Princess Margaret Cancer Centre Research Articles

A Phase 2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Cfi-400945 As a Single Agent or in Combination with Azacitidine or Decitabine in Patients with Acute Myeloid Leukemia

A Phase 2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of Cfi-400945 As a Single Agent or in Combination with Azacitidine or Decitabine in Patients with Acute Myeloid Leukemia

Tobacco exposure and immunotherapy response in PD-L1 positive lung cancer patients

BackgroundTobacco exposure contributes to over 80 % of lung cancer cases. Smoking is associated with programmed death-ligand 1 (PD-L1) tumor expression and better outcomes from anti-programmed cell death protein 1 (anti-PD-1) therapy in patients with advanced non-small cell lung cancer (NSCLC). PD-L1 tumor expression is now routinely used to predict benefit from anti-PD-1 therapy in patients with advanced NSCLC. In this study, we explored the impact of smoking status on patient outcomes with anti-PD-1 therapy in addition to PD-L1 tumor expression. MethodsA prospective real-world cohort of 268 patients with advanced NSCLC treated with anti-PD-1 monotherapy at the Princess Margaret Cancer Centre (PMCC) was used for this analysis. Logistic regression was performed to test factors associated with treatment response (RECIST v1.1), including PD-L1 tumour proportion score (TPS) and smoking status. ResultsOverall response rates (ORR) to immunotherapy were significantly higher in current and former smokers than never smokers (36 % vs 26 % vs 14 %; p = 0.02). In patients with PD-L1 tumour proportion score (TPS) ≥50 %, current smokers continued to experience better ORR to anti-PD-1 therapy than never smokers (58 % vs 19 %; p = 0.03). Current smoking was associated with higher response even after adjusting for level of PD-L1 TPS expression (adjusted odds ratio 5.9, 95 % CI 1.6–25.0, p = 0.03). Exploratory analysis demonstrated higher 1-year survival rates in smokers compared to never smokers (p = 0.003). ConclusionsSmoking remains an important factor associated with response to anti-PD-1 monotherapy. Advanced NSCLC patients with positive PD-L1 expression are more likely to respond to anti-PD-1 monotherapy if they are current smokers compared to never smokers.

The reality of virtual care: Implications for cancer care beyond the pandemic

There has been longstanding interest in virtual care in oncology, but outdated reimbursement structures and a paradoxical lack of agility within electronic systems limited widespread adoption. Through the example of the Province of Ontario, Canada and the Princess Margaret Cancer Centre, we describe how a collective sense of action from COVID-19, a system of distributed leadership and decision-making, and the use of a Service Design process to map the ambulatory encounter onto a digital workflow were critical enablers of a large-scale virtual transition. Rigorous evaluation of virtual care models will be essential to maintain integration of virtual care post-pandemic.

Chemoradiotherapy Using Carboplatin plus Paclitaxel versus Cisplatin plus Fluorouracil for Esophageal or Gastroesophageal Junction Cancer

Background: Trimodality therapy (TMT) with neoadjuvant chemoradiotherapy (nCRT) using concurrent carboplatin plus paclitaxel (CP) followed by surgery is the standard of care for locoregional esophageal or gastroesophageal junction (GEJ) cancers. Alternatively, nCRT with cisplatin plus fluorouracil (CF) can be used. Definitive chemoradiotherapy (dCRT) with CP or CF can be used if surgery is not planned. In the absence of comparative trials, we aimed to evaluate outcomes of CP and CF in the settings of TMT and dCRT. Methods: A single-site, retrospective cohort study was conducted at the Princess Margaret Cancer Centre to identify all patients who received CRT for locoregional esophageal or GEJ cancer. Overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method and multivariable Cox regression model. The inverse probability treatment weighting (IPTW) method was used for sensitivity analysis. Results: Between 2011 and 2015, 93 patients with esophageal (49%) and GEJ (51%) cancers underwent nCRT (n = 67; 72%) or dCRT (n = 26; 28%). Median age was 62.3 years and 74% were male. Median follow-up was 23.9 months. Comparing CP to CF in the setting of TMT, the OS and DFS rates were similar. In the setting of dCRT, CP was associated with significantly inferior 3-year OS (36 vs. 63%; p = 0.001; HR 3.1; 95% CI: 1.2–7.7) and DFS (0 vs. 41%; p = 0.004; HR 3.6; 95% CI: 1.4–8.9) on multivariable and IPTW sensitivity analyses. Conclusions: TMT with CF and CP produced comparable outcomes. However, for dCRT, CF may be a superior regimen.

