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.

Capturing the True Cost of Breast Cancer Treatment: Molecular Subtype and Stage-Specific per-Case Activity-Based Costing.

BACKGROUND: Breast cancer (BC) treatment is rapidly evolving with new and costly therapeutics. Existing costing models have a limited ability to capture current treatment costs. We used an Activity-Based Costing (ABC) method to determine a per-case cost for BC treatment by stage and molecular subtype. METHODS: ABC was used to proportionally integrate multidisciplinary evidence-based patient and provider treatment options for BC, yielding a per-case cost for the total duration of treatment by stage and molecular subtype. Diagnostic imaging, pathology, surgery, radiation therapy, systemic therapy, inpatient, emergency, home care and palliative care costs were included. RESULTS: BC treatment costs were higher than noted in previous studies and varied widely by molecular subtype. Cost increased exponentially with the stage of disease. The per-case cost for treatment (2023C$) for DCIS was C$ 14,505, and the mean costs for all subtypes were C$ 39,263, C$ 76,446, C$ 97,668 and C$ 370,398 for stage I, II, III and IV BC, respectively. Stage IV costs were as high as C$ 516,415 per case. When weighted by the proportion of molecular subtype in the population, case costs were C$ 31,749, C$ 66,758, C$ 111,368 and C$ 289,598 for stage I, II, III and IV BC, respectively. The magnitude of cost differential was up to 10.9 times for stage IV compared to stage I, 4.4 times for stage III compared to stage I and 35.6 times for stage IV compared to DCIS. CONCLUSION: The cost of BC treatment is rapidly escalating with novel therapies and increasing survival, resulting in an exponential increase in treatment costs for later-stage disease. We provide real-time, case-based costing for BC treatment which will allow for the assessment of health system economic impacts and an accurate understanding of the cost-effectiveness of screening.

Management of genitourinary symptoms in patients with breast cancer: an updated systematic review of available evidence from randomized trials.

PURPOSE: The purpose of this systematic review update is to synthesize available data on management of genitourinary symptoms (GUS) in breast cancer patients, a common and challenging clinical scenario. METHODS: EMBASE, Ovid Medline, and the Cochrane Library were searched from September 2014 to December 2021 for randomized controlled trials which examined various interventions for GUS in breast cancer patients. Outcomes of interest included improvements in vaginal symptoms (e.g., dryness, pain, dyspareunia, itching), vaginal hormone response measured by validated scales (e.g., Vaginal Health Index, and Vaginal Maturation Index), and Female Sexual Function Index (FSFI). A team of reviewers participated in the processes of study selection, data collection, and risk of bias appraisal. A descriptive approach to synthesis was used. RESULTS: Of 842 unique citations identified (412 from this update, 430 from previous review), eight studies (n = 539) met inclusion criteria. Interventions included 0.005% estriol gel (EG; n = 50), intravaginal testosterone (IVT; n = 21), intravaginal prebiotic (n = 13), hyaluronic acid (HA; n = 12), polyacrylic acid (PA; n = 25), pH-balanced gel (n = 118), Replens® (n = 24), and Lidocaine (n = 22). These were compared to placebo/saline/lubricants/usual care (n = 228). FSFI total score was significantly improved by all interventions except IVT and lidocaine, and not measured for Replens®. Significant improvements in vaginal hormone responses were reported for EG and pH-balanced gel; however, no significant effects were found for IVT, HA, or prebiotics. Vaginal symptoms were significantly improved by EG, IVT, PA, and PH-balanced gel. CONCLUSION: Treatment of GUS remains a challenging issue. It is evident that more prospective trials are needed.

Reproductive Outcomes in Young Breast Cancer Survivors Treated (15-39) in Ontario, Canada.

We conducted a population-based, retrospective, matched-cohort study to examine the impact of breast cancer diagnosis and treatment on fertility outcomes. Relative risks of infertility, childbirth, premature ovarian insufficiency (POI; age < 40) and early menopause (age < 45) were calculated using modified Poisson regression. Our primary cohort included young women (15-39) with early stage BC diagnosed 1995-2014. Five cancer-free patients were matched to each BC patient by birth year and census subdivision. The BC cohort was further divided by treatment with chemotherapy vs. no chemotherapy treatment. 3903 BC patients and 19,515 cancer-free women. BC patients treated with chemotherapy were at increased risk of infertility (RR 1.81; 95% CI 1.60-2.04), and POI (RR 6.25; 95% CI 5.15-7.58) and decreased childbirth (RR 0.85; 95% CI 0.75-0.96), compared to women without cancer. BC patients who did not receive chemotherapy were also at increased risk of infertility (RR 1.80 95% CI 1.48-2.18) and POI (RR 2.12 95% CI 1.37-3.28). All young BC survivors face an increased risk of diagnosed infertility and POI relative to women without cancer, independent of chemotherapy. These results emphasize the importance of pre-treatment fertility counselling for young women diagnosed with BC.

Cardiac Monitoring and Heart Failure in Advanced Breast Cancer Patients Treated With Trastuzumab in Ontario, Canada.

