Development of a comprehensive approach to adult hereditary cancer testing in Ontario.

BACKGROUND: Genetic testing for hereditary cancer susceptibility has advanced over time due to the discovery of new risk genes, improved technology and decreased cost. In the province of Ontario, testing eligibility criteria were initially developed to include hereditary breast, ovarian and colorectal cancer syndromes. The rapid evolution of genetic technologies has facilitated the ability to interrogate a large number of genes concurrently. This, coupled with new knowledge about risk genes, necessitated a coordinated approach to expanding the scope of genes and indications tested and synchronisation of access and test utilisation across the province as required in a publicly funded universal healthcare system. METHODS: Ontario Health-Cancer Care Ontario convened expert working groups to develop a standardised and comprehensive cancer gene list for adults and accompanying hereditary cancer testing (HCT) criteria using an evidence-based framework and broad laboratory and clinical genetics engagement. RESULTS: A standardised 76-cancer-gene panel, organised into 13 larger disease site panels and 25 single/small gene panels, was developed and endorsed by the working groups. Provincial genetic testing eligibility criteria were updated to align with the new panels and to guide clinical decision-making. In the first year following the implementation of these changes, 10 564 HCT panels were performed with an overall mutation detection rate of 12.2%. CONCLUSION: Using an evidence framework and broad clinical engagement to develop and endorse an updated guidance document, cancer genetic testing for adults in Ontario is now standardised and coordinated across the province.

Third-line treatment patterns in HER2-positive metastatic breast cancer: a retrospective analysis of real-world data in Canada.

There is an increasing demand for real-world data pertaining to the usage of cancer treatments, especially in settings where no standard treatment is specifically recommended. This study presents the first real-world analysis of third-line treatment patterns in HER2-positive metastatic breast cancer (mBC) patients in Canada. The purpose was to assess evolution of clinical practice and identify unmet needs in post-second-line therapy. Retrospective data from medical records of 66 patients who received third-line treatment before 31st October 2018, and data from 56 patients who received third-line treatment after this date, extracted from the Personalize My Treatment (PMT) cancer patient registry, were analyzed. In the first cohort, the study revealed heterogeneity in the third-line setting, with trastuzumab, lapatinib, and T-DM1 being the main treatment options. Even though data were collected before the wide availability of tucatinib, neratinib and trastuzumab deruxtecan in Canada, the PMT cohort revealed the emergence of new therapeutic combinations and a shift from lapatinib usage to T-DM1 choice was observed. These findings underscore the evolving nature of third-line treatment strategies in Canada, a facet that is intrinsically tied to the availability of new drugs. The absence of a consensus on post-second-line treatment highlights the pressing need for more efficient therapeutic alternatives beyond the currently available options. This study not only offers valuable insights into the present landscape of third-line treatment in Canada but validates the significance and effectiveness of the PMT registry as a tool for generating pan-Canadian real-world evidence in oncology and its capacity to provide information on evolution of therapeutic practices.

Symptomatic skeletal-related events in patients receiving longer term bone-modifying agents for bone metastases from breast and castration resistant prostate cancers.

BACKGROUND: The effect of longer-term use of bone-modifying agent (BMA) on symptomatic skeletal event (SSE) rates in patients with bone metastases remains unclear. This retrospective study of a cohort of patients in a randomized controlled trial evaluated SSEs in patients receiving BMAs at a single cancer center. METHODS: Data from patients with metastatic breast and castration-resistant prostate cancer (CRPC) were interrogated to evaluate the effects of longer-term use of BMAs on incidence, type, and risk factors for SSEs. RESULTS: Of 162 patients, 109 (67%) had breast cancer (BC) and 53 (33%) CRPC. Median age at diagnosis of bone metastases was 61.9 years (range 27.5-97.2) for BC patients and 72.1 (range 37.0-92.2) for CRPC patients. Median duration of BMA use was 2.3 years (range 0.1-9.9 years) for BC and 3.8 years (range 1.5-9.4) for CRPC patients. The initial BMAs in BC patients were pamidronate (46.8%), denosumab (31.2%), and zoledronate (22%). All CRPC patients received denosumab. During follow-up, 59% of BC and 75% of CRPC patients had at least one SSE. The number of patients experiencing ≥ 1 SSE per year was higher in the first year after bone metastasis diagnosis (63/162; 38.9%) compared with that in the second (26/149; 17.5%) and third years (30/123; 24.4%). Neither age, visceral disease, multiple bone metastases, nor biological markers for BC had a significant impact on time to first SSE. CONCLUSIONS: The risk for SSEs was greatest in the first year after diagnosis of bone metastasis. Studies evaluating de-escalation and even stopping of BMAs with longer-term use may therefore be warranted.