Diagnostic patterns of non-small-cell lung cancer at Princess Margaret Cancer Centre.

Accurate classification of lung cancer subtypes has become critical in tailoring lung cancer treatment. Our study aimed to evaluate changes in diagnostic testing and pathologic subtyping of advanced non-small-cell lung cancer (nsclc) over time at a major cancer centre. In a review of patients diagnosed with advanced nsclc at Princess Margaret Cancer Centre between 2007-2009 and 2013-2015, diagnostic method, sample type and site, pathologic subtype, and use of immunohistochemistry (ihc) staining and molecular testing were abstracted. The review identified 238 patients in 2007-2009 and 283 patients in 2013-2015. Over time, the proportion of patients diagnosed with adenocarcinoma increased to 73.1% from 60.9%, and diagnoses of nsclc not otherwise specified (nos) decreased to 6.4% from 18.9%, p < 0.0001. Use of diagnostic bronchoscopy decreased (26.9% vs. 18.4%), and mediastinal sampling procedures, including endobronchial ultrasonography, increased (9.2% vs. 20.5%, p = 0.0001). Use of ihc increased over time to 76.3% from 41.6% (p < 0.0001). Larger surgical or core biopsy samples and those for which ihc was performed were more likely to undergo biomarker testing (both p < 0.01). Customizing treatment based on pathologic subtype and molecular genotype has become key in treating patients with advanced lung cancer. Greater accuracy of pathology diagnosis is being achieved, including through the routine use of ihc.

Supported self-management as an innovative model of care for advanced gynecologic cancer patients with malignant bowel obstruction: A qualitative study

Objective: Women with advanced gynecologic cancer and malignant bowel obstruction (MBO) undergo repeated hospitalizations, experience feelings of isolation and abandonment, and often die in acute settings. Innovative outpatient models of care are needed to address the unmet needs of this population at the end of life. We implemented a novel supported self-management program at Princess Margaret Cancer Centre (Toronto, Canada) focused on increasing patients’ own skill and confidence in managing MBO proactively in the ambulatory setting.

Palliative care provision at a tertiary cancer center during a global pandemic.

COVID-19 was first reported in Wuhan, China, in December 2019; it rapidly spread around the world and was declared a global pandemic by the World Health Organization in March 2020. The palliative care program at the Princess Margaret Cancer Centre, Toronto, Canada, provides comprehensive care to patients with advanced cancer and their families, through services including an acute palliative care unit, an inpatient consultation service, and an ambulatory palliative care clinic. In the face of a global pandemic, palliative care teams are uniquely placed to support patients with cancer who also have COVID-19. This may include managing severe symptoms such as dyspnea and agitation, as well as guiding advance care planning and goals of care conversations. In tandem, there is a need for palliative care teams to continue to provide care to patients with advanced cancer who are COVID-negative but who are at higher risk of infection and adverse outcomes related to COVID-19. This paper highlights the unique challenges faced by a palliative care team in terms of scaling up services in response to a global pandemic while simultaneously providing ongoing support to their patients with advanced cancer at a tertiary cancer center.

COVID-19 Testing in Patients with Cancer: Does One Size Fit All?

