Ultrasensitive plasma-based monitoring of tumor burden using machine-learning-guided signal enrichment.

In solid tumor oncology, circulating tumor DNA (ctDNA) is poised to transform care through accurate assessment of minimal residual disease (MRD) and therapeutic response monitoring. To overcome the sparsity of ctDNA fragments in low tumor fraction (TF) settings and increase MRD sensitivity, we previously leveraged genome-wide mutational integration through plasma whole-genome sequencing (WGS). Here we now introduce MRD-EDGE, a machine-learning-guided WGS ctDNA single-nucleotide variant (SNV) and copy-number variant (CNV) detection platform designed to increase signal enrichment. MRD-EDGESNV uses deep learning and a ctDNA-specific feature space to increase SNV signal-to-noise enrichment in WGS by ~300× compared to previous WGS error suppression. MRD-EDGECNV also reduces the degree of aneuploidy needed for ultrasensitive CNV detection through WGS from 1 Gb to 200 Mb, vastly expanding its applicability within solid tumors. We harness the improved performance to identify MRD following surgery in multiple cancer types, track changes in TF in response to neoadjuvant immunotherapy in lung cancer and demonstrate ctDNA shedding in precancerous colorectal adenomas. Finally, the radical signal-to-noise enrichment in MRD-EDGESNV enables plasma-only (non-tumor-informed) disease monitoring in advanced melanoma and lung cancer, yielding clinically informative TF monitoring for patients on immune-checkpoint inhibition.

Circulating tumour mutation detection in triple-negative breast cancer as an adjunct to tissue response assessment.

Circulating tumour DNA (ctDNA) detection via liquid biopsy is an emerging alternative to tissue biopsy, but its potential in treatment response monitoring and prognosis in triple negative breast cancer (TNBC) is not yet well understood. Here we determined the prevalence of actionable mutations detectable in ctDNA using a clinically validated cancer gene panel assay in patients with TNBC, without recurrence at the time of study entry. Sequencing of plasma DNA and validation of variants from 130 TNBC patients collected within 7 months of primary treatment completion revealed that 7.7% had detectable residual disease with a hotspot panel. Among neoadjuvant treated patients, we observed a trend where patients with incomplete pathologic response and positive ctDNA within 7 months of treatment completion were at much higher risk of reduced progression free survival. We propose that a high risk subset of early TNBC patients treated in neoadjuvant therapy protocols may be identifiable by combining tissue response and sensitive ctDNA detection.

RNA-based translation activators for targeted gene upregulation.

Technologies capable of programmable translation activation offer strategies to develop therapeutics for diseases caused by insufficient gene expression. Here, we present "translation-activating RNAs" (taRNAs), a bifunctional RNA-based molecular technology that binds to a specific mRNA of interest and directly upregulates its translation. taRNAs are constructed from a variety of viral or mammalian RNA internal ribosome entry sites (IRESs) and upregulate translation for a suite of target mRNAs. We minimize the taRNA scaffold to 94 nucleotides, identify two translation initiation factor proteins responsible for taRNA activity, and validate the technology by amplifying SYNGAP1 expression, a haploinsufficiency disease target, in patient-derived cells. Finally, taRNAs are suitable for delivery as RNA molecules by lipid nanoparticles (LNPs) to cell lines, primary neurons, and mouse liver in vivo. taRNAs provide a general and compact nucleic acid-based technology to upregulate protein production from endogenous mRNAs, and may open up possibilities for therapeutic RNA research.

A thalamo-parietal cortex circuit is critical for place-action coordination.