Adjuvant bisphosphonate use in patients with early stage breast cancer: a physician survey.

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.

A scoping review characterizing "Choosing Wisely®" recommendations for breast cancer management.

PURPOSE: Choosing Wisely (CW)® was created by the American Board of Internal Medicine (ABIM) to promote patient-physician conversations about unnecessary medical interventions. Similarly, other countries created their own panels of experts called "CW® campaigns" which 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 was designed by an information specialist for publications presenting CW® recommendations for breast cancer care practices from 2011-2020. We also reviewed the websites of all CW® campaigns and reference sections of each CW® recommendation. Two reviewers independently screened studies for inclusion and performed data extraction. Findings were summarized narratively. RESULTS: Review of ABIM CW® recommendations showed 19 breast cancer-related recommendations pertaining to; screening (n = 4), radiological staging (n = 2), treatment (n = 10), surveillance (n = 2), and miscellaneous (genetic testing; n = 1). Of 22 countries with CW® campaigns, 10 published recommendations for breast cancer. Over half (57%) of recommendations were supported by more than one country. No recommendations were refuted between campaigns. Two campaigns developed 3 novel recommendations on new topics, including chemotherapy in ductal carcinoma in situ (Italy) and comparison of screening imaging modalities (Portugal). CONCLUSIONS: CW® recommendations focus on reducing overutilization of investigations and treatments. There was a high rate of consensus between different CW® campaigns. 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.

Perceptions around bone-modifying agent use in patients with bone metastases from breast and castration resistant prostate cancer: a patient survey.

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.

A prospective multi-centre, randomized study comparing the addition of tapering dexamethasone to other standard of care therapies for taxane-associated pain syndrome (TAPS) in breast cancer patients.

PURPOSE: Taxane-associated pain syndrome (TAPS) is common with docetaxel and is characterised by myalgias and arthralgias starting 2-3 days after treatment and can last for up to 7 days. Anecdotal evidence suggests that corticosteroids can reduce TAPS. This multicentre, randomized trial evaluated the effect of additional tapering dexamethasone on TAPS. METHODS: 130 breast cancer patients commencing docetaxel were randomized to dexamethasone premedication (8 mg/twice daily for 3 days) or dexamethasone premedication followed by tapering dexamethasone (4 mg/daily for 2 days followed by 2 mg/daily for 2 days). The primary endpoint was absolute change in FACT-Taxane questionnaire during the first chemotherapy cycle. Secondary endpoints: proportion of patients with clinically significant TAPS, QoL, pain and toxicity. RESULTS: 110/130 patients had complete data included in the primary analysis. The fall in FACT-Taxane scores was lower in the experimental group on day 5 (p = 0.05), but not on day 7 (p = 0.21). There was no difference in FACT-Taxane scores over the entire study duration (p = 0.59). Fewer patients in the experimental arm reported TAPS on day 5 (30 vs. 47%). There was a borderline significant attenuation of impairment of QoL with experimental treatment on day 5 (p = 0.06), but not day 7 (p = 0.53). Tapered schedule was associated with more dyspepsia and insomnia. CONCLUSION: A tapering schedule of dexamethasone was associated with a brief reduction in docetaxel-associated symptoms which was observed only during dexamethasone exposure and did not persist after discontinuation of the drug. TRIAL REGISTRATION: ClinicalTrials.gov NCT03348696.

Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review.