The COVID-19 global pandemic has drastically impacted cancer care, posing challenges in treatment and diagnosis. There is increasing evidence that cancer patients, particularly those who have advanced age, significant comorbidities, metastatic disease, and/or are receiving active immunosuppressive therapy may be at higher risk of COVID-19 severe complications. Controlling viral spread from asymptomatic carriers in cancer centers is paramount, and appropriate screening methods need to be established. Universal testing of asymptomatic cancer patients may be key to ensure safe continuation of treatment and appropriate hospitalized patients cohorting during the pandemic. Here we perform a comprehensive review of the available evidence regarding SARS-CoV-2 testing in asymptomatic cancer patients, and describe the approach adopted at Princess Margaret Cancer Centre (Toronto, Canada) as a core component of COVID-19 control.

Enhancing International Cancer Organization Collaborations: King Hussein Cancer Center and Princess Margaret Cancer Centre Model for Collaboration.

Collaborative partnerships, which link two health organizations with shared characteristics to achieve common goals and to improve healthcare quality, are becoming increasingly common in oncology. The purpose of this study is to review the collaboration between King Hussein Cancer Center (KHCC) and Princess Margaret Cancer Centre (PM). The context, input, process, and product (CIPP) model, a quasi-experimental form of program evaluation, has been applied to the KHCC-PM collaboration. This model is well suited to evaluate complex collaborations as it does not assume linear relationships. Data sources include stakeholders' judgements of the collaboration, assessment of achievements, and informal interviews with key participants involved in the program. KHCC and PM are recognized as high-caliber comprehensive cancer centers, with a common goal of delivering high-quality care to patients. Through personal relationships among faculty in the centers and the perceived opportunities for mutual benefit, KHCC and PM signed a memorandum of understanding in 2013 to enter into a formal partnership. This partnership has been an evolving process that started with collaboration on education and grew to include clinical care. Research is an area for potential future collaboration. Enabling factors in the collaboration include dedication of individuals involved, trusting relationships amongst faculty, and the reciprocal nature of the relationship. Challenges have been financial, competing interests, and the absence of a successful collaborative model to follow. The KHCC and PM collaboration has been successful. A strategic plan is being developed and followed to guide areas of expansion.

Abstract 3209: The cBioPortal for Cancer Genomics

Abstract The cBioPortal for Cancer Genomics is an open-source software platform that enables interactive, exploratory analysis of large-scale cancer genomics data sets with a biologist-friendly interface. It integrates genomic and clinical data, and provides a suite of visualization and analysis options, including OncoPrint, mutation diagram, variant interpretation, survival analysis, expression correlation analysis, alteration enrichment analysis, cohort and patient-level visualization, among others. The public site (https://www.cbioportal.org) hosts data from more than 280 studies from diverse sources including individual labs and large consortia. All data is also available in the cBioPortal Datahub (https://github.com/cBioPortal/datahub/). Data from 40 studies, totaling more than 10,000 samples, was added in 2019, including the latest release from the Cancer Cell Line Encyclopedia and the Pediatric Preclinical Testing Consortium. The site is accessed by over 30,000 unique visitors per month. cBioPortal also supports AACR Project GENIE with a dedicated instance hosting the GENIE cohort of 80,000 clinically sequenced samples from 19 institutions worldwide (http://genie.cbioportal.org). In addition, more than 40 instances are installed locally at academic institutions and pharmaceutical/biotechnology companies. In support of these local installations, cBioPortal now has improved documentation and simplified installation via container technologies such as Docker and Kubernetes. Building on our successful refactoring of the code base, we have released a variety of new features and enhancements to cBioPortal over the past year. Most notably, we released a group comparison feature, enabling users to define groups of interest based on any clinical or genomic features. User-defined groups can be compared simultaneously across genomic and clinical data, including survival analysis and genomic alteration enrichment analysis. Additional new features include: integration of mutation annotations from dbSNP, ClinVar and gnomAD; support for waterfall plots to enable treatment response analysis; saving user preferences for chart layout on study view. The cBioPortal remains under active development. The portal is fully open source (https://github.com/cBioPortal/) under a GNU Affero GPL license. Development is a collaborative effort among groups at Memorial Sloan Kettering Cancer Center, Dana-Farber Cancer Institute, Children's Hospital of Philadelphia, Princess Margaret Cancer Centre, and The Hyve. Ongoing and future development is focused on: (1) building the open source community; (2) continued performance improvements; (3) expanding user support, documentation and training resources; (4) supporting longitudinal data analysis and visualization; (5) developing novel features to support immunogenomics and immunotherapy; (6) enhancing individual variants and overall patient interpretation; (7) supporting single cell data visualizations and analysis. Citation Format: Jianjiong Gao, Tali Mazor, Adam Abeshouse, Ino de Bruijn, Benjamin Gross, Karthik Kalletla, Priti Kumari, Ritika Kundra, Xiang Li, James Lindsay, Aaron Lisman, Pieter Lukasse, Ramyasree Madupuri, Angelica Ochoa, Oleguer Plantalech, Sander Rodenburg, Fedde Schaeffer, Robert Sheridan, Lucas Sikina, Jing Su, S. Onur Sumer, Yichao Sun, Paul van Dijk, Sjoerd van Hagen, Pim van Nierop, Avery Wang, Manda Wilson, Hongxin Zhang, Gaofei Zhao, Kelsey Zhu, Kees van Bochove, Ugur Dogrusoz, Allison Heath, Adam Resnick, Trevor J. Pugh, Chris Sander, Ethan Cerami, Nikolaus Schultz. The cBioPortal for Cancer Genomics [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3209.