The anterior and lateral thalamus (ALT) contains head direction cells that signal the directional orientation of an individual within the environment. ALT has direct and indirect connections with the parietal cortex (PC), an area hypothesized to play a role in coordinating viewer-dependent and viewer-independent spatial reference frames. This coordination between reference frames would allow an individual to translate movements toward a desired location from memory. Thus, ALT-PC functional connectivity would be critical for moving toward remembered allocentric locations. This hypothesis was tested in rats with a place-action task that requires associating an appropriate action (left or right turn) with a spatial location. There are four arms, each offset by 90°, positioned around a central starting point. A trial begins in the central starting point. After exiting a pseudorandomly selected arm, the rat had to displace the correct object covering one of two (left versus right) feeding stations to receive a reward. For a pair of arms facing opposite directions, the reward was located on the left, and for the other pair, the reward was located on the right. Thus, each reward location had a different combination of allocentric location and egocentric action. Removal of an object was scored as correct or incorrect. Trials in which the rat did not displace any objects were scored as "no selection" trials. After an object was removed, the rat returned to the center starting position and the maze was reset for the next trial. To investigate the role of the ALT-PC network, muscimol inactivation infusions targeted bilateral PC, bilateral ALT, or the ALT-PC network. Muscimol sessions were counterbalanced and compared to saline sessions within the same animal. All inactivations resulted in decreased accuracy, but only bilateral PC inactivations resulted in increased non selecting, increased errors, and longer latency responses on the remaining trials. Thus, the ALT-PC circuit is critical for linking an action with a spatial location for successful navigation.

Real-world experience of tyrosine kinase inhibitors in children, adolescents and adults with relapsed or refractory bone tumours: A Canadian Sarcoma Research and Clinical Collaboration (CanSaRCC) study.

OBJECTIVES: We conducted a retrospective multi-centre study to assess the real-world outcome of regorafenib (REGO) and cabozantinib (CABO) in recurrent/refractory bone tumours (BTs) including osteosarcoma (OST), Ewing sarcoma (EWS) and chondrosarcoma (CS)/extra-skeletal mesenchymal CS (ESMC). METHODS: After regulatory approval, data from patients with recurrent BT (11 institutions) were extracted from CanSaRCC (Canadian Sarcoma Research and Clinical Collaboration) database. Patient characteristics, treatment and outcomes were collected. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS: From July 2018 to May 2022, 66 patients received REGO or CABO; 39 OST, 18 EWS, 4 CS and 5 ESMC. Median age was 27.8 years (range 12-76); median starting dose was 60 mg for CABO (n = 37, range 40-60) and 120 mg for REGO (n = 29, range 40-160). Twenty-eight (42.4%) patients required dose reduction: hand-foot syndrome 7 (10.6%), nausea/vomiting 1 (1.5%), diarrhoea 1 (1.5%), 2 elevated LFTs (3%), elevated bilirubin 1 (1.5%) and mucositis 1 (1.5%). The median OS for patients with OST, EWS, CS and ESMC was 8.5 months (n = 39, 95% CI 7-13.1); 13.4 months (n = 18, 95% CI 3.4-27.2), 8.1 (n = 4, 95% CI 4.1-9.3) and 18.2 (n = 5, 95% CI (10.4-na), respectively. Median PFS for OST, EWS, CS and ECMS was 3.5 (n = 39, 95% CI 2.8-5), 3.9 (n = 18, 95% CI 2.1-5.9), 5.53 (n = 4. 95% CI 2.13-NA) and 11.4 (n = 5, 95% CI 1.83-14.7), respectively. Age, line of therapy, REGO versus CABO, or time from diagnosis to initiation of TKI were not associated with PFS on univariable analysis. CONCLUSION: Our real-world data show that TKIs have meaningful activity in recurrent BT with acceptable toxicities when started at modified dosing. Inclusion of TKIs in earlier lines of treatment and/or maintenance therapy could be questions for future research.

Current Challenges and Disparities in the Delivery of Equitable Breast Cancer Care in Canada.