PURPOSE: Bone-modifying agents (BMAs) for bone metastases are commonly prescribed for many years even though randomized clinical trials are only 1-2 years in duration. A systematic review on the risk-benefit of BMA use for > 2 years in breast cancer or castrate-resistant prostate cancer was conducted. METHODS: MEDLINE, Embase, and Cochrane databases were searched (1970-February 2019) for randomized and observational studies, and case series reporting on BMA efficacy (skeletal-related events and quality of life) and toxicity (osteonecrosis of the jaw, renal impairment, hypocalcemia, and atypical femoral fractures) beyond 2 years. RESULTS: Of 2107 citations, 64 studies were identified. Three prospective and 9 retrospective studies were eligible. Data beyond 2 years was limited to subgroup analyses in all studies. Only one study (n = 181) reported skeletal-related event rates based on bisphosphonate exposure, with decreased rates from 27.6% (0-24 months) to 15.5% (> 24 months). None reported on quality of life. All 12 studies (denosumab (n = 948), zoledronate (n = 1036), pamidronate (n = 163), pamidronate-zoledronate (n = 522), ibandronate (n = 118)) reported ≥ 1 toxicity outcome. Seven bisphosphonate studies (n = 1077) and one denosumab study (n = 948) reported on osteonecrosis of the jaw. Across three studies (n = 1236), osteonecrosis of the jaw incidence ranged from 1 to 4% in the first 2 years to 3.8-18% after 2 years. Clinically significant hypocalcemia ranged from 1 to 2%. Severe renal function decline was ≤ 3%. Atypical femoral fractures were rare. CONCLUSIONS: Evidence informing the use of BMA beyond 2 years is heterogeneous and based on retrospective analysis. Prospective randomized studies with greater emphasis on quality of life are needed. PROSPERO REGISTRATION NUMBER: CRD42019126813.

A randomized trial comparing vascular access strategies for patients receiving chemotherapy with trastuzumab for early-stage breast cancer.

PURPOSE: Trastuzumab-based chemotherapy is usually administered through either a peripherally inserted central catheter (PICC) or a totally implanted vascular access device (PORT). As the most effective type of access is unknown, a feasibility trial, prior to conducting a large pragmatic trial, was undertaken. METHODS: The trial methodology utilized the integrated consent model incorporating oral consent. Patients receiving trastuzumab-based neo/adjuvant chemotherapy for early-stage breast cancer were randomized to a PICC or PORT insertion. Feasibility was reflected through a combination of endpoints; however, the a priori definition of feasibility was > 25% of patients approached agreed to randomization and > 25% of physicians approached patients. Secondary outcomes included rates of line-associated complications such as thrombotic events requiring anticoagulation, line infections or phlebitis. RESULTS: During the study period, 4/15 (26.7%) medical oncologists approached patients about study participation. Of 59 patients approached, 56 (94.9%) agreed to randomization, 29 (51.8%) were randomized to PICC and 27 (48.2%) to PORT access. Overall, 17.2% (5/29) and 14.8% (4/27) of patients had at least one line-associated complication in the PICC and PORT arms respectively. The study was terminated early due to slow accrual. CONCLUSION: The study met its feasibility endpoints with respect to patient and physician engagement. However, the slow rate of accrual (56 patients in 2 years) means that conducting a large pragmatic trial would require additional strategies to make such a study possible. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02632435.

De-escalation of bone-modifying agents in patients with bone metastases from breast cancer: a systematic review and meta-analysis.

PURPOSE: Bone-modifying agents (BMAs) such as bisphosphonates and denosumab are usually administered every 4 weeks (standard) in patients with bone metastases from breast cancer to prevent skeletal-related events (SREs). Recent randomized controlled trials suggest every 12-week (de-escalated) dosing interval may be non-inferior. The objective of this systematic review and meta-analysis was to compare the efficacy and harms of standard with de-escalated administration of BMA's in patients with bone metastases from breast cancer. METHODS: We searched Medline, PubMed, and the Cochrane Register of Controlled Trials from 1947 to March 14, 2018 and conference abstracts from (2014-March 14, 2018) for randomized clinical trials comparing every 4-week and every 12-week dosing interval of bone-modifying agents. Using PRISMA guidelines, meta-analyses were performed using random-effects models, with findings reported as risk ratios with 95% confidence intervals (CI). RESULTS: From a total of 1311 citations, we identified 8 full-text articles and 1 abstract comprising data from 5 completed randomized clinical trials (n = 1807). Zoledronate administration every 12 weeks compared to every 4 weeks produced a summary risk ratio of 1.05 (95% CI 0.88-1.25) for patients with ≥ 1 on-study SRE indicating similar efficacy. These results did not differ whether patients had received prior intravenous bisphosphonate. De-escalation was associated with a non-statistically significant lower risk of increased creatinine (summary risk ratio 0.41 [95% CI 0.15-1.16]). Currently, there are insufficient data for pamidronate and denosumab de-escalation. CONCLUSIONS: These data are supportive of de-escalation of zoledronate from onset for patients with bone metastases from breast cancer.

