Search

Background: Genitourinary symptoms (GUS) such as vaginal dryness, dyspareunia, itching, urinary incontinence, urinary tract infections and discharge are common in patients with breast cancer (BC). Optimal management of GUS remains unclear. Our group previously published a systematic review (SR) on GUS management in 2014 which showed a paucity of RCT evidence addressing this knowledge gap (Mazzarello et al. 2015). We performed an updated SR to assess if more prospective trial data had been published in the past 7 years to inform management of this common complication of BC. Methods: EMBASE, Ovid Medline and the Cochrane Library were searched for RCTs evaluating treatments for GUS in BC patients from September 2014 to December 2021. A PICOS (population, intervention/comparators, outcomes and study design) framework was utilized. Population: women with breast cancer. Intervention/comparators: all forms of oral, intra-vaginal and topical hormonal and non-hormonal treatments. Outcomes of interest: improvements in vaginal symptoms (e.g., dryness, pain, dyspareunia, itching); vaginal hormone response, measured by validated scales [e.g., Vaginal Health Index (VHI) and Vaginal Maturation Index (VMI)] and quality of life [e.g., Female Sexual Function Index (FSFI)]. Study design: only RCTs were included. Two independent reviewers performed the tasks of study selection, data collection, and risk of bias assessment. Results: Of 842 unique citations identified (412 from this update, 430 from previous SR), eight studies (n = 539 patients) met inclusion criteria. Interventions included 0.005% estriol gel (EG; n=50 patients), intravaginal testosterone (IVT; n=21), intravaginal prebiotic (n=13), hyaluronic acid (HA; n=12), polyacrylic acid (PA; n=25), pH-balanced gel (two studies; n=118), Replens(n=24) and Lidocaine gel (n=22). These interventions were compared to placebo/saline/usual care (n=254). One study had three arms comparing prebiotics, HA and usual care. Study sample sizes ranged from 44 to 136 patients. Given the heterogeneity of the studies, a narrative synthesis was performed. Compared to placebo, FSFI total score was significantly improved by all interventions except IVT (which demonstrated significant improvement in only the satisfaction domain) and 4% aqueous lidocaine before vaginal penetration (which improved significantly all domains except for orgasm). FSFI changes were not reported for Replens. Significant improvements in vaginal hormone responses (VHI and VMI) were reported for 0.005% EG and pH-balanced gel; however, no significant effects were found for IVT, HA or prebiotics. Vaginal symptoms (vaginal dryness, dyspareunia and pruritis) were significantly improved by EG, IVT, and PA. Vaginal symptoms were significantly improved in the single study of pH-balanced gel that reported this outcome. Conclusion: GUS is reported in 75% of BC patients but despite its frequency, the management of GUS remains a challenging issue for patients and health care providers. Due to study heterogenicity, there remains insufficient RCT evidence to define optimal therapy. More prospective trials comparing commonly used interventions are needed. Keywords: Genitourinary symptoms, Topical moisturizers, Intra-vaginal testosterone Citation Format: Parvaneh Fallah, Dianna M. Wolfe, Brian Hutton, Mark Clemons, Risa Shorr, Lisa Vandermeer, Moira Rushton-Marovac. Management of genitourinary symptoms in breast cancer patients: An updated systematic review of available evidence from randomized trials [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-12-07.

Purpose Machine learning (ML) is a powerful tool for interrogating datasets and learning relationships between multiple variables. We utilized a ML model to identify those early breast cancer (EBC) patients at highest risk of developing severe vasomotor symptoms (VMS). Methods A gradient boosted decision model utilizing cross-sectional survey data from 360 EBC patients was created. Seventeen patient- and treatment-specific variables were considered in the model. The outcome variable was based on the Hot Flush Night Sweats (HFNS) Problem Rating Score, and individual scores were dichotomized around the median to indicate individuals with high and low problem scores. Model accuracy was assessed using the area under the receiver operating curve, and conditional partial dependence plots were constructed to illustrate relationships between variables and the outcome of interest. Results The model area under the ROC curve was 0.731 (SD 0.074). The most important variables in the model were as follows: the number of hot flashes per week, age, the prescription, or use of drug interventions to manage VMS, whether patients were asked about VMS in routine follow-up visits, and the presence or absence of changes to breast cancer treatments due to VMS. A threshold of 17 hot flashes per week was identified as being more predictive of severe VMS. Patients between the ages of 49 and 63 were more likely to report severe symptoms. Conclusion Machine learning is a unique tool for predicting severe VMS. The use of ML to assess other treatment-related toxicities and their management requires further study.