Recent exciting advances in the diagnosis and management of breast cancer have improved outcomes for Canadians diagnosed and living with breast cancer. However, the reach of this progress has been uneven; disparities in accessing care across Canada are increasingly being recognized and are at risk of broadening. Members of racial minority groups, economically disadvantaged individuals, or those who live in rural or remote communities have consistently been shown to experience greater challenges in accessing 'state of the art' cancer care. The Canadian context also presents unique challenges-vast geography and provincial jurisdiction of the delivery of cancer care and drug funding create significant interprovincial differences in the patient experience. In this commentary, we review the core concepts of health equity, barriers to equitable delivery of breast cancer care, populations at risk, and recommendations for the advancement of health equity in the Canadian cancer system.

Evaluating the childcare needs of cancer patients undergoing radiation therapy.

PURPOSE: About one-fifth of newly diagnosed cancer patients are parents to young children. These patients are at higher risk of psychosocial stress and inability to attend treatment due to having to balance their own healthcare needs with childcare duties. This study aims to explore the impact of childcare on cancer parents and elicit their perspectives on potential supports. The results could help inform the implementation of suitable childcare programs to remove this barrier in accessing care. METHODS: Patients at a large Canadian cancer treatment center were screened by oncologists for having minor children at home. Secure electronic surveys were then distributed to consenting participants. Domains surveyed included patient demographics, childcare burden, impact on treatment, and preference for childcare supports. RESULTS: The mean age of correspondents was 43.9 (range 33-54), 46 patients (92%) were female, and breast cancer was the most common primary tumor. The median number of children per correspondent was two, and their mean age was 8.4. Balancing childcare with cancer treatment had a significant impact on self-reported stress levels for most correspondents. Twenty (40%) participants had to reschedule and 7 (14%) participants missed at least one appointment due to childcare conflicts. During the COVID-19 pandemic, access to childcare resources decreased while childcare responsibilities increased. Three-quarters of correspondents reported that a flexible childcare would make it easier for them to adhere to appointment schedules. CONCLUSION: Childcare is a significant psychosocial barrier for patients accessing cancer care. Our results indicate that most parents undergoing treatment may benefit from hospital-based childcare services.

Targeting HER2-low in metastatic breast cancer: an evolving treatment paradigm.

The results of the Phase III DESTINY-Breast04 trial of trastuzumab deruxtecan (T-DXd) are leading to a shift in both the classification and treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. In this trial, T-DXd was associated with a substantial survival benefit among patients with hormone receptor-positive and hormone receptor-negative disease and low expression of HER2, a biomarker previously considered unactionable in this treatment setting. Herein, we discuss the evolving therapeutic pathway for HER2-low disease, ongoing clinical trials, and the potential challenges and evidence gaps arising with treatment of this patient population.

Survival Outcomes of Ewing Sarcoma and Rhabdomyosarcoma by High- versus Low-Volume Cancer Centres in British Columbia, Canada.

Due to the rarity and complexity of treatment for Ewing sarcoma and rhabdomyosarcoma, studies demonstrate improved patient outcomes when managed by a multidisciplinary team at high-volume centres (HVCs). Our study explores the difference in outcomes of Ewing sarcoma and rhabdomyosarcoma patients based on the centre of initial consultation in British Columbia, Canada. This retrospective study assessed adults diagnosed with Ewing sarcoma and rhabdomyosarcoma between 1 January 2000 and 31 December 2020 undergoing curative intent therapy in one of five cancer centres across the province. Seventy-seven patients were included, 46 seen at HVCs and 31 at low-volume centres (LVCs). Patients at HVCs were younger (32.1 vs. 40.8 years, p = 0.020) and more likely to receive curative intent radiation (88% vs. 67%, p = 0.047). The time from diagnosis to first chemotherapy was 24 days shorter at HVCs (26 vs. 50 days, p = 0.120). There was no significant difference in overall survival by treatment centre (HR 0.850, 95% CI 0.448-1.614). Variations in care exist amongst patients treated at HVCs vs. LVCs, which may reflect differences in access to resources, clinical specialists, and varying practice patterns across centres. This study can be used to inform decisions regarding triaging and centralization of Ewing sarcoma and rhabdomyosarcoma patient treatment.