Creating a pragmatic trials program for breast cancer patients: Rethinking Clinical Trials (REaCT).

BACKGROUND: The proportion of breast cancer patients enrolled in clinical trials is falling. The Rethinking Clinical Trials (REaCT) program was developed to challenge some of the contemporary barriers responsible for this fall in accrual. In this article, we review the successes and challenges our program has faced. METHODS: The REaCT program was created to improve care and outcomes for cancer patients through surveys of patients and healthcare providers, systematic reviews, economic evaluations, and the performance of pragmatic randomized trials with patient-centered outcomes. Likely, the greatest difference to conventional trial methodologies has been our widespread use of the integrated consent model (ICM) incorporating oral consent. RESULTS: Between 2014 and 2018, the program has recruited over 2000 patients to 15 randomized studies at 11 Canadian cancer centers. The REaCT program has completed and published five patient surveys, six healthcare provider surveys, ten systematic reviews, performed four economic evaluations, opened 15 clinical trials comparing standard of care interventions (two surgical, two adjuvant chemotherapy, five adjuvant supportive care, one radiology, two vascular devices, two palliative supportive care, and one molecular diagnostics). Patient surveys have shown high levels of satisfaction with the ICM. CONCLUSION: The REaCT program was developed to tackle important practice questions that will better guide optimal practice and to increase the availability of pragmatic clinical trials. While many challenges remain, future strategies will involve including more study sites and efforts to integrate novel information technology strategies.

A multicentre, randomized pilot trial comparing vascular access strategies for early stage breast cancer patients receiving non-trastuzumab containing chemotherapy.

PURPOSE: All vascular access strategies foradministering chemotherapy in early stage breast cancer (EBC) are associated with risks and benefits. As the most effective type of access is unknown a feasibility trial, prior to conducting a large pragmatic trial, was undertaken. METHODS: The trial methodology utilized broad eligibility criteria and the integrated consent model incorporating oral consent. EBC patients receiving non-trastuzumab-containing chemotherapy were randomized to peripheral access or central line insertion. The a priori definition of feasibility was: > 25% of patients approached agreed to randomisation and > 25% of physicians approached patients. Secondary outcomes included rates of line-associated complications. RESULTS: Of 159 patients approached, 150 (94.3%) agreed to randomisation, 77 (51.3%) were randomized to peripheral and 73 (48.7%) to central access. 6/26 (23.1%) of medical oncologists approached patients. Rates of complications per chemotherapy cycles in the peripheral vs central access groups with risk difference (RD) (95% CI) were: thrombotic events requiring anticoagulation [1 (0.3%) vs. 3 (1.0%), RD - 0.7(- 1.9,0.5)], line infections [0 (0%) vs. 1 (0.3%), RD - 0.3(- 0.9,0.3)], phlebitis [2 (0.6%) vs. 0 (0%), RD 0.3(- 0.3,0.8)], and tissue infiltrations [4 (1.1%) vs. 1 (0.3%), RD 0.8(- 0.4,2.1)]. Overall, 8.0% (6/75) and 7.7% (5/65) of patients had at least one of these complications in the peripheral and central access arms respectively [RD - 0.9(- 9.4,7.6)]. The study was terminated early due to slow accrual. CONCLUSION: While meeting its a priori feasibility criteria for patient engagement, the slow accrual means that conducting a large pragmatic trial would require overcoming the barriers to physician recruitment. TRIAL REGISTRATION: NCT02688998.

Cut homeobox 1 causes chromosomal instability by promoting bipolar division after cytokinesis failure.

