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.

Alemtuzumab and CHOP Chemotherapy for the Treatment of Aggressive Histology Peripheral T Cell Lymphomas: A Multi-Center Phase I Study.

BACKGROUND: Alemtuzumab has single-agent activity in relapsed peripheral T cell lymphoma (PTL), but the optimal dose and/or schedule in combination with chemotherapy for first-line use is unknown. The primary objectives were to establish the maximally tolerated dose and pharmacokinetics (PK) of alemtuzumab combined in this way. PATIENTS AND METHODS: Adult patients with untreated CD52-positive (CD52(+)) PTL were enrolled in a phase I trial. Alemtuzumab was given subcutaneously in escalating doses and/or schedules in combination with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) using a 3+3 design. Trough PK of alemtuzumab were measured on day 1 of each 21-day cycle and B and T cell subsets were serially measured. RESULTS: Twenty patients were enrolled across 4 dose levels. Dose-limiting toxicities necessitated expansion at 10 mg weekly (fatal tuberculosis reactivation) and 60 mg every 3 weeks (grade 4 thrombocytopenia) dose levels. Maximally tolerated dose was not reached. Ten patients developed asymptomatic cytomegalovirus reactivations at a median of 39 days (range, 4-99 days). Two patients developed fungal pneumonias. The overall and complete response rates were 68% and 37%, respectively. Highest day 1 alemtuzumab trough levels were achieved at 60 mg (1973 ng/mL), but with significant inter- and intradose variability. Lymphopenia at baseline was common and T cell recovery was significantly delayed. CONCLUSION: With monitoring and prophylaxis, alemtuzumab 60 mg combined with CHOP showed activity in CD52(+) PTL and achieved the highest drug levels.

Adjuvant endocrine therapy in hormone receptor-positive postmenopausal breast cancer: evolution of NCCN, ASCO, and St Gallen recommendations.

Endocrine therapy has a firm role in adjuvant treatment of women with hormone receptor-positive invasive breast cancer. Until recently, tamoxifen was the most commonly used adjuvant endocrine therapy in premenopausal and postmenopausal women. Several randomized clinical trials have studied the third-generation selective aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) as adjuvant endocrine therapy in postmenopausal women. These studies compared therapy with an AI alone versus tamoxifen alone; 2 to 3 years of tamoxifen followed by switching to an AI versus continuation of tamoxifen; or extended therapy with an AI after approximately 5 years of tamoxifen therapy. No statistically significant differences in overall survival were observed. A single trial using extended treatment with an adjuvant AI suggests a small, statistically significant survival advantage in women with axillary lymph node-positive disease while showing no statistically significant decrease in survival with the use of an AI. The toxicities of the AIs are generally acceptable, with fewer endometrial cancers, gynecologic complaints, and thromboembolic events, but more bone fractures and arthralgias compared with tamoxifen alone. Three widely disseminated treatment guidelines, the National Comprehensive Cancer Network Breast Cancer Clinical Practice Guidelines in Oncology, the American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors, and the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer, now incorporate AIs in the adjuvant therapy of postmenopausal women with estrogen receptor-positive breast cancer.

Selection of adjuvant chemotherapy for treatment of node-positive breast cancer.

Over the past two decades, several studies have suggested that regimens that contain anthracyclines are more effective than those that do not. A meta-analysis by the 2005 Early Breast Cancer Trialists' Collaborative Group confirmed that about 6 months of anthracycline-based polychemotherapy in the adjuvant setting reduced the yearly death rate from breast cancer by about 38% for women younger than 50 years and by 20% for women aged 50-69 years. Although this meta-analysis found that survival was better with regimens that contain anthracycline than with regimens based on cyclophosphamide, methotrexate, and fluorouracil, the best use of anthracycline-based regimens remains unclear. Adjuvant regimens in use can be categorised into three groups: standard-dose anthracycline; escalated-dose epirubicin; and anthracyclines and taxanes. The duration of treatment and combination of dose and drugs varies between these three categories. We reviewed the three types of regimen to establish which provide a better outcome in terms of safety, efficacy, cost, and convenience to patients. We found that both escalated-dose epirubicin and anthracycline-taxane regimens were most effective in terms of disease-free survival and overall survival. Of the specific anthracycline-based regimens, the docetaxel, doxorubicin, and cyclophosphamide regimen (TAC); the fluorouracil, 100 mg epirubicin, and cyclophosphamide regimen (FEC100); and the cyclophosphamide, epirubicin, and fluorouracil regimen (CEF) produced the greatest proportional decreases in 5-year death rate.

Clinical trial update: National Cancer Institute of Canada.

The Breast Cancer Site Group (BCSG) of the National Cancer Institute of Canada (NCIC) Clinical Trials Group (CTG) has conducted a wide variety of clinical trials focussing on large phase III trials of adjuvant chemotherapy, adjuvant hormonal therapy, and optimal delivery of adjuvant radiation therapy. The Group has also fostered, together with the NCIC CTG Investigational New Drug (IND) Program, a series of phase II and phase I/II studies which will be carried through if possible, into the phase III setting.