Background: Current guidelines recommend the use of granulocyte colony-stimulating factors (G-CSF) as primary prophylaxis to prevent febrile neutropenia (FN) associated with commonly used breast cancer chemotherapy regimens. Filgrastim (FIL) is a short-acting G-CSF injection that requires daily subcutaneous injection starting 24-72 hours after chemotherapy for 5 to 10 days. Pegfilgrastim (PEG) is a long-acting, pegylated formulation that requires a single injection 24-72 hours after chemotherapy. G-CSF causes bone pain in approximately 70% of patients, which can be severe in over 25% of cases. While registration trials for PEG showed bone pain from PEG was comparable to FIL when given for a median duration of 11 days, many oncologists are now only prescribing FIL for 5 days based on a multicenter RCT showing that 5 days of FIL is non-inferior to 7 or 10 days of FIL in terms of FN and treatment-related hospitalizations. Furthermore, the cost of 5 days of FIL ($CA 721.55 for 300 mcg dose) is half of the price of a single dose of PEG ($CA 1424.63). Therefore, if 5 days of FIL leads to significantly less bone pain, this may improve health-related quality of life (HR-QoL) for patients, improve adherence to G-CSF, and improve cost-effectiveness. Methods: Patients receiving neo-/adjuvant chemotherapy for early stage breast cancer requiring primary FN prophylaxis with G-CSF will be approached for this pragmatic, multicenter, open-label superiority RCT. Using the Rethinking Clinical Trials (REaCT) methodology that incorporates an integrated oral consent model, eligible and consented patients will be randomized to either 5 days of FIL or one day of PEG with each cycle of chemotherapy. The primary endpoint is bone pain during the first 5 days after G-CSF injection using area under the curve (AUC) of the daily pain score from days 1-5 (AUC score 0 to 40) of the Bone Pain Diary. Secondary endpoints include incidence of FN and treatment-related hospitalizations, incidence of chemotherapy delay, dose-reduction, or discontinuation, incidence of chemotherapy-related mortality, rate of G-CSF compliance, healthcare resource utilization, HR-QoL, and cost-effectiveness. Participants will also complete a Treatment Preference Questionnaire (TPQ) exploring the relative importance of different factors in deciding between PEG vs. 5 days of FIL both before randomization and at the end of the study. To achieve 80% power in an ANCOVA analysis and assuming 5% are loss to follow-up, the planned sample size is 232 patients (116 per arm). The randomization (1:1 ratio) will be stratified by treatment center (4 centers) and chemotherapy regimen (taxane-based vs. anthracycline-based in the first 4 cycles). Results: The study opened for enrollment on June 9, 2021. As of July 6, 2021, the study has opened at one site, and 13 patients have been randomized.Conclusion: This will be the first RCT using a patient-reported Bone Pain Diary that was co-developed by patient partners to measure bone pain between 5 days of FIL vs. PEG. In collaboration with patient partners, the study incorporates a tool (TPQ) that explores factors that may be important in deciding between PEG and FIL, with the aim of translating the findings of this study into real world clinical practice. Citation Format: Terry L. Ng, Monica Taljaard, Marie-France Savard, Carol Stober, Stuart Nicholls, Lisa Vandermeer, Kednapa Thavorn, Claudia Hampel, Jennifer Shamess, Natalie Mills, John F. Hilton, Mark Clemons. A randomized, multicenter pragmatic trial comparing bone pain from a single dose of pegfilgrastim to 5 doses of daily filgrastim in breast cancer patients receiving neoadjuvant/adjuvant chemotherapy (REaCT-5G) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-21-01.

Background. Endocrine therapy (ET) is the mainstay treatment for hormonal receptor positive (HR+) breast cancer. ET non-compliance and non-persistence vary from 30 to 70% and are associated with reduced disease-free and overall survival. ET side effects are an important cause of non-adherence. In clinical practice, there are anecdotal reports that time of the day at which ET is taken may affect ET side effects and compliance. However, we are not aware of any high-quality studies supporting this practice. In other fields of medicine, there is evidence to suggest that the time of the day at which medication is taken can alter its effect and/or the adherence. This is known as chronotherapy. Methods. In this pragmatic, open-label, multicenter trial, eligible and consented patients with an early stage or locally advanced HR+ breast cancer will be randomized (1:1) to receive either: an ET morning dose (Arm A: within 1 hour of the patient wake up time) or an ET evening dose (Arm B: within 1 hour of patient bed time). The primary endpoint is endocrine toxicity and tolerability measured by the change in total Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES) score from baseline to 12 weeks following the beginning of ET. Secondary endpoints include: endocrine toxicity/tolerability and quality of life measured respectively by the change in total score and individual items of FACT-ES and FACT-B (a validated Functional Assessment of Cancer Therapy for patients with a Breast cancer) from baseline to 4, 8, 12 and 52 weeks following the beginning of ET, rates of non-persistence or non-compliance and cost-effectiveness. A timing preference questionnaire will be filled out at the beginning and the end of the study by patients to evaluate their preferred time. As per the Rethinking Clinical Trials (REaCT) program, the integrated consent model will be used and patients will complete questionnaires in the online patient portal. For randomization, a permuted block design developed by the Ottawa Methods Centre will be used and patients will be stratified by center, type of endocrine therapy (tamoxifen yes/no) and if prior chemotherapy was received. Using a two-sided, alpha=0.05 Fisher’s exact test, and assuming a 10% of loss to follow up, the planned sample size is 235 patients. Accrual. This study opened for enrollment at The Ottawa Hospital Cancer Centre on June 30, 2021 and will open soon at the Thunder Bay Regional Health Sciences Centre. The maximum accrual period is 2 years. Conclusion. This will be world’s first prospective randomized clinical trial to evaluate ET dose timing (morning versus evening) and its effects on tolerability and adherence. Changing the time of the day at which a medication is taken is a new, simple and easy intervention that does not generate additional costs and can improve the quality of life of breast cancer patients. Funding provided by: NOAMA (Northern Ontario Academic Medicine Association) Innovation Grant (2021) Clinical Trial Registration: NCT04864405 Citation Format: Marie-France Savard, Mohammed Ibrahim, Gregory Pond, Deanna Saunders, Lisa Vandermeer, Ana-Alicia Beltran-Bless, Lesley Fallowfield, Mark Clemons. A pragmatic, randomised, multicentre trial evaluating the dose timing (morning vs evening) of endocrine therapy and its effects on tolerability and compliance (REaCT-CHRONO Study) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-11-02.

Background Despite the frequency of vasomotor symptoms (VMS) in patients with early breast cancer (EBC), their optimal management remains unknown. A patient survey was performed to determine perspectives on this important clinical challenge. Methods Patients with EBC experiencing VMS participated in an anonymous survey. Patients reported on the frequency and severity of VMS using the validated Hot Flush Rating Scale (HFRS) and ranked their most bothersome symptoms. Respondents were also asked to determine endpoints that defined effective treatment of VMS and report on the effectiveness of previously tried interventions. Results Responses were received from 373 patients, median age 56 years (range 23–83), who experienced an average of 5.0 hot flashes per day (SD 6.57). Patients reported the most bothersome symptoms to be feeling hot/sweating (155/316, 49%) and sleeping difficulties (86/316, 27%). Fifty-five percent (201/365) of patients would consider a treatment to be effective if it reduced night-time awakenings. While 68% of respondents were interested in trying interventions from their healthcare team to manage VMS, only 18% actually did so. Of the 137 patients who had tried an intervention for VMS, pharmacological treatments, exercise, and relaxation strategies were more likely to be effective, while therapies such as melatonin and black cohosh were deemed less effective. Conclusion VMS are a common and bothersome problem for EBC patients, with a minority receiving interventions to manage these symptoms. Further research is needed to identify patient-centered strategies for managing these distressing symptoms.

