Background Approximately 10% of new breast cancer patients will present with overt synchronous metastatic disease. The optimal local management of those patients is controversial. Several series suggest that removal of the primary tumour is associated with a survival benefit, but the retrospective nature of those studies raises considerable methodologic challenges. We evaluated our clinical experience with the management of such patients and, more specifically, the impact of surgery in patients with synchronous metastasis. Methods We reviewed patients with primary breast cancer and concurrent distant metastases seen at our centre between 2005 and 2007. Demographic and treatment data were collected. Study endpoints included overall survival and symptomatic local progression rates. Results The 111 patients identified had a median follow-up of 40 months (range: 0.6–71 months). We allocated the patients to one of two groups: a nonsurgical group (those who did not have breast surgery, n = 63) and a surgical group (those who did have surgery, n = 48, 29 of whom had surgery before the metastatic diagnosis). When compared with patients in the nonsurgical group, patients in the surgical group were less likely to present with T4 tumours (23% vs. 35%), N3 nodal disease (8% vs. 19%), and visceral metastasis (67% vs. 73%). Patients in the surgical group experienced longer overall survival (49 months vs. 33 months, p = 0.01) and lower rates of symptomatic local progression (14% vs. 44%, p < 0.001). Conclusions In our study, improved overall survival and symptomatic local control were demonstrated in the surgically treated patients; however, this group had less aggressive disease at presentation. The optimal local management of patients with metastatic breast cancer remains unknown. An ongoing phase III trial, E2108, has been designed to assess the effect of breast surgery in metastatic patients responding to first-line systemic therapy. If excision of the primary tumour is associated with a survival benefit, then the preselected subgroup of patients who have responded to initial systemic therapy is the desired population in which to put this hypothesis to the test.

FMS-like tyrosine kinase 3 (FLT3) mutations are detected in approximately 20–30% of patients with acute myeloid leukemia (AML), with the presence of a FLT3 internal tandem duplication (FLT3-ITD) mutation being associated with an inferior outcome. Assessment of FLT3 mutational status is now essential to define optimal upfront treatment in both newly diagnosed and relapsed AML, to support post-induction allogeneic hematopoietic stem cell transplantation (alloSCT) decision-making, and to evaluate treatment response via measurable (minimal) residual disease (MRD) evaluation. In view of its importance in AML diagnosis and management, the Canadian Leukemia Study Group/Groupe canadien d’étude sur la leucémie (CLSG/GCEL) undertook the development of a consensus statement on the clinical utility of FLT3 mutation testing, as members reported considerable inter-center variability across Canada with respect to testing availability and timing of use, methodology, and interpretation. The CLSG/GCEL panel identified key clinical and hematopathological questions, including: (1) which patients should be tested for FLT3 mutations, and when?; (2) which is the preferred method for FLT3 mutation testing?; (3) what is the clinical relevance of FLT3-ITD size, insertion site, and number of distinct FLT3-ITDs?; (4) is there a role for FLT3 analysis in MRD assessment?; (5) what is the clinical relevance of the FLT3-ITD allelic burden?; and (6) how should results of FLT3 mutation testing be reported? The panel followed an evidence-based approach, taken together with Canadian clinical and laboratory experience and expertise, to create a consensus document to facilitate a more uniform approach to AML diagnosis and treatment across Canada.

Allogeneic hematopoietic cell transplantation (HCT) is used increasingly to treat blood and immune-based disorders. Post-transplantation testing of HCT recipients can lead to unexpected molecular, cytogenetic, and other information in donor-derived cells, raising questions regarding the potential impact on donor health. This study was conducted to identify the breadth of donor-derived abnormalities identified by testing HCT recipients and to determine the extent to which disclosure and donor follow-up are described. A systematic search and scoping review were conducted following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) extension for scoping review guidelines in OVID MEDLINE and Embase (1947 to May 24, 2021). We identified 38 studies (63 donor-recipient pairs) addressing nonleukemic abnormalities to complement existing literature describing donor cell leukemia and donor-derived myelodysplasia. Donors were unrelated adults (n = 20), related family members (n = 28), cord blood donors (n = 6), or not reported (n = 9). Acquired cytogenetic, molecular, and morphologic abnormalities were reported. Donor origin was confirmed by cytogenetic analysis via karyotyping, fluorescence in situ hybridization, single tandem repeat PCR, and other techniques. A disease in donor-derived cells was described in 35 recipients (56.5%). Despite the relevance for testing and disclosure to donors, only 22 cases (32%) mentioned donor follow-up, and in 5 cases the donor developed a disease associated with the identified abnormality. Unrelated donor disclosure was mentioned in 3 of 26 cases (12%), with the findings reported back to the registry. Incidental abnormalities identified in transplanted donor cells may contribute to the post-transplantation risk of illness in the recipient and may be relevant to donor health. A framework for donor disclosure is proposed that incorporates consideration of analytic validity of the testing, potential significance of the finding, and the extent to which the abnormality is actionable. Adoption of effective processes to safeguard both donor and recipient health outcomes related to this issue is needed.

