Canadian Expert Recommendations on Safety Overview and Toxicity Management Strategies for Sacituzumab Govitecan Based on Use in Metastatic Triple-Negative Breast Cancer.

Sacituzumab Govitecan (SG) is an antibody-drug conjugate (ADC) comprised of an anti-Trop-2 IgG1 molecule conjugated to SN-38, the active metabolite of irinotecan, via a pH-sensitive hydrolysable linker. As a result of recent Canadian funding for SG in advanced hormone receptor (HR)-positive breast cancer and triple-negative breast cancer (TNBC), experience with using SG and managing adverse events (AEs) has grown. This review presents a summary of evidence and adverse event recommendations derived from Canadian experience, with SG use in metastatic TNBC for extrapolation and guidance in all indicated settings. SG is dosed at 10 mg/kg on day 1 and day 8 of a 21-day cycle. Compared to treatment of physicians' choice (TPC) the phase III ASCENT and TROPiCS-02 studies demonstrated favorable survival data in unresectable locally advanced or metastatic TNBC and HR-positive HER2 negative metastatic breast cancer, respectively. The most common AEs were neutropenia, diarrhea, nausea, fatigue, alopecia, and anemia. This review outlines AE management recommendations for SG based on clinical trial protocols and Canadian guidelines, incorporating treatment delay, dose reductions, and the use of prophylactic and supportive medications.

An Overview of Long-Acting GnRH Agonists in Premenopausal Breast Cancer Patients: Survivorship Challenges and Management.

Managing breast cancer in premenopausal women poses unique challenges due to its considerable effect on both morbidity and mortality. Goserelin, a gonadotropin-releasing hormone agonist, has emerged among the various modalities as a preferred option for ovarian function suppression, owing to its efficacy in reducing ovarian estrogen production in premenopausal women with hormone receptor-positive breast cancer. Recent studies have affirmed the efficacy and safety of long-acting (LA) goserelin 10.8 mg every 12 weeks, offering comparable outcomes to monthly injections. This flexibility enables personalized treatment approaches, potentially enhancing patient satisfaction. Off-label utilization of goserelin LA surged during the coronavirus disease pandemic, prompting initiatives to broaden its use for breast cancer treatment. Switching to goserelin LA can streamline treatment, boost adherence, and optimize resource utilization. With the recent approval of goserelin 10.8 mg LA by Health Canada on 6 May 2024, for use in breast cancer, Canada is the latest to join over 60 countries worldwide to expand the accepted indications for goserelin LA and ensure its availability to potentially enhance healthcare delivery, patient care, and breast cancer outcomes. Goserelin LA offers premenopausal patients a means to more effectively manage the constraints imposed by breast cancer treatment and its impact on survivorship.

Access to Oncology Medicines in Canada: Consensus Forum for Recommendations for Improvement.

Patient access to new oncology drugs in Canada is only possible after navigating multiple sequential systemic checkpoints for national regulatory approval, health technology assessment (HTA) and collective government price negotiation. These steps delay access and prevent health care providers from being able to prescribe optimal therapy. Eighteen Canadian oncology clinicians from the medicine, nursing and pharmacy professions met to develop consensus recommendations for defining reasonable government performance standards around process and timeliness to improve Canadian cancer patients' access to best care. A modified Delphi methodology was used to identify consensus on 30 questions involving five themes: accountability, disparities, endpoints, timeliness, and cost-effectiveness. It was agreed that greater transparency is required across regulatory and HTA processes. Health professionals in oncology are frustrated for their patients because they are unable to deliver the modern guideline-supported therapies they want to provide due to delays in approval or funding. Canadian health care providers request improvements in timely access to life-saving therapeutics in line with other comparator countries. Clinicians expect urgent improvements in Canadian health systems to give our patients their best chance of survival.

Outcomes of Rural Men with Breast Cancer: A Multicenter Population Based Retrospective Cohort Study.

BACKGROUND: Breast cancer is rare in men. This population-based study aimed to determine outcomes of male breast cancer in relation to residence and other variables. METHODS: In this retrospective cohort study, men diagnosed with breast cancer in Saskatchewan during 2000-2019 were evaluated. Cox proportional multivariable regression analyses were performed to determine the correlation between survival and clinicopathological and contextual factors. RESULTS: One hundred-eight eligible patients with a median age of 69 years were identified. Of them, 16% had WHO performance status ≥ 2 and 61% were rural residents. The stage at diagnosis was as follows: stage 0, 7%; I, 31%; II, 42%; III, 11%; IV, 8%. Ninety-eight percent had hormone receptor-positive breast cancer. The median disease-free survival of urban patients was 97 (95% CI: 50-143) vs. 64 (46-82) months of rural patients (p = 0.29). The median OS of urban patients was 127 (94-159) vs. 93 (32-153) months for rural patients (p = 0.27). On multivariable analysis, performance status ≥ 2, hazard ratio (HR) 2.82 (1.14-6.94), lack of adjuvant systemic therapy, HR 2.47 (1.03-5.92), and node-positive disease, HR 2.32 (1.22-4.40) were significantly correlated with inferior disease-free survival in early-stage invasive breast cancer. Whereas stage IV disease, HR 7.8 (3.1-19.5), performance status ≥ 2, HR 3.25 (1.57-6.71), and age ≥ 65 years, HR 2.37 (1.13-5.0) were correlated with inferior overall survival in all stages. CONCLUSIONS: Although residence was not significantly correlated with outcomes, rural men had numerically inferior survival. Poor performance status, node-positive disease, and lack of adjuvant systemic therapy were correlated with inferior disease-free survival.