Doxycycline is often used as a promoter of inducible gene expression in preclinical models; however, it can also have direct effects on tumor growth and survival. This is due in part to its ability to inhibit cell invasion and regulate matrix metalloproteinase (MMP) expression. Given that doxycycline is also osteotropic, a clinical study to assess its effects on modulation of tumor progression or prevention of skeletal-related events (SRE) in patients with bone metastases from breast cancer (the Achilles trial) was undertaken. Patients received 100 mg of oral doxycycline twice daily for 12 weeks, with serum obtained at baseline and 4, 8 and 12 weeks post-initiation of doxycycline treatment. Exploratory analysis of the effects of doxycycline on circulating levels of MMP or tissue inhibitor of matrix metalloproteinase 2 (TIMP2) was performed in enrolled patients. Statistically significant associations were observed between MMP2, MMP9 and TIMP2 at baseline with significant associations maintained between absolute levels and changes in levels of MMP2 and TIMP2 at weeks 4–12 post initiation of doxycycline. Treatment with doxycycline generally resulted in decreases in MMP2 and MMP9 levels with concurrent upregulation of TIMP2 at 12 weeks post-initiation of doxycycline treatment. Despite this, we observed no association with the levels of any of these factors with either SRE-free or overall survival in this patient cohort. In summary, despite observing hypothesized effects of doxycycline administration on surrogate markers of its anti-tumor activity, measures of circulating levels of these biomarkers were not prognostic in this patient population.

We reviewed patient and health care provider (HCP) surveys performed through the REaCT program. The REaCT team has performed 15 patient surveys (2298 respondents) and 13 HCP surveys (1033 respondents) that have addressed a broad range of topics in breast cancer management. Over time, the proportion of surveys distributed by paper/regular mail has fallen, with electronic distribution now the norm. For the patient surveys, the median duration of the surveys was 3 months (IQR 2.5–7 months) and the median response rate was 84% (IQR 80–91.7%). For the HCP surveys, the median survey duration was 3 months (IQR 1.75–4 months), and the median response rate, where available, was 28% (IQR 21.2–49%). The survey data have so far led to: 10 systematic reviews, 6 peer-reviewed grant applications and 19 clinical trials. Knowledge users should be an essential component of clinical research. The REaCT program has integrated surveys as a standard step of their trials process. The COVID-19 pandemic and reduced face-to-face interactions with patients in the clinic as well as the continued importance of social media highlight the need for alternative means of distributing and responding to surveys.

Background Primary febrile neutropenia (FN) prophylaxis with ciprofloxacin or granulocyte-colony stimulating factors (G-CSF) is recommended with docetaxel-cyclophosphamide (TC) chemotherapy for early-stage breast cancer (EBC). A pragmatic randomised trial compared the superiority of G-CSF to ciprofloxacin and a cost-utility analysis were conducted. Methods EBC patients receiving TC chemotherapy were randomised to ciprofloxacin or G-CSF. The primary outcome was a composite of FN and non-FN treatment-related hospitalisation. Secondary outcomes included; rates of FN, non-FN treatment-related hospitalisation, chemotherapy dose reductions/delays/discontinuations. Primary analysis was performed with the intention to treat population. Cost-utility analyses were conducted from the Canadian public payer perspective. Results 458 eligible patients were randomised: 228 to ciprofloxacin and 230 to G-CSF. For the primary endpoint there was non-statistically significant difference (Risk difference = −6.7%, 95%CI = −13.5%–0.1%, p = 0.061) between ciprofloxacin patients (46,20.2%) and G-CSF (31,13.5%). Patients receiving ciprofloxacin were more likely to experience FN (36/228, 15.8% vs 13/230, 5.7%) than patients receiving G-CSF (p, Highlights • Primary febrile neutropenia (FN) prophylaxis is indicated for docetaxel-cyclophosphamide (TC) chemotherapy. • In this multicentre trial 458 breast cancer patients receiving TC chemotherapy were randomised to ciprofloxacin or to G-CSF. • For the primary endpoint of FN and non-FN treatment-related hospitalizations, G-CSF was not superior over ciprofloxacin. • While there were reduced FN rates with G-CSF, the incremental cost-effectiveness ratio was C$1,760,796 per one QALYWALY gained.

Background: Non-compliance and non-persistence with endocrine therapy for breast cancer is common and usually related to treatment-induced side effects. There are anecdotal reports that simply changing the time of day when taking endocrine therapy (i.e., changing morning dosing to evening dosing or vice versa) can reduce side effects. Literature review: We conducted a literature review to evaluate whether changing the timing of tamoxifen and/or aromatase inhibitor administration impacted patient outcomes. No randomized control trials or prospective cohort studies that looked at time of day of endocrine therapy were identified through our review of literature from 1947 until August 2020. Conclusions: Given the rates of endocrine therapy non-compliance and non-persistence reported in the literature, ranging from 41–72% and 31–73%, respectively, simply changing the time of day when medications are taken could be an important strategy. We could identify no trials evaluating the effect of changes in timing of administration of endocrine therapy on breast cancer patient outcomes. Randomized control trials are clearly indicated for this simple and cost-effective intervention.

Although it is accepted that oncologists should plan for a future beyond full-time oncology, there is little practical guidance for a successful transition into retirement. Previously, we provided strategies for various aspects of retirement planning. However, this became significantly more complicated as we face newer issues such as the COVID-19 pandemic, the move to virtual patient care, greater awareness of burnout, and the increasing burden of regulatory issues such as the electronic medical record. It is evident that more prospective information is needed to guide oncologists in planning their retirement.