Cell populations able to generate a large repertoire of genetic variants have increased potential to generate tumor cells that survive through the multiple selection steps involved in tumor progression. A mechanism for the generation of aneuploid cancer cells involves passage through a tetraploid stage. Supernumerary centrosomes, however, can lead to multipolar mitosis and cell death. Using tissue culture and transgenic mouse models of breast cancer, we report that Cut homeobox 1 (CUX1) causes chromosomal instability by activating a transcriptional program that prevents multipolar divisions and enables the survival of tetraploid cells that evolve to become genetically unstable and tumorigenic. Transcriptional targets of CUX1 involved in DNA replication and bipolar mitosis defined a gene expression signature that, across 12 breast cancer gene expression datasets, was associated with poor clinical outcome. The signature not only was higher in breast tumor subtypes of worse prognosis, like the basal-like and HER2(+) subtypes, but also identified poor outcome among estrogen receptor-positive/node-negative tumors, a subgroup considered to be at lower risk. The CUX1 signature therefore represents a unique criterion to stratify patients and provides insight into the molecular determinants of poor clinical outcome.

Does Pre-Emptive Availability of PREDICT 2.1 Results Change Ordering Practices for Oncotype DX? A Multi-Center Prospective Cohort Study.

For early-stage hormone receptor (HR)-positive and HER2-negative breast cancer, tools to estimate treatment benefit include free and publicly available algorithms (e.g., PREDICT 2.1) and expensive molecular assays (e.g., Oncotype DX). There remains a need to identify patients who de-rive the most benefit from molecular assays and where this test may be of poor value. In this multicenter prospective cohort study, we evaluated whether use of PREDICT 2.1 would impact physician decision making. For the first 6 months of the study, data on physician use of both PREDICT 2.1 and Oncotype DX ordering were collected on all newly diagnosed patients eligible for molecular testing. After 6 months, an educational intervention was undertaken to see if providing physicians with PREDICT 2.1 results affects the frequency of Oncotype DX requests. A total of 602 patients across six cancer centers in Ontario, Canada were recruited between March 2020 and November 2021. Providing PREDICT 2.1 results and an educational intervention did not alter the ordering of an Oncotype DX. For patients with low clinical risk, either by clinico-pathologic features or by PREDICT 2.1, the probability of obtaining a high Oncotype DX recurrence score was substantially lower compared to patients with high-clinical-risk disease. The introduction of an educational intervention had no impact on molecular assay requests. However, routine ordering of molecular assays for patients with low-clinical-risk disease is of poor value.

The REthinking Clinical Trials Program Retreat 2023: Creating Partnerships to Optimize Quality Cancer Care.

Patients, families, healthcare providers and funders face multiple comparable treatment options without knowing which provides the best quality of care. As a step towards improving this, the REthinking Clinical Trials (REaCT) pragmatic trials program started in 2014 to break down many of the traditional barriers to performing clinical trials. However, until other innovative methodologies become widely used, the impact of this program will remain limited. These innovations include the incorporation of near equivalence analyses and the incorporation of artificial intelligence (AI) into clinical trial design. Near equivalence analyses allow for the comparison of different treatments (drug and non-drug) using quality of life, toxicity, cost-effectiveness, and pharmacokinetic/pharmacodynamic data. AI offers unique opportunities to maximize the information gleaned from clinical trials, reduces sample size estimates, and can potentially "rescue" poorly accruing trials. On 2 May 2023, the first REaCT international symposium took place to connect clinicians and scientists, set goals and identify future avenues for investigator-led clinical trials. Here, we summarize the topics presented at this meeting to promote sharing and support other similarly motivated groups to learn and share their experiences.

Long-range transcriptional regulation by the p110 CUX1 homeodomain protein on the ENCODE array.