Efficacy of Fulvestrant in Women with Hormone-Resistant Metastatic Breast Cancer (mBC): A Canadian Province Experience.

INTRODUCTION: Fulvestrant has demonstrated efficacy in hormone receptor positive (HR+) metastatic breast cancer (mBC), both in first-and second-line settings. In clinical practice, however, fulvestrant has been used as a later-line therapy. This study assessed the efficacy of fulvestrant in women with mBC in early-versus later-line therapy. METHODS: This retrospective cohort study assessed Saskatchewan women with HR+ mBC who received fulvestrant between 2003-2019. A multivariate Cox proportional survival analysis was performed. RESULTS: One hundred and eighty-six women with a median age of 63.5 years were identified-178 (95.6%) had hormone-resistant mBC, 57.5% had visceral disease, and 43.0% had received chemotherapy before fulvestrant. 102 (54.8%) women received ≤2-line-therapy, and 84 (45.2%) received ≥3 line-therapy before fulvestrant. The median time to progression (TTP) was 12 months in the early-treatment vs. 6 months in the later-treatment group, p = 0.015. Overall survival (OS) from the start of fulvestrant was 26 months in the early-treatment group vs. 16 months in the later-treatment group, p = 0.067. On multivariate analysis, absence of visceral metastasis, HR: 0.70 (0.50-0.99), was significantly correlated with better TTP, whereas post-fulvestrant chemotherapy, HR: 0.32 (0.23-0.47), clinical benefit from fulvestrant, HR: 0.44 (0.30-0.65), and absence of visceral metastasis, HR: 0.70 (0.50-0.97), were correlated with better OS. CONCLUSIONS: Fulvestrant has demonstrated efficacy as both early-and later-line therapy in hormone-resistant mBC. Our results show that women with clinical benefit from fulvestrant, who received post-fulvestrant chemotherapy, or had non-visceral disease, had better survival.

Current Landscape of Targeted Therapy in Hormone Receptor-Positive and HER2-Negative Breast Cancer.

Background: Hormone receptor-positive and HER2-negative breast cancer (HR + BC) is the most prevalent breast cancer. Endocrine therapy is the mainstay of treatment, however, due to the heterogeneous nature of the disease, resistance to endocrine therapy is not uncommon. Over the past decades, the emergence of novel targeted therapy in combination with endocrine therapy has shown improvement in outcomes of HR + BC. This paper reviews available data of targeted therapy and the results of pivotal clinical trials in the management of HR + BC. Methods: A literature search in PubMed and Google Scholar was performed using keywords related to HR + BC and targeted therapy. Major relevant studies that were presented in international cancer research conferences were also included. Results: Endocrine therapy with tamoxifen and aromatase inhibitors are backbone treatments for women with early-stage HR + BC leading to a significant reduction in mortality. They can also be used for primary prevention in women with a high risk of breast cancer. Preliminary data has shown the efficacy of adjuvant cyclin-dependent kinase (CDK) 4/6 inhibitor, abemaciclib, in high-risk disease in combination with aromatase inhibitors. For most women with advanced HR + BC, endocrine therapy is the primary treatment. Recent evidence has shown that the use of CKD 4/6 inhibitors, mTOR inhibitors, and PI3K inhibitors in combination with endocrine therapy has been associated with better outcomes and delays initiation of chemotherapy. Several novel agents are under study for HR + BC. Discussion: Targeted treatment options for HR + BC have evolved. The future of overcoming resistance to targeted therapy, novel compounds, and predictive markers are key to improving HR + BC outcomes.

Autologous transplantation improves survival rates for follicular lymphoma patients who relapse within two years of chemoimmunotherapy: a multi-center retrospective analysis of consecutively treated patients in the real world.