A cost–utility analysis was performed based on the Rethinking Clinical Trials (REaCT) bone-targeted agents (BTA) clinical trial that compared 12-weekly (once every 12 weeks) (n = 130) versus 4-weekly (once every 4 weeks) (n = 133) BTA dosing for metastatic breast and castration-resistant prostate (CRPC) cancer. Using a decision tree model, we calculated treatment and symptomatic skeletal event (SSE) costs as well as quality-adjusted life-years (QALYs) for each treatment option. Deterministic and probabilistic sensitivity analyses were performed to assess the robustness of the study findings. The total cost of BTA treatment in Canadian dollars (C$) and estimated QALYs was C$8965.03 and 0.605 QALY in the 4-weekly group versus C$5669.95 and 0.612 QALY in the 12-weekly group, respectively. De-escalation from 4-weekly to 12-weekly BTA reduces cost (C$3293.75) and improves QALYs by 0.008 unit, suggesting that 12-weekly BTA dominates 4-weekly BTA in breast and CRPC patients with bone metastases. Sensitivity analysis suggests high levels of uncertainty in the cost-effectiveness findings. De-escalation of bone-targeted agents is cost-effective from the Canadian public payer’s perspective.

Background Optimal use of bone-modifying agent (BMA) therapy in patients with bone metastases from breast and castrate-resistant prostate cancer (CRPC) is evolving. Methods Patients receiving BMA for bone metastases from breast or CRPC were surveyed. Information was collected on patient and disease characteristics, BMA treatments and perceptions regarding BMA benefits and side effects. Interest in participation in trials of de-escalated BMA therapy was also gauged. Results Of 220 patients contacted, 172 eligible patients responded (response rate 78%). Median age was 67 (range: 21–91); 137 (80%) had breast cancer and 35 (20%) CRPC. Symptomatic skeletal events (SSEs) occurred prior to starting BMAs in 61% (84/137) of breast and 48% (17/35) of CRPC patients. Among breast cancer patients, 47, 33 and 13% received zoledronate, pamidronate and denosumab, respectively. Eighty-five percent (30/35) of CRPC patients received denosumab. De-escalation of therapy was more common among breast cancer patients. Although most patients correctly reported the goals of BMA therapy were to “help stop fractures” (62%) and “[improve] quality of life” (63%), 46.5% felt it prolonged survival and 54% felt it reduced bone progression. Most respondents (102/129, 79%) were comfortable with de-escalating to 6-monthly treatment after 2 years of BMA therapy. Patients considered the most important endpoints of de-escalation studies to be “stability of bone metastases” (45%), “quality of life” (22%) and “SSE rates” (14%). Conclusion Twelve weekly BMA was more common in breast than in prostate cancer. There remain misconceptions about the benefits of BMAs, highlighting potential gaps in patient education. Patients were interested in further BMA de-escalation after 2 years of prior BMA and provided study endpoints that were most important to them. Supplementary Information The online version contains supplementary material available at 10.1007/s00520-021-06238-1.

Background: The results of the Early Breast Cancer Trialist Group (EBCTCG) meta-analysis (Lancet 2015) led to the widespread adoption of bisphosphonates as adjuvant therapy for postmenopausal early-stage breast cancer (EBC). Despite evaluating multiple bisphosphonate agents and regimens, there was no signal of varying efficacy with different agents, routes of administration or dose/dose intensity. We evaluated the question of treatment de-escalation using long-term outcome data from the prospective randomized ABCSG-12 trial. Patients and methods: Between 1999 and 2006, ABCSG-12 accrued 1803 patients with hormone-receptor positive EBC on ovarian function suppression for three years that were randomized to receive 4 mg zoledronic acid 6-monthly or not (and tamoxifen or anastrozole, in a 2:2 factorial design). In the current retrospective study, we evaluated whether the number of zoledronate infusions actually received had an impact on breast cancer-specific and fragility fracture outcomes. Based on the results of the EBCTCG meta-analysis, we hypothesized that amongst patients who receive less infusions than the planned seven zoledronate infusion in this trial, the number of infusions has no differential effect on these outcomes. Time to event endpoints were analyzed with Cox models and Kaplan Meier curves starting from a 3-year landmark. BMD subset analyses were restricted to patients who participated in the BMD sub-study with available BMD data. Results: 725 patients who received at least one zoledronate infusion were included in the time-to-event-analysis. There was no statistically significant difference in disease-free survival (adjusted HR 0.83, 95% CI 0.48–1.44, p=0.51) or overall survival (HR 0.97, 95% 0.30-3.11, p=0.96) in patients who received ≤6 zoledronate infusions (n=170) compared to those who received ≥7 zoledronate infusions (n=555) (adjusted HR 0.83, 95% CI 0.48 – 1.44, p=0.51). Both subgroups show stable lumbar spine and total hip BMD measurements across the five years. Conclusions: Comparable to the metastatic bone disease and fragility fracture settings, there was no evidence observed to indicate that a reduced number of zoledronate infusions is associated with reduced adjuvant efficacy. Further studies to define optimal regimens of adjuvant bone-targeted therapies (prospective evaluation of “how-low-can-you-go”) are required. Table 1: Multivariate Cox Regression: DFS and OS Table 2: BMD and percent change from baseline at the total hip and lumbar spine (L1-L4) over 60 months Citation Format: Ana-Alicia Beltran-Bless, Mark Clemons, Christian Fesl, Dominik Hlauschek, Lidija Soelkner, Gregory R. Pond, Lisa Vandermeer, Richard Greil, Marija Balic, Vesna Bjelic-Radisic, Christian F. Singer, Guenther Steger, Ruth Helfgott, Daniel Egle, Simon P. Gampenrieder, Stephanie Kacerovsky-Strobl, Christoph Suppan, Magdalena Ritter, Gabriel Rinnerthaler, Georg Pfeiler, Hannes Fohler, John Hilton, Michael Gnant. De-escalation of bone-targeted treatment: Does the number of 6-monthly adjuvant zoledronate infusions received affect treatment efficacy for early breast cancer? A sub-study of ABCSG-12 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-04.