BACKGROUND: Overexpression of the Cut homeobox 1 gene, CUX1, inversely correlates with patient survival in breast cancers. Cell-based assays and molecular studies have revealed that transcriptional regulation by CUX1 involves mostly the proteolytically processed p110 isoform. As there is no antibody specific to p110 CUX1 only, an alternate strategy must be employed to identify its targets. RESULTS: We expressed physiological levels of a tagged-p110 CUX1 protein and performed chromatin affinity purification followed by hybridization on ENCODE and promoter arrays. Targets were validated by chromatin immunoprecipitation and transcriptional regulation by CUX1 was analyzed in expression profiling and RT-qPCR assays following CUX1 knockdown or p110 CUX1 overexpression. Approximately 47% and 14% of CUX1 binding sites were respectively mapped less than 4 Kbp, or more than 40 Kbp, away from a transcription start site. More genes exhibited changes in expression following CUX1 knockdown than p110 CUX1 overexpression. CUX1 directly activated or repressed 7.4% and 8.4% of putative targets identified on the ENCODE and promoter arrays respectively. This proportion increased to 11.2% for targets with 2 binding sites or more. Transcriptional repression was observed in a slightly higher proportion of target genes. The CUX1 consensus binding motif, ATCRAT, was found at 47.2% of the CUX1 binding sites, yet only 8.3% of the CUX1 consensus motifs present on the array were bound in vivo. The presence of a consensus binding motif did not have an impact on whether a target gene was repressed or activated. Interestingly, the distance between a binding site and a transcription start site did not significantly reduced the ability of CUX1 to regulate a target gene. Moreover, CUX1 not only was able to regulate the next adjacent gene, but also regulated the gene located beyond this one as well as the gene located further away in the opposite direction. CONCLUSION: Our results demonstrate that p110 CUX1 can activate or repress transcription when bound at a distance and can regulate more than one gene on certain genomic loci.

Young Women with Breast Cancer: The Current Role of Precision Oncology.

Young adults aged 40 years and younger with breast cancer represent less than 5% of all breast cancer cases, yet it is the leading cause of death among young women with cancer worldwide. Breast cancer that develops at a young age is more aggressive and has biological features that carry an increased risk of relapse and death. Young adults are more likely to have a genetic predisposition and key biomarkers, including endocrine receptors, the HER2 receptor, and proliferation biomarkers, that appear different compared to older adults. Despite being more aggressive, management strategies are largely the same irrespective of age. Given the higher rates of genetic predisposition, fast access to genetic counselling and testing is a necessity. In this review, the biological differences in young adult breast cancer and the current role precision medicine holds in the treatment of young adults with breast cancer are explored. Given the relatively high risk of relapse, developing novel genomic tools to refine the treatment options beyond the current standard is critical. Existing predictive genomic tests require careful interpretation with consideration of the patient's clinical and pathological features in the young patient cohort. Careful evaluation is also required when considering extended endocrine therapy options. Improved characterization of mutations occurring in tumors using next-generation sequencing could identify important driver mutations that arise in young women. Applying the advances of precision medicine equitably to patients in resource-rich and low- and middle-income countries will be critical to impacting the survival of young adults with breast cancer worldwide.

Hemorrhage Risk Among Patients With Breast Cancer Receiving Concurrent Direct Oral Anticoagulants With Tamoxifen vs Aromatase Inhibitors.

Importance: Tamoxifen is commonly used as adjuvant therapy in breast cancer and is proposed to interfere with cytochrome P450 enzyme and P-glycoprotein pathways. Concurrent use with direct oral anticoagulants (DOACs) poses the threat of a potentially dangerous drug-drug interaction by leading to an increase in hemorrhage risk. Objective: To assess the risk of hemorrhage in patients with breast cancer coprescribed a DOAC and tamoxifen compared with a DOAC and an aromatase inhibitor (AI). Design, Setting, and Participants: This population-based, retrospective cohort study was conducted among adults aged 66 years or older who were prescribed tamoxifen (compared with an AI) concurrently with a DOAC in Ontario, Canada, between June 23, 2009, and November 30, 2020, and followed up until December 31, 2020. Interventions: Concurrent prescription of a DOAC and tamoxifen compared with a DOAC and an AI. Main Outcomes and Measures: The primary outcome was major hemorrhage requiring an emergency department visit or hospitalization after prescription. Overlap weighted Cox proportional hazards models, accounting for multiple covariates, were used to assess the association between hemorrhage and tamoxifen or AI use with a DOAC. Results: Among a total of 4753 patients (4679 [98.4%] women; mean [SD] age, 77.4 [7.4] years), 1179 (24.8%) were prescribed tamoxifen, and 3574 (75.2%) were prescribed an AI. Rivaroxaban (2530 [53.2%]) and apixaban (1665 [35.0%]) were the most frequently used DOACs. Patients taking AIs were younger than patients taking tamoxifen (mean [SD] age, 77.1 [7.3] vs 78.3 [7.6] years), with higher Charlson Comorbidity Index (mean [SD], 1.8 [2.4] vs 1.5 [2.2]) and more advanced cancer stage (stages III and IV, 569 [15.9%] vs 127 [10.8%]). During a median follow-up of 166 days (IQR, 111-527 days), tamoxifen was not associated with a higher risk of major hemorrhage (29 of 1179 [2.5%]) compared with an AI (119 of 3574 [3.3%]) when combined with a DOAC (absolute risk difference, -0.8%; weighted hazard ratio, 0.68 [95% CI, 0.44-1.06]). These results were similar in additional analyses using a more liberal definition of hemorrhage, accounting for kidney function, limiting follow-up to 90 days, stratifying by incident and prevalent DOAC users, and accounting for cancer duration and the competing risk of death. Conclusions and Relevance: In this cohort study, findings suggest that among DOAC users, the concurrent use of tamoxifen was not associated with a higher risk of hemorrhage compared with the concurrent use of an AI. These findings should directly inform prescribers regarding the apparent safety of concurrent DOAC and tamoxifen use.