Quantitative ultrasound radiomics for therapy response monitoring in patients with locally advanced breast cancer: Multi-institutional study results.

BackgroundNeoadjuvant chemotherapy (NAC) is the standard of care for patients with locally advanced breast cancer (LABC). The study was conducted to investigate the utility of quantitative ultrasound (QUS) carried out during NAC to predict the final tumour response in a multi-institutional setting.MethodsFifty-nine patients with LABC were enrolled from three institutions in North America (Sunnybrook Health Sciences Centre (Toronto, Canada), MD Anderson Cancer Centre (Texas, USA), and Princess Margaret Cancer Centre (Toronto, Canada)). QUS data were collected before starting NAC and subsequently at weeks 1 and 4 during chemotherapy. Spectral tumour parametric maps were generated, and textural features determined using grey-level co-occurrence matrices. Patients were divided into two groups based on their pathological outcomes following surgery: responders and non-responders. Machine learning algorithms using Fisher’s linear discriminant (FLD), K-nearest neighbour (K-NN), and support vector machine (SVM-RBF) were used to generate response classification models.ResultsThirty-six patients were classified as responders and twenty-three as non-responders. Among all the models, SVM-RBF had the highest accuracy of 81% at both weeks 1 and week 4 with area under curve (AUC) values of 0.87 each. The inclusion of week 1 and 4 features led to an improvement of the classifier models, with the accuracy and AUC from baseline features only being 76% and 0.68, respectively.ConclusionQUS data obtained during NAC reflect the ongoing treatment-related changes during chemotherapy and can lead to better classifier performances in predicting the ultimate pathologic response to treatment compared to baseline features alone.

Clinical Trials in the Evolving Landscape of Precision Medicine

Landmark discoveries in cancer research improve clinical therapies. To bring these therapies to the right patients quickly and safely requires well-designed clinical trials. Harmony Turk of Cancer Cell and Sara Hamilton of Cell Reports Medicine spoke with Dr. Lillian Siu of Princess Margaret Cancer Center, Dr. Carl June of the University of Pennsylvania's Perelman School of Medicine, and Dr. Patrick Ott of Dana-Farber Cancer Institute on improving the design of oncology clinical trials in the evolving landscape of precision medicine. Excerpts from this conversation are presented below, and the full conversation is available with the article online. Editor's note: Some text was subsequently revised for clarity and conciseness.