An Evaluation of the Quality of COVID-19 Internet Resources for Cancer Patients.

Cancer patients may face difficulty evaluating web-based COVID-19 resources in context with their cancer diagnosis. The purpose of this study is to systematically evaluate educational resources available for cancer patients seeking online information on COVID-19 and cancer. The term "COVID-19 and Cancer" was searched in Google and metasearch engines Yippy and Dogpile. After applying inclusion and exclusion criteria, the results from the 3 lists were systematically combined for a final ranked list. This list was analyzed using a validated structured rating tool with respect to accountability, interactivity, organization, readability, and content coverage and accuracy. Three hundred ninety-eight websites were identified, and 37 websites were included for analysis. Only 43% of sites disclosed authorship, 24% cited sources, and 32% were updated within 3 months of the search date. Fifty-four percent of websites had high school readability (8.0-12.0), 43% were at university level or above, and no websites demonstrated the recommended reading level for health information for the public (< 6.0). Topics most discussed were special considerations for cancer patients during COVID-19 (84%) and COVID-19 risk factors (73%). Topics least covered were COVID-19 incidence/prevalence (5%) and prognosis (8%). There is some COVID-19 information for cancer patients available online, but quality is variable. Healthcare professionals may direct cancer patients to the most reliable COVID-19 and cancer websites shown in this study and results may be helpful when designing future online health information resources.

The Role of Imaging in the Diagnosis of Primary and Secondary Breast Angiosarcoma: Twenty-Five-Year Experience of a Provincial Cancer Institution.

BACKGROUND: Breast angiosarcoma may arise spontaneously (primary breast angiosarcoma (PBA)) or may arise secondary to a biological insult, such as radiation therapy (secondary breast angiosarcoma (SBA)). We evaluated the imaging findings of patients diagnosed with PBA and SBA within the province of British Columbia, Canada. MATERIALS AND METHODS: This was a multi-center, retrospective study of patients diagnosed with PBA and SBA over a 25-year period. Patients were identified via a provincial database which registers all cases of sarcoma. Patients diagnosed with histologically proven PBA and SBA were eligible for inclusion. Multimodal breast imaging reviewed included mammography, ultrasound, magnetic resonance imaging, and computed tomography. RESULTS: Thirteen patients were diagnosed with PBA and 22 patients were diagnosed with SBA. The median (interquartile range (IQR)) age of patients diagnosed with PBA (45.5 years (19.7 years)) was less than that of patients diagnosed with SBA (75.8 years (13.8 years), P < .001). Patients diagnosed with PBA (90.9%) were more likely to present with a parenchymal mass clinically and radiographically than those with SBA (28.6%, P < .002). Patients diagnosed with SBA (71.4%) were more likely to present with cutaneous findings than patients diagnosed with PBA (0.0%, P < .05). Without specific clinical context, the imaging findings of PBA and SBA were observed to be non-specific. CONCLUSION: This is the only study which evaluated the imaging findings of patients diagnosed with PBA and SBA within a large, defined geographical area. Given non-specific imaging findings, awareness of the disease and clear and timely communication between radiologists and clinicians is required to ensure appropriate diagnosis and management.

Locoregional Treatments for Metastatic Gastrointestinal Stromal Tumor in British Columbia: A Retrospective Cohort Study from January 2008 to December 2017.