Background: Despite extensive use of bone modifying agents (BMA) in patients with bone metastases from breast cancer (BC), the optimal choice, frequency, and duration of BMA treatment remains unclear. A physician survey was performed to identify current practices and attitudes towards performing trials of de-escalation after 2 years of treatment, where very little prospective data exists. Methods: Canadian oncologists treating breast cancer were surveyed from May to June 2020 via an anonymized online survey. Physicians were approached by e-mail invitation, and a follow-up e-mail was sent 2 weeks later. The study was approved by the Ontario Cancer Research Ethics Board. The survey collected physician demographics, current practice patterns, perception on risk of symptomatic skeletal events (SSE) and BMA-associated toxicity. It also assessed attitudes towards conducting a study evaluating further de-escalation of BMAs after 2 years of treatment. Results: Of 238 potentially eligible breast oncologists on initial screening, 40 responded (response rate 16.8%; 97.5% medical oncologist). The most common BMA regimens during the first 2 years in patients with no limitations in drug coverage were denosumab q4wks for 3-4 months then q12wks [13/40 physicians (32.5%)], denosumab q4wks [7/40 (17.5%)], and zoledronate q12wks [8/40 (20%)]. For patients with no public funding for denosumab, the most common regimens were zoledronate q4wks for 3-4 months then q12wks [14/40 (35%)] and zoledronate q12wks [12/40 (30%)]. Most physicians [33/40 (82.5%)] routinely de-escalated BMA, with the most common approaches being de-escalation from the start of treatment [9/33 (27.3%)], after 3 months [7/33 (21.2%)], 6 months [6/33 (18.2%)], or 12 months [5/33 (15.2%)]. In terms of continuing BMA after 2 years, 11/40 (27.5%) felt there was benefit, 5/40 (12.5%) felt there was no benefit, and 24/40 (60%) were unsure. There was no consensus on the perceived risk of SSE or BMA-related toxicity after ≥ 2 years of BMA in breast cancer. Most physicians treating breast cancer-related bone metastases felt a de-escalation study after more than 2 years of BMA would be clinically important [i.v. bisphosphonate (BP) q12wks vs q24wks: 65%; i.v. BP q12wks vs. discontinue: 70%; denosumab q12wks vs q24wks: 57.5%; denosumab q12wks vs. discontinue: 67.5%]. Most physicians would accept SSE rate increase of < 5% with BMA de-escalation. If a study of BMA de-escalation showing non-inferiority in terms of SSE rate was not feasible, physicians would consider changing practice to de-escalated therapy if: BMA toxicity was reduced (64.1%), pain was no worse (48.7%), physical function was no worse (48.7%), or cost-utility or cost-effectiveness was improved (41%). 38.5% would only change practice if the SSE rate was not significantly worse. Conclusion: Despite their extensive use and costs, questions around optimal use of BMAs still exist. It is evident that practice varies according to patient insurance coverage, however most physicians are de-escalating BMAs. There is interest amongst clinicians in performing trials of de-escalation, especially after 2 years of treatment. Citation Format: Mashari Alzahrani, Mark Clemons, Lisa Vandermeer, Marta Sienkiewicz, Arif Awan, Brian Hutton, Gregory Pond, Terry Ng. A physician survey evaluating real-world practice patterns and attitudes towards de-escalation of bone-modifying agents in patients with bone metastases from breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-18.

Background: Choosing Wisely (CW)® was created by the American Board of Internal Medicine (ABIM) to promote patient-physician conversations about unnecessary medical tests and treatment. It is estimated that 20% of healthcare cost is wasted on ineffective interventions. National societies such as American Society of Clinical Oncology, Americal Society of Breast Surgeons, and American Society for Radiation Oncology have developed lists of recommendations within the Choosing Wisely initiative to to eliminate non-evidence based practices and improve patient outcomes. Similarly, other countries outside of the US have created their own national panels of experts called “CW® campaigns” which typically review recommendations submitted by that country’s oncology societies. We performed a scoping review to consolidate CW® recommendations from different groups with respect to breast cancer care. Methods: A systematic search of Medline and Embase for English language publications presenting CW® recommendations for breast cancer care practices was conducted from Jan 1, 2011 - May 11, 2020. The search was designed and peer reviewed by information specialists. We also reviewed the CW® websites of ABIM and associated international CW® campaigns. Two reviewers independently screened studies for inclusion and performed data extraction, and findings were summarized narratively. Results: Review of ABIM CW® recommendations showed 26 breast cancer-related recommendations. These pertained to: screening (n=5), radiological staging (n=2), treatment (n=15), surveillance (n=2), and miscellaneous (genetic testing and pathology; n=2). Treatment recommendations were sub-classified into surgery (n= 9), chemotherapy (n= 2), radiation therapy (n= 2), and supportive therapy (n= 2). Of 20 countries which have a CW® campaign and endorse recommendations for a range of diseases, 13 have published recommendations for breast cancer. While most international campaigns published recommendations on the same topics as the ABIM campaign, 6 campaigns developed recommendations on new topics. These included: follow-up visits (Canada), involvement of multi-disciplinary teams and imaging in palliative care setting (India) and comparison of screening imaging modalities (Portugal). There was concordance in screening, treatment, and surveillance recommendations between the CW® campaigns. Conclusion: CW® recommendations focus on reducing overutilization of investigations and treatments. Breast cancer screening and treatment were most frequently addressed by CW® recommendations. There was a high rate of consensus between international CW® recommendations with respect to breast cancer care. As health care systems globally move attention to reduce low value care, further studies are required to address adherence to these current recommendations and develop new recommendations addressing topics not currently included in the US CW campaigns. Citation Format: Hely Shah, Julian Surujballi, Arif A Awan, Brian Hutton, Angel Arnaout, Risa Shorr, Lisa Vandermeer, Meshari J Alzahrani, Mark Clemons. A scoping review characterizing “choosing wisely” recommendations for breast cancer management [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-47.