Allogeneic hematopoietic cell transplantation (allo-HCT) for acute myeloid leukemia (AML) is associated with considerable morbidity and mortality. Machine learning (ML) techniques are increasingly applied to predict outcomes in medicine. To evaluate the role of ML in predicting overall survival (OS) after allo-HCT for AML and compare ML with traditional Cox regression. Using an internal cohort of 2,253 patients and 14 pre-allo-HCT variables, we developed three models: Cox regression with time-varying coefficients (Cox-TVC), Elastic-net Cox Regression (Cox-EN), and Random Survival Forest (RSF). Performance was evaluated using multiple metrics including C-index, net reclassification improvement (NRI) and decision curve analysis (DCA). Patients were stratified into tertiles of model predicted 24-month mortality. External validation was performed in 252 single-center patients with uniform measurable residual disease (MRD) assessment. Model-derived risk scores strongly correlated (r=0.886-0.963). Across models, age ≥ 60 years, MRD positivity, and adapted European LeukemiaNet (aELN) adverse risk were the strongest predictors. Effects of age attenuated over time (HR for age ≥60: 2.59 [95% CI: 1.54-4.35] at 1 year, 1.92 [95% CI: 1.04-3.56] at 5 years). Compared with Hematopoietic Cell Transplant Comorbidity-Index (HCT-CI) and aELN, models improved risk stratification (NRI: 31-44%, p <0.001). Discrimination remained modest but was higher in external cohort compared with internal cohort (0.69-0.71 versus 0.60-0.61), likely reflecting uniform MRD assessment. At a 25% risk threshold for clinical decision-making, models identified approximately 1 additional high-risk patient per 100 versus HCT-CI, or aELN. At 2-years, 25-27% of patients categorized as low-risk had died, while 44.6-47.2% categorized as high-risk were alive. ML approaches improved risk stratification over HCT-CI and aELN but performed comparably with Cox model. Individual outcome prediction using static pre-transplant models remained modest. Progress will require MRD standardization, richer data. and dynamic peri- and post-transplant modeling.

Hans’ algorithm (HA) is the most frequently used surrogate biomarker scheme for subtyping Diffuse large B-cell lymphoma (DLBCL) by the cell-of-origin (COO) into GCB and non-GCB subtypes. The originally published positive and negative predictive value (PPV and NPV) against gene expression profiling (GEP) subtypes were less than perfect and were not fully reproducible in published literature. Furthermore, little is known about how the HA performs in clinical practice. The Canadian Association of Pathologists National Standard Committee for High Complexity Testing (CAP-ACP NSCHCT) initiated a Canada-wide project to assess the current diagnostic accuracy of the HA in clinical practice, harmonize the analytical phase of the IHC assays used for HA, and to optimize its overall diagnostic sensitivity and specificity against GEP subtypes. We divided a DLBCL cohort (n=96), where COO was defined by GEP (Lymph2CX, NanoString technologies) into training (TC, N=45) and validation cohort (VC, N=51) and tissue microarray (TMA)-TC and TMA-VC were constructed. Selected major Canadian laboratories applied their routine CD10, Bcl-6, and MUM1 IHC protocols and sent stained slides to the reference laboratory for review. The IHC protocols from laboratories were designated as “weak” (1/10), “moderate” (4/10), and “strong” (5/10) based on their overall analytical sensitivity. The results of the central review HA readouts were compared with GEP results. Furthermore, in TC, the original HA readout was modified to adjust the cutoff to overall IHC protocol sensitivity. The new readout criteria were also assessed in the VC set. The original HA readout showed good results against GEP for low sensitivity protocol only. For all other laboratories that had IHC protocols with moderate and high analytical sensitivity, a readout was adjusted to higher IHC protocol analytical sensitivity using a cutoff of >30% of >2+ staining intensity. This modification yielded significantly improved diagnostic accuracy against GEP even without any changes to the IHC protocols and was widely applicable to the range of analytical sensitivities of IHC protocols, which are currently in use. IHC biomarkers for HA can be highly accurate and harmonized across different laboratories for clinical application if the following criteria are met: (i) testing laboratories use standardized reference materials to set up and monitor analytical sensitivity, and (ii) the pathologist’s readout and cutoff are adjusted to the overall IHC protocol analytical sensitivity.

Clinical decision making in Acute Myeloid Leukemia (AML) critically relies on rapid genomic characterization. To better understand the AML diagnostic landscape in Canada, the Canadian Leukemia Study Group (CLSG) conducted a survey of laboratory hematology leadership (n = 18) at 16 laboratories across 10 provinces, administered using Google Forms in September 2024. Nearly all surveyed sites were equipped to deliver a full suite of testing platforms through existing on-site infrastructure or laboratory partnerships. Reporting practices varied in terms of genomic integration into bone marrow results and the use of AML classification systems. Turn-around-time (TAT) targets were predominantly determined through internal institutional consensus (62%) or recommendations by provincial cancer agencies/international groups (44%). TAT reduction was a top priority for 56% of laboratories, suggesting timely biomarker results to be an active area for improvement. Various treatment-determining biomarkers were frequently assessed as rapid-tests (defined as a 5-day TAT), including FLT3-ITD (69%), FLT3-TKD (56%), and NPM1 (56%), while others such as IDH1 and TP53 were rapid at a limited number of laboratories. Respondents demonstrated a strong shared interest in joint projects such as the validation of AML measurable residual disease (MRD) assays (56%). There was also unanimous support for establishing CLSG AML laboratory consensus guidelines. This survey documents the current state of Canadian AML laboratories and provides a foundation for future shared development projects.