INTRODUCTION: The role of surgery and non-surgical locoregional treatments (LRT) such as radiation therapy (RT) and local ablation techniques in patients with metastatic gastrointestinal stromal tumor (GIST) is unclear. This study examines LRT practice patterns in metastatic GIST and their clinical outcomes in British Columbia (BC). METHODS: Patients diagnosed with either recurrent or de novo metastatic GIST from January 2008 to December 2017 were identified. Clinical characteristics and outcomes were analyzed in patients who underwent LRT, including surgical resection of the primary tumor or metastectomy, RT, or other local ablative procedures. RESULTS: 127 patients were identified: 52 (41%) had de novo metastasis and 75 (59%) had recurrent metastasis. Median age was 67 (23-90 years), 58.2% were male, primary site was 33.1% stomach, 40.2% small intestine, 11% rectum/pelvis, and 15.7% others. 37 (29.1%) of patients received palliative surgery, the majority of which had either primary tumor removal only (43.3%) or both primary tumor removal and metastectomy (35.1%). A minority of patients underwent metastectomy only (21.6%). A total of 12 (9.5%) patients received palliative RT to metastatic sites only (58.3%) or primary tumors only (41.7%), mostly for symptomatic control (n = 9). A few patients (n = 3) received local ablation for liver metastatic deposits with 1 patient receiving microwave ablation (MWA) and 2 receiving radiofrequency ablation (RFA). Most patients (n = 120, 94.5%) received some type of systemic treatment. It is notable that prolonged progression free survival (PFS) was observed for the majority of patients who underwent surgery in the metastatic setting with a median PFS of 20.5 (95% confidence interval (CI): 14.29-40.74) months. In addition, significantly higher median overall survival (mOS) was observed in patients who underwent surgery (97.15 months; 95% CI: 77.7-not reached) and LRT (78.98 months; 95% CI: 65.58-not reached) versus no surgery (45.37 months; 95% CI: 38.7-64.69) and no LRT (45.27 months; 95% CI: 33.25-58.66). Almost all patients (8 out of 9) achieved symptomatic improvement after palliative RT. All 3 patients achieved partial response and 2 out of 3 patients had relatively durable responses of 1 year or more after local ablation. DISCUSSION: This study is among the first to systematically examine the use of various LRT in metastatic GIST management. Integration of LRT with systemic treatments may potentially provide promising durable response and prolonged survival for highly selected metastatic GIST patients with low volume disease, limited progression and otherwise well controlled on systemic treatments. These observations, consistent with others, add to the growing evidence that supports the judicious use of LRT in combination with systemic treatments to further optimize the care of metastatic GIST patients.

A Canadian national guideline on the neoadjuvant treatment of invasive breast cancer, including patient assessment, systemic therapy, and local management principles.

PURPOSE: The neoadjuvant treatment of breast cancer (NABC) is a rapidly changing area that benefits from guidelines integrating evidence with expert consensus to help direct practice. This can optimize patient outcomes by ensuring the appropriate use of evolving neoadjuvant principles. METHODS: An expert panel formulated evidence-based practice recommendations spanning the entire neoadjuvant breast cancer treatment journey. These were sent for practice-based consensus across Canada using the modified Delphi methodology, through a secure online survey. Final recommendations were graded using the GRADE criteria for guidelines. The evidence was reviewed over the course of guideline development to ensure recommendations remained aligned with current relevant data. RESULTS: Response rate to the online survey was almost 30%; representation was achieved from various medical specialties from both community and academic centres in various Canadian provinces. Two rounds of consensus were required to achieve 80% or higher consensus on 59 final statements. Five additional statements were added to reflect updated evidence but not sent for consensus. CONCLUSIONS: Key highlights of this comprehensive Canadian guideline on NABC include the use of neoadjuvant therapy for early stage triple negative and HER2 positive breast cancer, with subsequent adjuvant treatments for patients with residual disease. The use of molecular signatures, other targeted adjuvant therapies, and optimal response-based local regional management remain actively evolving areas. Many statements had evolving or limited data but still achieved high consensus, demonstrating the utility of such a guideline in helping to unify practice while further evidence evolves in this important area of breast cancer management.

Current and future landscape of targeted therapy in HER2-positive advanced breast cancer: redrawing the lines.

