhibited Aurora A binding activity but not the microtubule-binding activity of TPX2. Inhibition of the interaction between TPX2 and Aurora A prevented Aurora A activation and recruitment to microtubules. In addition we identified nuclear targeting information in both the amino-terminal microtubule-binding domain and the carboxy-terminal DNA binding domain of Kid. However, the binding of nuclear transport receptors to Kid only inhibited the microtubule-binding activity of Kid. Therefore, by regulating a subset of TPX2 and Kid activities, Ran modulates at least two processes involved in spindle assembly.