Abstract 26: A novel electronic platform to improve clinical trial workflow and screening

Abstract Background: Early-phase clinical trials are increasingly complex, with “seamless” phase I/II trial designs that include multiple parallel disease and/or biomarker-selected expansion cohorts. Challenges for participating sites in phase 1 (P1) trials include rapid identification of patients for available trial slots, high screen failure (SF) rates, and workload distribution among nurses and data coordinators. The Princess Margaret (PM) Cancer Centre Solid Tumor P1 program is the largest early-phase clinical trial program in Canada. There are currently 53 actively recruiting clinical trials, and approximately 250-300 patients are enrolled annually. To improve operational efficiency at the point of care, we designed a novel electronic platform, termed Phase One Spot Tracker (POST). Methods: An electronic, password-restricted, web-based tracker and smartphone-enabled app was created using PHP Laravel, JavaScript (iOS), and Java (Android). The intention was to replace the two previously used Excel spreadsheets, where one listed the trial information and the other included available slot allocations by trial. These spreadsheets were cumbersome to use in clinic, without the ability to search or filter. POST enabled all users to access the data from any computer or phone, increased the ease of updating information in real time, and functioned as a search engine to locate available spots more quickly. It contains specific information including brief trial description, key eligibility criteria, biopsy requirements, status of trial slots (e.g., screening, available, pending, etc.). The data security of POST is ensured by Amazon Web Services. Results: Prior to launching POST, three time-measured simulations showed that it reduced the coordinators’ workload to update trial information by 30 minutes. Currently POST is used by 65 users, including 7 physicians, 14 nurses, and 29 coordinators at the PM Cancer Centre. POST is used by investigators during a weekly P1 new patient consultation clinic to identify trial candidates as well as in weekly P1 team meetings to review all patients enrolled and approached for clinical trials. We are enhancing the POST platform to enable tracking of SF (patients who undergo study-specific screening procedures but are not enrolled in a clinical trial), timeline for replacing patients who screen fail, and reasons for SF. Conclusions: POST is an electronic, smart phone-enabled platform that can be implemented at the point of care for early-phase clinical trials. POST can also provide real-time tracking data about operational metrics (startup time, screening time, enrollment data, nursing and data coordinator workload, and screen failures) that can be used to drive quality improvement. POST can be extended to other disease site groups as well as to other institutions. This will eventually lead to an increase in work efficiency and provide a better quality of care for cancer patients. Citation Format: Ramy R. Saleh, Olivia Chan, Silvi Kuld, Patrick Marban, Anna Spreafico, Aaron Hansen, Albiruni Razak, Lillian L. Siu, Philippe L. Bedard. A novel electronic platform to improve clinical trial workflow and screening [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 26.

Setting a baseline: A 7-year review of referral rates and outcomes for serous ovarian cancer prior to implementation of oncologist mediated genetic testing

ObjectiveDespite guidelines recommending that all women with invasive serous ovarian cancer (SOC) are offered genetic testing, published referral and testing rates have been poor. Many centers have implemented novel genetic counseling service delivery models to increase testing rates. In light of increased awareness and implementation of small process changes at our center, this study aims to establish baseline referral rates and testing outcomes prior to diverging from the traditional model of care. MethodsA list of women diagnosed with SOC at Princess Margaret Cancer Center (PM) between 2010 and 2016 was obtained from the PM Cancer Registry and cross-referenced against the genetics database to determine referral rates and outcomes of genetic testing. ResultsOf 724 women with SOC, 68% were referred for genetic counseling, with an overall testing rate of 61%. Higher referral rates were seen among women with younger ages at diagnosis and high-grade tumors. Of women tested, 22% were found to have a pathogenic variant in BRCA1/2 and 9% in another cancer gene. Notably, 24% of women with a pathogenic variant reported no family history of breast or ovarian cancer. ConclusionGenetic counseling referral and testing rates for women with SOC are higher than previously reported, yet barriers to referral remain. To maximize genetic testing rates and address increasing patient volumes, clinics may be faced with integrating novel genetic counseling delivery models. Findings from this study may serve as a more accurate baseline to which large scale service delivery changes can be compared.