Although chemoimmunotherapy improves outcomes for patients with follicular lymphoma (FL), approximately 20% of patients experience early disease progression within two years of treatment and subsequently poor median survival. We conducted a retrospective study to evaluate survival rates of patients with early relapse who were treated with or without autologous transplantation. Of 517 patients with FL and who received chemoimmunotherapy, 152 relapsed and survived a minimum of four months after progression, including 84 (55.3%) with early relapse ≤2 years following initial therapy and 68 (44.7%) with later relapse. Five-year survival was superior for patients who received autologous transplantation compared to non-transplanted patients within the early relapse group (85.4% vs 57.9%, p = .001), but not within the late relapse group (p = .64). Given the limitations of a retrospective study, our study may suggest that the use of autologous transplantation for FL patients who relapse within two years of initial chemoimmunotherapy is associated with improved survival.

The Adverse Consequences of Initial Watchful Waiting for Patients With Follicular Lymphoma.

BACKGROUND: Patients with low tumor burden follicular lymphoma (FL) are commonly managed with watchful waiting (WW). The incidence of organ dysfunction and/or transformation at disease progression, and subsequent impact on outcomes is poorly understood. PATIENTS AND METHODS: Patients managed with WW during 1994 to 2011 were identified through the Alberta Lymphoma Database. Individuals receiving immediate rituximab (R)-chemotherapy were identified as a comparator group to those on WW who received R-chemotherapy at progression. Endpoints included transformation, organ dysfunction, time to progression, time to next treatment, progression-free survival (PFS) after chemotherapy, and overall survival (OS). RESULTS: We identified 238 patients managed with WW (28.9% of registry patients) during this 17-year period. The median follow up was 8.2 years. At a median of 29.9 months, 58 (24.4%) of these patients developed organ dysfunction and/or transformation. Of 169 (71%) patients who required therapy, 10-year OS was inferior for those with transformation (hazard ratio, 2.88; P = .002) and organ dysfunction (hazard ratio, 2.10; P = .028). PFS after R-chemotherapy and OS in patients without organ dysfunction and/or transformation was not affected by the initial WW period, compared with immediate R-chemotherapy. WW resulted in increased high risk FL International Prognostic Index scores at initiation of R-chemotherapy (45% vs. 20%), and more frequent transformation at progression (5-year risk, 17.8% vs. 3.5%; P < .001). Baseline characteristics did not predict organ dysfunction. CONCLUSION: Patients with FL accepting initial WW should be aware of the 1 in 4 risk of organ dysfunction and/or transformation, and subsequent inferior OS. Physicians should consider surveillance for progression to consider early therapy.

Detection of CD34, TdT, CD56, CD2, CD4, and CD14 by flow cytometry is associated with NPM1 and FLT3 mutation status in cytogenetically normal acute myeloid leukemia.

UNLABELLED: In 83 patients with cytogenetically normal acute myeloid leukemia (CN-AML), those with NPM1 and wild-type FLT3 (FLT3-wt) mutation and their poor prognostic combination had distinctive flow cytometric findings: CN-AML with a mutation of NPM1 (NPMI-Mt) were CD34(-), CD14(-), and CD2pos and CD4; those with FLT3-internal tandem duplications (ITD) were CD56pos, those with NPM1-Mt and FLT3-wt were CD34(-) and CD56(-); and those with poor prognostic combination NPM1-wt and FLT3-ITD were CD34pos and TdTpos. METHODS: We retrospectively correlated NPM1 and FLT3 mutation status with flow cytometric profile of leukemic blasts in 83 adult patients with cytogenetically normal acute myeloid leukemia (CN-AML). RESULTS: Mutation of the NPM1 gene (NPM1.mt) was found in 39 (47%) of 83 patients, and internal tandem duplication (ITD) of the FLT3 gene (FLT3-ITD) was seen in 38 (46%) of 83 patients. Patients with CN-AML and with NPM1.mt were less likely to express CD34 (33% vs. 93%; 2P = .0001), CD2 (0% vs. 14%; 2P = .0187), and CD14 (6% vs. 22%, 2P = .0476), and were more likely to express CD4 (65.5% vs. 37%; 2P = .0367) and CD19 (49% vs. 27%; 2P = .0506). The patients with CN-AML and with FLT3-ITD were more likely to express CD56 (47% vs. 23%; 2P = .0393). Moreover, patients with favorable prognostic combination of NPM1.mt and wild-type (wt) FLT3 (n = 18) were less likely to express CD34 (33% vs. 74% all others; 2P = .0021) and CD56 (6% vs. 37% all others; 2P = .0072). The group with an unfavorable prognostic combination of NPM1-wt and FLT3-ITD (n = 17) were more likely to express CD34 (88% vs. 45% all others; 2P = .0011) and TdT (40% vs. 2% all others; 2P = .0054). CONCLUSIONS: In patients with CN-AML, characteristic flow cytometric profile is associated with NPM1 and FLT3 mutation status.