BACKGROUND: Evidence to date supports continued human epidermal growth factor receptor 2 (HER2) suppression beyond progression on HER2-directed therapy for advanced HER2-positive breast cancer. Data from several phase II and III trials evaluating HER2-directed therapy following second-line T-DM1 have recently become available. METHODS: We performed a systematic search of the published and presented literature to identify phase II and phase III trials assessing novel HER2-targeted agents as third-line therapy or beyond for HER2-positive advanced breast cancer using search terms 'breast cancer' AND 'HER2' AND 'advanced' AND ('phase II' OR 'phase III'). RESULTS: Eight clinical trials reporting efficacy outcomes on third-line or greater HER2-directed therapy for HER2-positive advanced breast cancer were identified. In phase III trials, margetuximab and neratinib combinations demonstrated significant 1.3-month (hazard ratio, HR = 0.71, p < 0.001) and 0.1-month (HR = 0.76, p = 0.006) net improvements in median progression-free survival (PFS), respectively, with no significant improvements in overall survival (OS). Tucatinib added to trastuzumab and capecitabine demonstrated a significant 2.7-month improvement in median PFS (HR = 0.57, p < 0.00001) and a 5.5-month improvement in median OS (HR = 0.73, p = 0.004) in a randomized phase II trial, including significant clinical benefit for patients with brain metastases. Finally, trastuzumab-deruxtecan, zenocutuzumab, and poziotinib demonstrated benefit in phase II trials with the most robust overall response rate (62.0%) and median duration of response (18.2 months) observed for trastuzumab-deruxtecan among heavily pretreated patients. CONCLUSION: Tucatinib plus trastuzumab and capecitabine significantly prolongs OS, and promising preliminary response outcomes for trastuzumab-deruxtecan suggest that sequencing of these regimens following second-line therapy is reasonable.

Mapping childcare support for patients at a sample of North American hospitals and cancer centers: an environmental scan.

PURPOSE: Approximately a quarter of cancer patients are parents to young children. One unique challenge faced by this patient group is the difficulty of accessing childcare support during medical appointments. Hospital-based childcare options could represent a solution to this problem, but to this point, no comprehensive scans have described existing on-site childcare centers. The purpose of this study is to identify and characterize on-site childcare services available to patients at selected North American hospitals. This information could inform the development of similar programs for cancer patients. METHODS: Using publicly available information, an environmental scan of the grey literature was conducted to investigate Canadian and American hospitals for the presence of childcare services. A standardized data collection tool was used to extract center characteristics. RESULTS: Twenty-six childcare centers were identified across 161 hospitals in both Canada and the USA, with 8/55 Canadian hospitals and 18/106 American hospitals having patient-accessible on-site services. The majority of the centers were associated with pediatric hospitals (77%). Only a single childcare center was associated with a cancer hospital. All centers accommodated children between the ages of 3 and 8. Most centers were open for over 30 h per week (77%) and were free of charge to users (89%). Other characteristics, including capacity and staffing, varied widely. CONCLUSIONS: These results represent an inventory of patient-accessible, on-site childcare services currently available at selected North American hospitals. Cancer patients who are also parents may especially benefit from this kind of support.

Utilization of Mutational Analysis (MA) in Gastrointestinal Stromal Tumor (GIST) Management in British Columbia (BC) Between January 2008 to December 2017: a Retrospective Population-Based Study.

PURPOSE: To examine oncologists' practice pattern of ordering MA in localized and metastatic GISTs in British Columbia (BC). METHODS: Patients diagnosed with GIST from January 2008 to December 2017 in BC were identified. Chart review was performed to determine clinical characteristics and the use of MA as part of their oncologic care. RESULTS: The cohort included 411 patients: median age 64 (18-94 years), 49.1% male, primary site included stomach (53%), small intestine (32%), and others (15%). Sixty-nine percent had localized disease, while 13% presented with de novo metastatic disease and 18% had recurrent metastatic disease. MA was ordered in 41% of the patients overall, 28% in localized, and 70% in metastatic settings (63% in de novo metastasis and 78% in recurrent metastasis). Among patients with localized disease, higher MA use rates were observed among those undergoing neoadjuvant/adjuvant treatment (45%) compared to those not receiving systemic therapy (18%). While MA use rates in localized GIST did not change over time (28.5% before 2015 and 28% after 2015), MA use in metastatic disease increased from 54% before 2015 to 79% after 2015. Among all MA ordered for metastatic disease, 82.4% were ordered at the time of de novo metastatic diagnosis, and 77.4% were ordered either at the time of recurrent metastatic diagnosis or earlier when the disease was localized. CONCLUSION: MA use has remained stable for localized disease but has increased after 2015 in the metastatic setting which may be due to evolving sequencing technology, expansion of metastatic treatment options, and enhanced awareness of MA.

