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Addition of platinums to combination chemotherapy for triple negative breast cancer (TNBC) has shown efficacy and is increasingly accepted in the clinic, yet optimal delivery is unknown. A prospective clinical trial with TNBC patients was conducted to determine the optimal chemotherapy regimen to deliver carboplatin with standard dose dense ACT. Tissue microarray was conducted to isolate markers indicative of response to treatment. 90 TNBC patients were enrolled onto our trial. The most successful version placed the carboplatin on the second and final paclitaxel treatment with liberal hematological parameters. Our final regimen had the lowest grade 3 or 4 toxicities, no delays, no dose reductions of carboplatin, and 32% reduction in paclitaxel doses. Stage I (AJCC7) patients did well with carboplatin-based chemotherapy with zero relapse rate. Reduction in protein levels of androgen receptor and PD-L1 were found to be potential indicators of patient relapse. We have optimized a protocol for the addition of carboplatin to standard of care chemotherapy in TNBC patients. Early data indicates reduced protein levels of androgen receptor and PD-L1 as indicators of response to treatment.Trial registration This trial was registered at Canadian Cancer Trials. http://www.canadiancancertrials.ca/., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To assess the toxicity and effectiveness of contemporary metastatic castrate-resistant prostate cancer (mCRPC) treatments at a population level, among all patients in Ontario particularly treated with newer agents, including abiraterone, enzalutamide, docetaxel, and cabazitaxel., Methods: We performed a population-based, retrospective cohort study of 2439 men aged ≥65 years treated for mCRPC with abiraterone, enzalutamide, docetaxel, or cabazitaxel from 2003 to 2015 in Ontario, Canada. Our primary outcome was treatment-related toxicity, defined as hospitalizations and emergency room (ER) visits during mCRPC treatment. Based on toxicity profiles identified during phase III trials, we further identified specific treatment-related toxicity. We calculated hazard ratios (HRs) using multivariable Cox proportional hazards models with time-varying exposures., Results: Abiraterone and enzalutamide exposure were not associated with any-cause (P = .19 and .52, respectively) or treatment-related (P = .45 and .64, respectively) toxicities. In contrast, docetaxel exposure was associated with an increased risk of any-cause (HR 1.29, 95% confidence interval [CI] 1.15-1.44) and treatment-related (HR 1.52, 95% CI 1.33-1.74) toxicities. Cabazitaxel exposure was associated with a significant risk of treatment-related toxicity (HR 5.94, 95% CI 1.87-18.92) but not any-cause toxicity (HR 2.37, 95% CI 0.59-9.63)., Conclusion: Among patients with mCRPC, we failed to show any increased risk of hospitalizations and ER visits for treatment-related complications for abiraterone or enzalutamide. In contrast, treatment with intravenous chemotherapeutic agents was associated with an increased risk of hospitalizations and ER visits to manage these complications., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment., Methods: We did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II-III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0-1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m 2 ; carboplatin area under the concentration-time curve 6 mg/mL × min; trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab [same dosing as in the other group]). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing., Findings: Between June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference -11·3 percentage points, 95% CI -20·5 to -2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3-4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3-4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3-4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [<1%] of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 [15%] vs 2 [<1%]), and febrile neutropenia (33 [15%] vs 0). No deaths were reported during neoadjuvant treatment., Interpretation: Traditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3-4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted., Funding: F Hoffmann-La Roche and Genentech., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Capecitabine is frequently used in the treatment of recurrent/progressive metastatic breast cancer (MBC) after prior anthracycline and taxane therapy. With the intention of improving the efficacy of single agent capecitabine, we initiated a randomized, double-blind, placebo-controlled Phase II study of the novel serine/threonine kinase inhibitor enzastaurin in combination with capecitabine in a heavily pretreated patient population. Patients received capecitabine 1,250 mg/m(2) twice daily plus enzastaurin 500 mg/day, or capecitabine plus placebo. The capecitabine was administered for the first 14 days of each 21 day cycle. The primary outcome was progression-free survival (PFS) using the log-rank test (1-sided significance level of 0.20). Of 109 patients assessed for eligibility, 85 were enrolled, randomized, and treated (42 and 43 patients in each respective treatment group). The study was terminated early following a preplanned futility analysis. Median PFS (95% CI) was 2.8 (2.1-4.6) months with capecitabine plus enzastaurin versus 4.3 (2.9-6.2) months with capecitabine plus placebo (adjusted hazard ratio: 1.728 [1.00-2.97]; P = 0.048). Median overall survival (95% CI) was lower with capecitabine plus enzastaurin than with capecitabine plus placebo (9.9 [7.0-16.6] months vs 14.9 [9.9-19.3] months, P = 0.181). Grade 3/4 adverse events were more frequent with capecitabine plus enzastaurin (42.9% vs 32.6%). Given the lack of PFS benefit, capecitabine plus enzastaurin is unsuitable as therapy for patients with recurrent/progressive MBC after prior anthracycline and taxane therapy. This trial is registered on www.clinicaltrials.gov (identifier: NCT00437294).