Feasibility randomised controlled trial of remote symptom chemotherapy toxicity monitoring using the Canadian adapted Advanced Symptom Management System (ASyMS-Can): a study protocol

IntroductionTechnology is emerging as a solution to develop home-based, proactive ‘real-time’ symptom monitoring and management in cancer care. The Advanced Symptom Monitoring and Management System—Canada (ASyMS-Can) is a remote phone-based...

Eat All Through Radiation Therapy (EAT-RT): Structured therapy model to facilitate continued oral intake through head and neck radiotherapy-User acceptance and content validation.

To develop and examine user acceptance and content validity of a structured program to facilitate safe but challenging oral intake during radiotherapy (RT) delivered by a speech language pathologist (SLP)-the Eat-All Through Radiation Therapy (EAT-RT) program. EAT-RT was developed through expert consensus of SLPs at the Princess Margaret Cancer Centre (Canada) and M D Anderson Cancer Center using a conceptual framework of a diet hierarchy and a mealtime routine. EAT-RT was refined by practicing SLPs, and then disseminated for a 4-week clinical pilot at seven sites who were subsequently invited to participate in an online survey. Twelve SLPs from six sites piloted EAT-RT therapy with a median of eight patients (IQR: 2-15) before and/or during RT. All SLPs reported EAT-RT added value to their practice, harmonized well with exercises, and its content was helpful; 11 (92%) reported EAT-RT facilitated patient understanding and indicated the desire to continue using EAT-RT. The EAT-RT program was accepted by North American SLPs. The findings support the content and value of EAT-RT to facilitate oral intake in patients with head and neck cancer throughout RT.

Prognostic significance of nutritional markers in metastatic gastric and esophageal adenocarcinoma.

4557 Background: Malnutrition and sarcopenia (defined as low skeletal muscle mass) are recognized as poor prognostic factors in many cancers. Studies to date in gastroesophageal cancer have largely focused on patients (pts) undergoing curative intent surgery. This study aims to evaluate the prognostic utility of nutritional markers and sarcopenia in pts with de novo metastatic gastric and esophageal adenocarcinoma (GEA). Methods: Pts with de novo metastatic GEA seen at the Princess Margaret Cancer Centre from 2010-2016 with available pre-treatment abdominal computed tomography imaging were identified from an institutional database. Nutritional index (NRI) was calculated using weight and albumin, with moderate/severe malnutrition defined as NRI &lt; 97.5. Skeletal muscle index (SMI) normalized by height was calculated at the L3 level using Slice-O-Matic software. Sarcopenia was defined as SMI &lt; 34.4cm2/m2 in women and &lt; 45.4cm2/m2 in men based on previously established consensus. Results: Of 175 consecutive pts, median age was 61, 69% were male, 79% had ECOG performance status 0-1, and 71% received chemotherapy. Median BMI was 24.2 (range 15.7-39.8), 70% of pts had &gt; 5% weight loss in the preceding 3 months, and 29% had moderate/severe malnutrition. 68 pts (39%) were sarcopenic, of whom 46% were malnourished. Median overall survival (OS) was 9.3 months (95% CI 7.3-11.4) for all pts. OS was significantly worse in malnourished pts (5.5 vs 10.9 months, p = 0.000475) and displayed a non-significant trend in sarcopenic pts (7.8 vs 10.6 months, p = 0.186). On univariable Cox proportional hazards (PH) analysis, ECOG (p &lt; 0.001), number of metastatic sites (p = 0.029) and NRI (p &lt; 0.001) were significant prognostic factors, while BMI (p = 0.57) and sarcopenia (p = 0.19) were not. On multivariable Cox PH analysis, ECOG (p &lt; 0.001) and NRI (p = 0.025) remained significant as poor prognostic factors for OS. Conclusions: This study demonstrates in a large cohort of de novo metastatic GEA pts that ECOG and NRI were significantly associated with poor OS. NRI was superior to BMI alone. Early identification of malnourished pts using NRI may allow for supportive interventions to optimize nutritional status. Further study is needed to determine whether these factors can be modified to improve prognosis in these pts.