Canadian consensus on TRK-inhibitor therapy for NTRK fusion-positive sarcoma.

Malignant sarcomas are rare accounting for <1% of all adult solid malignancies and approximately 11% to 13% of all pediatric malignancies. TRK-inhibitors have demonstrated robust and long-lasting responses in patients with NTRK fusion-positive solid tumors, including sarcoma. Access to these agents in many jurisdictions such as Canada remains limited. We undertook a modified Delphi consensus to articulate and convey the clinical importance of these agents for the Canadian sarcoma community. A systematic search of published and presented literature was conducted to identify clinical trials reporting outcomes on the use of TRK-inhibitors in relapsed/refractory NTRK fusion-positive sarcoma. Three main consensus questions were identified: (a) is there currently an unmet clinical need for systemic therapy options in relapsed/refractory sarcoma? (b) do TRK-inhibitors confer a clinical benefit to patients with NTRK fusion-positive sarcoma? (c) do phase I/II basket trials provide sufficient evidence to justify funding of TRK-inhibitors in NTRK fusion-positive sarcoma? Response rates to the first and second surveys were 57% (n = 30) and 42% (n = 22), respectively. There was strong agreement among the Canadian sarcoma community that there was unmet clinical need for effective systemic therapy options in relapsed/refractory sarcoma, that TRK-inhibitors are a safe and effective treatment option for patients with NTRK fusion-positive sarcoma, and that available phase I/II basket trials provide sufficient evidence to support funding of these agents in relapsed/refractory NTRK fusion-positive sarcoma. TRK-inhibitors are a safe and effective systemic therapy option for patients with relapsed/refractory NTRK fusion-positive sarcoma.

A Single-Center 10-Year Retrospective Analysis of Cryoablation for the Management of Desmoid Tumors.

PURPOSE: To determine the efficacy and safety of cryoablation in patients with desmoid tumors (DTs) retrospectively over a 10-year period at a single institution. MATERIALS AND METHODS: Between February 25, 2010, and February 25, 2020, 25 patients (age, 12-80 years) with 26 lesions (mean preprocedural tumor volume was 237 cm3) were treated over 44 cryoablation procedures. Eleven patients were treated with first-line therapy. Fourteen patients had previous medical therapy, radiotherapy, and/or surgery. Subsequent clinical follow-up, imaging outcomes, and safety were analyzed for technical success, change in total lesion volume (TLV) and viable tumor volume (VTV), modified response evaluation criteria in solid tumors (mRECIST), progression-free survival (PFS) for tumor progression and symptom recurrence, symptom improvement, and procedure-related complications. Symptomatic improvement was defined as documentation of relief of pain (partial or complete) and/or functional impairment. RESULTS: All procedures were technically successful. At 7-12 months, median changes in TLV and VTV were -6.7% (P = .809) and -43.7% (P = .01), respectively. At 10-12 months, the mRECIST responses were complete response, 0%; partial response, 61.5% (8/13); stable disease, 30.8% (4/13); and progressive disease, 7.7% (1/13). The median PFS for tumor progression and symptom recurrence were not reached, with a median follow-up of 15.3 and 21.0 months, respectively. Symptomatic relief (partial or complete) was achieved in 96.9% (32/33) of patients. One major complication was noted (2.4%). CONCLUSIONS: In this retrospectively identified cohort, cryoablation was effective and safe for the local control of extra-abdominal DTs in short-term follow-up.