Background: The effectiveness of different acellular dermal matrices (ADM) used for implant-based reconstruction immediately following mastectomy is an important clinical question. A prospective randomized clinical trial was performed to evaluate the superiority of DermACELL over Alloderm-RTU in reducing drain duration. Methods: Patients undergoing mastectomy with subpectoral immediate and permanent implant-based breast reconstruction were randomized to Alloderm-RTU or DermACELL. The primary outcome was seroma formation, measured by the duration of postoperative drain placement. Secondary outcomes included: post drain removal seroma aspiration, infection, redbreast syndrome, wound dehiscence, loss of the implant, and unplanned return to the operating room. Results: 62 patients were randomized for 81 mastectomies (41 Alloderm-RTU, 40 DermACELL). Baseline characteristics were similar. There was no statistically significant difference in mean drain duration (p = 0.16), with a trend towards longer duration in the Alloderm-RTU group (1.6 days, 95%CI, 0.7 to 3.9). The overall rate of minor and major complications were statistically similar between the two groups, although patients with Alloderm-RTU had 3 times as many infections requiring antibiotics (7.9% vs. 2.5%) with a risk difference of 5.4 (95%CI &minus, 4.5 to 15.2), and twice as many unplanned returns to the operating room (15.8% vs. 7.5%) with a risk difference of 8.3 (95% CI &minus, 5.9 to 22.5) as DermACELL. Conclusion: This is the first prospective randomized clinical trial comparing the two most commonly used human-derived ADMs. There was no statistically significant difference in drain duration, minor, or major complications between DermACELL over Alloderm-RTU in immediate subpectoral permanent implant-based breast reconstruction post-mastectomy.

Purpose: The COVID-19 pandemic resulted in a rapid move to virtual care. Questions exist as to whether reduced in-person assessment, with physical examination of early breast cancer patients (EBC), will affect the detection of recurrences. We evaluated recurrence patterns of patients transferred into a survivorship program through a single centre Wellness Beyond Cancer Program (WBCP).Methods: Consecutive EBC patients who returned to formal oncologist follow-up between February 1, 2013, and January 1, 2019, due to breast cancer recurrence were reviewed. Descriptive analyses were used to present patients and disease characteristics stratified by type of recurrence and mode of cancer detection.Results: Of 206 recurrences, 41 were ipsilateral breast recurrences (19.9%), 135 were distant recurrences (65.5%), and 30 were contralateral new breast cancers (14.6%). Ipsilateral breast recurrences were detected by patients in 53.7% (22/41) of cases and by routine imaging in 41.5% (17/21). The majority of distant recurrences (125/135, 92.6%) were detected via patient-reported symptoms. Contralateral breast primaries were primarily detected by imaging 83.3% (25/30) and patient-reported symptoms 16.7%, (5/30). Only 2/206 (1.14%) recurrences/new primaries were detected by healthcare providers at routinely scheduled follow-up visits.Conclusions: Despite following ASCO follow-up guidelines, healthcare providers rarely detect recurrences at routine follow-up appointments. While reduced in-person visits may affect other aspects of follow-up care (e.g. toxicity management), it appears unlikely, provided patients attend regular screening tests, that less frequent in-person follow-up is associated with worse breast cancer-related outcomes.

Background The optimal duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer patients is unknown, with 5, 7 or 10 days being commonly prescribed. This trial evaluates whether 5 days of filgrastim was non-inferior to 7/10 days. Patients and methods In this randomised, open-label trial, early breast cancer patients who were to receive filgrastim as primary FN prophylaxis were randomly allocated to 5 versus 7 versus 10 days of filgrastim for all chemotherapy cycles. A protocol amendment in November 2017 allowed subsequent patients (N = 324) to be randomised to either 5 or 7/10 days. The primary outcome was a composite of either FN or treatment-related hospitalisations. Secondary outcomes included chemotherapy dose reductions, delays and discontinuations. Analyses were carried out by per protocol (primary) and intention-to-treat, and the non-inferiority margin was set at 3% for the risk of having FN and/or hospitalisation per cycle of chemotherapy. Results Patients (N = 466) were randomised to receive 5 (184, 39.5%), or 7/10 (282, 60.5%) days of filgrastim. In our primary analysis, the difference in risk of either FN or treatment-related hospitalisation per cycle was −1.52% [95% confidence interval (CI): −3.22% to 0.19%] suggesting non-inferiority of a 5-day filgrastim schedule compared with 7/10-days. The difference in events per cycle for FN was 0.11% (95% CI: −1.05 to 1.27) while for treatment-related hospitalisations it was −1.68% (95% CI: −2.73% to −0.63%). The overall proportions of patients having at least one occurrence of either FN or treatment-related hospitalisation were 11.8% and 14.96% for the 5- and 7/10-day groups, respectively (risk difference: −3.17%, 95% CI: −9.51% to 3.18%). Conclusion Five days of filgrastim was non-inferior to 7/10 days. Given the cost and toxicity of this agent, 5 days should be considered standard of care. ClinicalTrials.gov registration NCT02428114 and NCT02816164.