Clinical predictors of long-term response to capecitabine in metastatic breast cancer (MBC).

1088 Background: Select patients (pts) with metastatic breast cancer (MBC) treated with capecitabine (cape) experience long-term disease control. We aimed to evaluate the clinical and biological predictors of long-term response. Methods: Pts receiving cape monotherapy for breast cancer from 01/2006 to 01/2016 at Princess Margaret Cancer Centre in Toronto, Canada (N = 352) or Alberta, Canada (N = 798) were identified through central pharmacy records. A median time-to-progression (MTTP) 3-fold higher (19.3 months) than those seen in published studies for patients treated with cape monotherapy at 1000mg/m2 was applied to select for pts with long-term response. MBC pts meeting these criteria were identified through chart review, with collection of clinical, pathological, and survival outcomes in addition to oncologist assessed (o) best response (eg: oCR, oPR, oSD) by radiology report review. Descriptive statistics, Kaplan-Meier and Cox-regressions were applied. Results: Overall, 41 (4%) pts met long-term response criteria. Median age of the study cohort was 62 (range 40-80), with 39% metastatic at diagnosis and 76% post-menopausal. At initiation of cape, a majority of pts were HR positive (85%), with an LDH &lt; ULN (56%), and had bone (83%) or visceral (63%) metastases. Only 1 (2%) patient was HER2+. In the metastatic setting, most patients were chemotherapy-naive (83%) and had received 0-1 lines of hormonal therapy (61%). Median treatment duration with cape was 2.2 years (range 1.7-5.7) with 37% of pts having ≥40 cycles (range 22-94). Visceral (49%), bone (34%), and lymph nodes (24%) were the most common sites of progression, with 41% requiring 1 dose reduction and 27% requiring 2 dose reductions of cape. Overall response rate was 56% (oCR = 2%, oPR = 54%) with 44% having oSD as best response. Median follow-up was 6.8 years (95%CI: 5.5-8.2). Median PFS was 2.3 years (2.0-2.6), with a median OS of 3.8 years (2.9-4.6). 5 patients (12%) remained alive at data-cutoff, and 1 (2%) remained on treatment after 94 cycles of cape. Conclusions: Clinical features associated with long-term response on cape include HR positive, HER2 negative postmenopausal patients with bone predominant metastasis who have received 0-2 lines of prior hormone therapy and 0-1 lines of chemotherapy in the metastatic setting. This is the largest reported analysis of MBC patients with prolonged responses to cape. In the absence of randomized controlled trials; real-world evidence could aid clinicians in the optimal patient selection for treatment with cape.

Genomic analysis of driver-negative lung adenocarcinoma (LA) in lifetime never smokers.