Management strategies and clinical outcomes in breast cancer patients who develop left ventricular dysfunction during trastuzumab therapy.

BACKGROUND: Trastuzumab reduces risk of breast cancer recurrence but carries risk of cardiotoxicity that may be reversible upon treatment cessation and institution of left ventricular (LV) enhancement therapies (LVETx). We assessed management patterns of trastuzumab-induced cardiotoxicity (TIC) in a contemporary real-world setting. METHODS: We reviewed charts of all breast cancer patients who received adjuvant trastuzumab in British Columbia between January 2010 and December 2013, spanning the opening of a cardio-oncology clinic. LV dysfunction (LVD) was classified as minimal (LVEF nadir 45-49%), mild (40-44%) or moderate-severe (< 40%). Charts were reviewed for baseline characteristics, management strategies, and outcomes. Multivariable analysis was performed to identify patient characteristics associated with trastuzumab completion and cardiology referral. RESULTS: Of 967 patients receiving trastuzumab, 171 (17.7%) developed LVD, including 114 patients (11.8%) with LVEF declines of ≥10 to < 50%. Proportions of patients receiving cardiology referrals and LVETx increased and wait times to consultation decreased after a dedicated cardio-oncology clinic opened. LVETx was used more frequently in patients with moderate-severe LVD compared to minimal or mild LVD. Factors associated with completion of trastuzumab included mastectomy (OR 5.1, 95% CI 1.1-23.0) and proximity to quaternary care centre (OR 7.7, 95% CI 2.2-26.2). Moderate-severe LVD was associated with a lower probability of completing trastuzumab (OR 0.07 vs. minimal LVD, 95% CI 0.01-0.74). Factors associated with cardiology referral included heart failure symptoms (OR 8.0, 95% CI 1.5-42.9), proximity to quaternary care centre (OR 6.8, 95% CI 1.3-34.2), later year of cancer diagnosis (OR 2.4 per year, 95% CI 1.4-4.3), node-positive disease (OR 0.18, 95% CI 0.06-0.56), mastectomy (OR 0.05, 95% CI 0.01-0.52), and minimal LVD (OR 0.14, 95% CI 0.05-0.46). LVEF recovered to > 50% in 90.7% of patients. CONCLUSIONS: Management strategies in patients with TIC are associated with cancer characteristics and severity of cardiotoxicity. Access to dedicated cardio-oncology clinics may facilitate optimal care of this complex patient population.

Canadian Consensus for Biomarker Testing and Treatment of TRK Fusion Cancer in Adults.

The tyrosine receptor kinase (TRK) inhibitors larotrectinib and entrectinib were recently approved in Canada for the treatment of solid tumours harbouring neurotrophic tyrosine receptor kinase (NTRK) gene fusions. These NTRK gene fusions are oncogenic drivers found in most tumour types at a low frequency (<5%), and at a higher frequency (>80%) in a small number of rare tumours (e.g., secretory carcinoma of the salivary gland and of the breast). They are generally mutually exclusive of other common oncogenic drivers. Larotrectinib and entrectinib have demonstrated impressive overall response rates and tolerability in Phase I/II trials in patients with TRK fusion cancer with no other effective treatment options. Given the low frequency of TRK fusion cancer and the heterogeneous molecular testing landscape in Canada, identifying and optimally managing such patients represents a new challenge. We provide a Canadian consensus on when and how to test for NTRK gene fusions and when to consider treatment with a TRK inhibitor. We focus on five tumour types: thyroid carcinoma, colorectal carcinoma, non-small cell lung carcinoma, soft tissue sarcoma, and salivary gland carcinoma. Based on the probability of the tumour harbouring an NTRK gene fusion, we also suggest a tumour-agnostic consensus for NTRK gene fusion testing and treatment. We recommend considering a TRK inhibitor in all patients with TRK fusion cancer with no other effective treatment options.