Background and aim Cancers originating in the breast, lung and prostate often metastasize to the bone, frequently resulting in cancer-induced bone pain that can be challenging to manage despite conventional analgesic therapy. This exploratory study's aim was to identify potential biomarkers associated with cancer-induced pain by examining a sample population of breast cancer patients undergoing bisphosphonate therapy. Methods A secondary analysis of the primary study was performed to quantify serum cytokine levels for correlation to pain scores. Cytokines with statistically significant correlations were then input into a stepwise regression analysis to generate a predictive equation for a patient's pain severity. In an effort to find additional potential biomarkers, correlation analysis was performed between these factors and a more comprehensive panel of cytokines and chemokines from breast, lung, and prostate cancer patients. Results Statistical analysis identified nine cytokines (GM-CSF, IFNγ, IL-1β, IL-2, IL-4, IL-5, IL-12p70, IL-17A, and IL-23) that had significant negative correlations with pain scores and they could best predict pain severity through a predictive equation generated for this specific evaluation. After performing a correlation analysis between these factors and a larger panel of cytokines and chemokines, samples from breast, lung and prostate patients showed distinct correlation profiles, highlighting the clinical challenge of applying pain-associated cytokines related to more defined nociceptive states, such as arthritis, to a cancer pain state. Conclusion Exploratory analyses such as the ones presented here will be a beneficial tool to expand insights into potential cancer-specific nociceptive mechanisms and to develop novel therapeutics.

Concerns around pharmacological interaction between tamoxifen and antidepressants have resulted in evidence-base guidelines that recommend avoidance or caution with concurrent use. It remains unclear however whether this interaction is clinically important. A systematic review of studies comparing endocrine therapy (including tamoxifen and aromatase inhibitors) alone or concurrent with antidepressants in breast cancer patients was performed. The literature search sought studies within MEDLINE, EMBASE, and the Cochrane Collaboration Library published from database inception until December 1, 2020. Outcomes of interest included recurrence, breast cancer-specific survival, overall mortality, quality of life, and treatment compliance. Studies were assessed with the Cochrane Risk of Bias tool for randomized controlled trials and the Newcastle Ottawa tool for case-control and cohort studies. From 695 citations, we included 15 studies (2 randomized controlled trials [255 patients], 10 retrospective cohort studies [75,678 patients], and 3 case-control studies [18,836 patients]). While between-study clinical and methodologic differences (including analysis of confounding variables) precluded formal meta-analysis, findings from included studies did not find consistent evidence that concurrent use of antidepressants (including paroxetine) with tamoxifen therapy has negative impacts on the outcomes of interest. In this systematic review, despite data from nearly 100,000 patients, concurrent use of tamoxifen and antidepressants showed no consistent negative effect on clinical outcomes. Given the recognized harm to patients of changing either endocrine therapy or antidepressants to avoid concurrent use, current evidence-based guidelines should be updated accordingly. More rigorously designed pharmacoepidemiologic studies are needed.

Background We present the 2-year results of a randomised trial comparing 4- versus 12-weekly bone-targeting agents (BTAs) in patients with bone metastases from breast or castration-resistant prostate cancer (CRPC). Patients and Methods Patients with bone metastases from breast or CRPC, who were going to start or were already receiving BTAs, were randomised to 4- or 12-weekly BTA treatment for 2 years. The endpoints were: symptomatic skeletal events (SSE) rates, time to SSEs, toxicity and cost-effectiveness. Results Of 263 patients (160 breast cancer, 103 CRPC), 133 (50.6%) and 130 (49.4%) were randomised to the 4- and 12-weekly groups, respectively. BTAs included denosumab (56.3%), zoledronate (24.0%) and pamidronate (19.8%). After 2 years, the cumulative incidence rate (95% CI) of SSEs was 32.7% (24.6% to 41.1%) and 28.1% (20.3% to 36.4%) for the 4- and 12-weekly intervention groups respectively. The hazard ratio for time to first SSE was 0.96 (95% CI = 0.63 to 1.47). However, in a post hoc analysis, those patients who had an on-study SSE, there was a small non-statistical increased risk of subsequent SSEs among patients on the 12-weekly dosing arm (HR = 1.14; 95% CI – 0.90–1.44). BTA-related toxicity rates were similar between study arms. A cost-utility analysis showed that 12-weekly BTA is cost-effective from a public payer’s perspective. Conclusion These results in addition to those previously reported for de-escalating zoledronate, would support that de-escalation of commonly used BTAs is a reasonable and economically valid treatment option. While not statistically significant, the increase in subsequent SSEs in the 12-weekly arm requires further exploration.

Purpose Vasomotor symptoms (VMS) such as hot flashes and night sweats are common in breast cancer patients and can affect both quality of life and treatment adherence. However, there is limited practical data to guide clinicians in the optimal selection of therapeutic strategies. A survey of health care providers was performed to better understand perspectives and prescribing practices for managing this problem. Methods Canadian health care providers who treat patients with early stage breast cancer (EBC) participated in an anonymous electronic survey. Participants provided their perspectives on the prevalence and severity of VMS among patients with EBC, outlined their management strategies, and provided feedback on the perceived efficacy of interventions for VMS. Results Responses were received from 65 providers including breast oncologists (36/65, 55%) and nurses with oncology expertise (29/65, 45%). Seventy-seven percent of participants reported regularly asking patients about VMS, and most indicated that bothersome VMS occurred in the majority of patients. Health care providers cited hot flash severity and sleep disruption as the most important issues for patients. The most common first- and second-line interventions recommended were lifestyle modifications (n = 32/65, 49.2%) and pharmacologic strategies (n = 27/65, 41.5%), respectively. Most respondents felt that interventions, including pharmacologic, over-the-counter, and complementary therapies, were only “somewhat effective”. Overall, half of respondents (n = 35/65, 54%) reported being “confident” in managing VMS. Conclusion Given the variability of treatment recommendations, and health care provider uncertainty around the benefits of therapies for VMS, more ‘real-world’ trials are needed to optimize patient care.