3571 Background: Genomic events giving rise to driver negative LA in never smokers remain elusive. Here we report results of whole exome sequencing (WES) and targeted RNA sequencing in NS who had no mutation drivers found on routine clinical testing by targeted next generation sequencing (NGS). Methods: The cohort of never smokers with EGFR/ALK negative LA by clinical biomarker testing at Princess Margaret Cancer Centre, were first subjected to various clinical NGS profiling platforms (table). Where tissue was available, those negative for potential drivers in the clinical NGS then underwent WES (mean coverage &gt; 200x) and Oncomine comprehensive v.3 RNA sequencing. We analyzed mutational signatures (MS) of the driver negative cohort based on the COSMIC catalog and assessed the median tumor mutation burden (mTMB mut/Mb -Megabase) in cases without a smoking MS, to avoid confounders. Results: Of 159 never smokers profiled with clinical NGS, potential drivers were found in 86 (54%): 75 (87%) with mutations in known LA driver genes and 11 (13%) with fusions. Among the remaining never smokers that tested negative by clinical NGS, 35 (48%) had available tissue for further testing. The Oncomine panel identified 9 cases (25%) with fusions or MET exon14 mutation (n = 7). Within the driver negative group, 24 (92%) underwent WES. Three tumors had WES base substitution patterns that were consistent with a smoking-related MS (MS4). Twenty-one patients exhibited signatures found common across all cancer types (MS 5), associated with DNA mismatch repair (MS 6, MS 20) or APOBEC over-activation (MS 2, MS13). In the driver-negative group, we identified 7 pts with somatic mutations in the KMT2 family (4 KMT2C, 4 KMT2A, 1 KMT2D), known for putative tumor suppressors and histone methyltransferases. mTMB on the driver negative group was 1.92, while one outlier with APOBEC MS and KMT2C/A mutations had a TMB of 16.8. Conclusions: Never smokers with driver negative LA are a heterogeneous group, with different MS and a wide TMB range. Mutations on KMT2 family are frequently found in driver negative LA in never smokers and warrant further investigations. [Table: see text]

Risk stratified multidisciplinary ambulatory management of malignant bowel obstruction (MAMBO) program for women with gynecological cancers: Preliminary results from a prospective single-center study.

6062 Background: Malignant Bowel Obstruction (MBO) is one of the most common and devastating complications in women with gynecological cancer (GC). There is currently no consensus guideline to improve patient (pt) care in this setting. MAMBO (NCT03260647) is an ongoing prospective study evaluating the clinical implementation of a novel management algorithm for multidisciplinary management of MBO in GC pts. We report preliminary patient outcomes. Methods: All GC pts at Princess Margaret Cancer Centre with a confirmed diagnosis of or are at risk of MBO are eligible for enrollment. Participants follow a low fiber diet titrated by severity of symptom and their monthly weight and albumin levels are recorded, along with standardized patient-reported outcome measures (PROMs) at different time points. For pts who develop MBO, inpatient and ambulatory management algorithms are applied using a multidisciplinary and interprofessional care model consisting of nurses, surgeons, oncologists, radiologists, nutritionists, total parenteral nutrition team, social work, and palliative care. Decisions regarding most optimal management strategies are made by this team with regular MAMBO rounds. A retrospective analysis of pts hospitalized with MBO between 2012 and 2017 was performed in order to have a historical comparison for outcome and survival analysis using Kaplan Meier methods. Results: Since August 2017, 70 pts have been enrolled in MAMBO. Most had high-grade serous ovarian carcinoma (75%), of whom 68% are platinum-resistant. So far, 36 (51%) developed MBO, 6 of whom had multiple sequential episodes. Mean number of days in hospital with MBO was 10 days (median 7, range 0-45), compared to 18 days (median 9, range 0-134) for historical control (p = 0.009). There was no significant loss in weight 6 months from MBO diagnosis but a significant reduction in albumin level by 2.75 g/L after 3 months (p = 0.005). PROMs suggest fatigue and general lack of wellbeing were the symptoms with highest distress. Most patients (78%) received chemotherapy following MBO and most received weekly paclitaxel (36%). Median time from first MBO to death was 219 days (95% CI: 101-not reached) for all-comers in MAMBO and 174 days (95% CI: 98-363) for MBO requiring hospitalization, compared to 108 days (95% CI: 79-160) for historical controls (p = 0.007 and p = 0.062, respectively). Conclusions: Patient care and outcomes from MBO seem to be improved in GC pts enrolled in MAMBO compared to historical controls. Clinical trial information: NCT03260647.