The Impact of Foundation Medicine Testing on Cancer Patients: A Single Academic Centre Experience.

BACKGROUND: The use of Next-Generation Sequencing (NGS) has recently allowed significant improvements in cancer treatment. Foundation Medicine® (FM) provides a genomic profiling test based on NGS for a variety of cancers. However, it is unclear if the Foundation Medicine test would result in a better outcome than the standard on-site molecular testing. In this retrospective chart review, we identified the FM cases from an academic Canadian hospital and determined whether these test results improved treatment options for those patients. MATERIALS AND METHODS: A retrospective analysis was performed on patients with solid tumors who had FM testing between May 1, 2014 and May 1, 2018. Clinical factors and outcomes were measured using descriptive statistics using Microsoft Excel® Software. RESULTS: Out of 66 FM tests, eight patients (= 12%) had a direct change in therapy based on the FM tests. Identified were 285 oncogenic mutations (median 1, range 0-31); where TP53 (n = 31, 10.9%), CDKN2A (n = 19, 6.7%), KRAS (n = 16, 5.6%) and APC (n = 9, 3.2%) were the most common FM mutations identified. CONCLUSION: A small proportion of FM reports identified actionable mutations and led to direct treatment change. FM testing is expensive and a few of the identified mutations are now part of routine on-site testing. NGS testing is likely to become more widespread, but this research suggests that its true clinical impact may be restricted to a minority of patients.

Real-world practice patterns and attitudes towards de-escalation of bone-modifying agents in patients with bone metastases from breast and prostate cancer: A physician survey.

BACKGROUND: There remain questions around the optimal use of bone-modifying agents (BMAs) in patients with bone metastases from breast and castration-resistant prostate cancer (CRPC). A physician survey was performed to identify current practices, as well as perceptions around long-term BMA use, BMA de-escalation, and further BMA de-escalation after 2 years of use. METHODS: Canadian oncologists treating breast cancer or CRPC were surveyed via an anonymized online survey. The survey collected physician demographics, current practice patterns, perception on risk of symptomatic skeletal events (SSE) and BMA-associated toxicities, and attitudes towards further de-escalation of BMAs after 2 years of treatment. RESULTS: A total of 334 physicians in Canada were contacted, of which 295 were eligible on initial screening, and 65 completed the survey (response rate 22%): 35 treated breast cancer, 25 treated prostate cancer and 5 treated both. The most common BMA regimens in patients with no limitation in drug coverage were denosumab q4wks for 3-4 months followed by a de-escalation to q12wks (breast cancer) and denosumab q4wks (prostate cancer). In patients with provincial health coverage only the common choices were zoledronate q4wks for 3-4 months followed by de-escalation to q12wks (breast cancer) and denosumab q4wks (prostate cancer). There was equipoise regarding the benefit of continuing BMA beyond 2 years and interest in further trials of de-escalation of BMA in both breast and prostate cancer. The most favored alternative primary study endpoints to SSE were BMA toxicity (67.2%), pain (46.9%), and physical function (48.4%). CONCLUSION: Despite their extensive use and costs, questions around optimal use of BMAs still exist. 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.