Highlights • Adjuvant bisphosphonates are an established standard in postmenopausal breast cancer. • Guidelines note the need to explore different agents, doses, and intervals of bisphosphonates. • Feasibility of randomizing to 6-monthly vs one dose of IV zoledronate was demonstrated., Background Adjuvant zoledronate is widely used in patients with early stage breast cancer (EBC), but its optimal duration and dosing interval is still unknown. While a single-dose of zoledronate can improve bone density for many years, a proper evaluation of its effects on breast cancer-related outcomes would require a large trial. In this pilot study we evaluated the feasibility of performing such a trial. Methods Eligible patients with EBC were randomised to receive either one dose of zoledronate or 7 doses (6-monthly dosing for 3 years). Feasibility was assessed by a combination of primary outcomes including: activation of at least 6 Ontario sites within a year, active participation (i.e. approaching eligible patients for study participation) of at least half of the medical oncologists, and enrolment of at least 100 patients across all sites within 9 months of the sixth site being activated. Results All 6 sites were activated within 1 year and of 47 medical oncologists, 27 (57%) approached patients. Between November 2018 and April 2020, 211 eligible patients were randomised, 106 (50.2%) to a single dose of zoledronate and 105 (49.8%) to 6-monthly dosing. Baseline characteristics of randomised patients included; median age 59 (range 36–88), ER and/or PR positive (85%), Her2 positive (23%), menopausal status (premenopausal [19%], perimenopausal [6.7%] and postmenopausal [74%]) and 74% received neo/adjuvant chemotherapy. Conclusions All study feasibility endpoints were met in this trial comparing alternative schedules for adjuvant zoledronate. We will now seek funding for performing a larger efficacy trial. Trial registration: NCT03664687.

Highlights • Guidelines recommend adjuvant bisphosphonates for postmenopausal higher risk breast cancer patients. • Use of these agents in clinical practice appears low. • We surveyed patients receiving adjuvant bisphosphonate therapy · Results showed that while patients plan to complete all treatment cycles, they are enthusiastic about future trials evaluating de-escalation strategies., Background Despite the increasing use of adjuvant bisphosphonates for early stage breast cancer (EBC), little is known about the patient experience with such treatments. A patient survey was performed to identify current prescribing practices, perceptions around the role of treatment, the impact of treatment on patients’ quality of life, and future trial designs. Methods EBC patients who had either completed or were currently receiving adjuvant bisphosphonates were sent an anonymized survey. The survey collected information on patient and disease characteristics, bisphosphonate scheduling, compliance, and tolerance. Questions also assessed patient interest in trials of de-escalated bisphosphonate therapy. Results A total of 255 patients were contacted, with 164 eligible respondents (eligible response rate 164/255, 64.3%). Median patient age was 52 years (range 28 to 82 years). The majority (111/163, 68.1%) were postmenopausal at the time of diagnosis, 23.3% (38/163) were premenopausal, and 7.4% (12/163) were perimenopausal. Most patients (78%) had received chemotherapy. Zoledronate was the most commonly used bisphosphonate (92%), with the majority receiving treatment every 6 months for 3 years (73%). While 66% (107/161) of respondents had experienced side effects with treatment, most had, or expected to, complete treatment (154/163, 94%). Provided there was no detriment in breast cancer outcomes, there was strong interest in future studies of de-escalating adjuvant bisphosphonate therapy. Conclusion While most patients tolerate their treatment, there is interest in performing trials of de-escalation of these agents.

Background Excess weight has been associated with increased morbidity and a worse prognosis in adult patients with early-stage cancer. The optimal lifestyle interventions to optimize anthropometric measures amongst cancer patients and survivors remain inconsistent. Objective To conduct a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) comparing the effects of exercise and dietary interventions alone or in combination on anthropometric measures of adult cancer patients and survivors. Methods A systematic search of Medline, Embase and the Cochrane Trials Registry was performed. Outcomes of interest included changes in weight, body mass index (BMI), and waist circumference. Screening and data collection were performed by two reviewers. Bayesian NMAs were performed. Results Overall, 98 RCTs were included; 75 were incorporated in NMAs (n = 12,199). Groups of intervention strategies included: 3 exercise interventions, 8 dietary interventions, 7 combination interventions of diet and exercise and standard care. Median intervention duration was 26 weeks. NMA suggested that diet alone (mean difference [MD] -2.25kg, 95% CrI -3.43 to -0.91kg) and combination strategies (MD -2.52kg, 95% CrI -3.54 to -1.62kg) were associated with more weight loss compared to standard care. All dietary interventions achieved a similar magnitude of weight loss (MD range from -2.03kg to -2.52kg). Both diet alone and combination strategies demonstrated greater BMI reductions versus standard care, and each of diet alone, exercise alone and combination strategies demonstrated greater reductions in waist circumference than standard care. Conclusion Diet and exercise alone or in combination are effective lifestyle interventions to improve anthropometric measures in cancer patients and survivors. All reputable diets appear to be similarly effective to achieve weight loss.

Purpose Despite the increasing use of adjuvant bone-modifying agents (BMAs) such as zoledronate and clodronate in the treatment of patients with early stage breast cancer (EBC), little is known about real world practice patterns. A physician survey was performed to address this deficit and determine interest in clinical trials of alternative strategies for BMA administration. Methods Canadian oncologists treating patients with EBC were surveyed via an anonymized online survey. The survey collected information on: physician demographics, knowledge and interpretation of adjuvant bisphosphonate guidelines, and real world prescribing practices. Questions also determined thoughts around the design of future adjuvant BMA trials. Results Of 127 surveyed physicians, 53 eligible invitees responded (response rate 42%). The majority of physicians are offering high-risk postmenopausal patients adjuvant BMAs. The most common BMA regimen was adjuvant zoledronate (45/53, 85%) every 6 months for 3 years. Concerns around toxicities and repeated visits to the cancer centre were perceived as the greatest barriers to adjuvant bisphosphonate use. Respondents were interested in future trials of de-escalation of BMAs comparing a single infusion of zoledronate vs. 6-monthly zoledronate for 3 years. The most favoured primary endpoints for such a trial included disease recurrence and fragility fracture rates. Conclusion Questions around optimal use of adjuvant bisphosphonates in patients with EBC still exist. There is interest among physicians in performing trials of de-escalation of these agents. The results of this survey will assist in designing pragmatic clinical trials to address this question. Supplementary Information The online version contains supplementary material available at 10.1007/s10549-021-06147-1.