Background: Trastuzumab has improved patient outcomes in HER2 + breast cancer (BC) but carries a risk of cardiotoxicity. Routine cardiac imaging is recommended for advanced breast cancer (aBC) patients during trastuzumab treatment despite a lack of evidence that this improves patient outcomes. This study was conducted to understand predictive factors for cardiac events and determine the impact of cardiovascular monitoring in aBC. Methods: This retrospective population-based cohort study included aBC patients treated with trastuzumab (all lines), in Ontario, Canada from 2007 to 2017. The overall cohort was divided into two groups; those who developed a cardiac event (CE) vs. those who did not. Patients with pre-existing heart disease were excluded. Logistic regression was performed to identify patient characteristics associated with an increased risk of CE. Results: Of 2,284 patients with HER2 + aBC treated with trastuzumab, 167 (7.3%) developed a CE. Median age at first dose of trastuzumab was 57 (IQR 49-66); 61 (IQR 51-70) for patients with a CE. Median number of cycles was 16 (IQR 7-32); 21 (IQR 8-45) for patients with a CE (p < 0.01). Twelve (0.5%) patients died of cardiac causes; all had a prior CE. Increased risk of CEs was associated with age > 60 (OR 5.21, 95% CI 1.83-14.84, p = 0.05) and higher number cycles of trastuzumab (OR 1.01; 95% CI 1-101, p = 0.028). Conclusion: This is the first population-based study to report on CEs and cardiac monitoring in HER2 + aBC patients during trastuzumab-based therapy. Older age and longer treatment with trastuzumab were associated with an increased risk of a CE.

Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies.

CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50-650 mg/m2) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.

Impact of Stopping Trastuzumab in Early Breast Cancer: A Population-Based Study in Ontario, Canada.

BACKGROUND: Adjuvant trastuzumab for early-stage (I-III) HER2-positive breast cancer (BC) has led to statistically significant improvement in cancer outcomes but carries a risk of cardiotoxicity. Trastuzumab is discontinued early in many patients for asymptomatic changes in left ventricular ejection fraction. We evaluated the impact of early discontinuation of trastuzumab on cancer outcomes. METHODS: We conducted a retrospective population-based cohort study of early BC patients treated with adjuvant trastuzumab in Ontario, Canada, 2007-2016. Four groups were analyzed: group A was full treatment, 17-18 cycles trastuzumab; group B was cardiac event (CE) within treatment period; group C was ≤16 cycles, no CEs, stopped within 30 days from last cardiac imaging; and group D was ≤16 cycles, no CEs, stopped more than 30 days from cardiac imaging. Primary outcome was disease-free survival (DFS); secondary outcomes were: overall survival, cancer-specific mortality, and cardiovascular mortality. Sensitivity analyses were performed 14 months after cycle 1 trastuzumab to control for early relapse. RESULTS: A total of 5547 patients met the inclusion criteria: group A = 3921, group B = 309, group C = 362, and group D = 955. The 5-year DFS was 94.1% in group A, 80.1% in group B, 81.4% in group C, and 82.4% in group D. Using a Cox model, the hazard ratio for 5-year DFS was 3.15 (95% confidence interval [CI] = 2.13 to 4.65) for group B, 1.94 (95% CI = 1.30 to 2.89) for group C, and 1.92 (95% CI = 1.46 to 2.53) for group D. Overall, 26 patients (0.5%) died of cardiac causes. CONCLUSIONS: BC patients in Ontario who did not complete adjuvant trastuzumab had a statistically significantly higher risk of BC relapse and death and low incidence of cardiac death. These findings support 1 year of adjuvant trastuzumab in early-stage BC.

Arsenic metalation of seaweed Fucus vesiculosus metallothionein: the importance of the interdomain linker in metallothionein.

The presence of metallothionein in seaweed Fucus vesiculosus has been suggested as the protecting agent against toxic metals in the contaminated waters it can grow in. We report the first kinetic pathway data for A3+ binding to an algal metallothionein, F. vesiculosus metallothionein (rfMT). The time and temperature dependence of the relative concentrations of apo-rfMT and the five As-containing species have been determined following mixing of As3+ and apo-rfMT using electrospray ionization mass spectrometry (ESI MS). Kinetic analysis of the detailed time-resolved mass spectral data for As3+ metalation allows the simulation of the metalation reactions showing the consumption of apo-rfMT, the formation and consumption of As1- to As4-rfMT, and subsequent, final formation of As5-rfMT. The kinetic model proposed here provides a stepwise analysis of the metalation reaction showing time-resolved occupancy of the Cys7 and the Cys9 domain. The rate constants (M(-1) s(-1)) calculated from the fits for the 7-cysteine gamma domain are k1gamma, 19.8, and k2gamma, 1.4, and for the 9-cysteine beta domain are k1beta, 16.3, k2beta, 9.1, and k3beta, 2.2. The activation energies and Arrhenius factors for each of the reaction steps are also reported. rfMT has a long 14 residue linker, which as we show from analysis of the ESI MS data, allows each of its two domains to bind As3+ independently of each other. The analysis provides for the first time an explanation of the differing metal-binding properties of two-domain MTs with linkers of varying lengths, suggesting further comparison between plant (with long linkers) and mammalian (with short linkers) metallothioneins will shed light on the role of the interdomain linker.