Management of Trastuzumab Deruxtecan-related nausea and vomiting in real-world practice.

Background: Nausea and vomiting are common side effects of Trastuzumab Deruxtecan (T-DXd), but guidelines for optimal management were not initially available. This retrospective single-center study aimed at evaluating the efficacy of two antiemetic regimens in patients receiving T-DXd. Methods: Data from metastatic breast cancer patients receiving T-DXd were collected. Two groups were defined: patients treated with 5-HT3 receptor antagonists (RA) ± dexamethasone (5-HT3-group) and patients treated with a fixed oral combination of netupitant (NK1RA) and palonosetron ± dexamethasone (NK1 group). Physicians preferentially offered the NK1 regimen to patients at higher risk of nausea and vomiting based on internal recommendations. Only nausea and vomiting during cycles 1 and 2 were considered. Comparisons of nausea and vomiting by the antiemetic prophylaxis group were assessed using chi-square. Results: A total of 53 patients were included in the analysis. At cycle 1, 72% and 28% of patients received the 5-HT3 and NK1 prophylaxis, respectively. Overall, 58% reported nausea, with no differences between groups (58% vs. 60%; p = 0.832), but with a trend for lower grade in the NK1 group (33.3% G1; 26.7% G2) compared to the 5-HT3 group (23.7% G1; 31.6% G2; 2.6% G3). Vomiting was reported by 21% and 0% of patients in the 5-HT3 and the NK1 group, respectively (p = 0.054). Among the 15 patients in the 5-HT3 group with nausea at cycle 1 who escalated to NK1 at cycle 2, nausea decreased from 100% to 53% (p = 0.022) and vomiting decreased from 47% to 13% (p = 0.046). Conclusions: The NK1 regimen improved vomiting control at cycle 1 and, when introduced at cycle 2, significantly improved both nausea and vomiting. The biased NK1 selection for higher-risk patients may have dampened the differences between groups at cycle 1. These findings support enhanced control of T-DXd-related nausea and vomiting with NK1RA.

Personalized Risk-Benefit Ratio Adaptation of Breast Cancer Care at the Epicenter of COVID-19 Outbreak.

Northern Italy has been one of the European regions reporting the highest number of COVID-19 cases and deaths. The pandemic spread has challenged the National Health System, requiring reallocation of most of the available health care resources to treat COVID-19-positive patients, generating a competition with other health care needs, including cancer. Patients with cancer are at higher risk of developing critical illness after COVID-19 infection. Thus, mitigation strategies should be adopted to reduce the likelihood of infection in all patients with cancer. At the same time, suboptimal care and treatments may result in worse cancer-related outcome. In this article, we attempt to estimate the individual risk-benefit balance to define personalized strategies for optimal breast cancer management, avoiding as much as possible a general untailored approach. We discuss and report the strategies our Breast Unit adopted from the beginning of the COVID-19 outbreak to ensure the continuum of the best possible cancer care for our patients while mitigating the risk of infection, despite limited health care resources. IMPLICATIONS FOR PRACTICE: Managing patients with breast cancer during the COVID-19 outbreak is challenging. The present work highlights the need to estimate the individual patient risk of infection, which depends on both epidemiological considerations and individual clinical characteristics. The management of patients with breast cancer should be adapted and personalized according to the balance between COVID-19-related risk and the expected benefit of treatments. This work also provides useful suggestions on the modality of patient triage, the conduct of clinical trials, the management of an oncologic team, and the approach to patients' and health workers' psychological distress.

A randomized, phase II, three-arm study of two schedules of ixabepilone or paclitaxel plus bevacizumab as first-line therapy for metastatic breast cancer.

The aim of this phase II trial was to estimate the objective response rate (ORR) of two different schedules of ixabepilone [weekly or every 3 weeks (Q3W)] combined with bevacizumab, relative to a reference arm of weekly paclitaxel and bevacizumab. Patients with human epidermal growth factor receptor 2-normal, chemotherapy-naïve metastatic breast cancer (MBC) were randomized 3:3:2 to ixabepilone 16 mg/m(2) weekly plus bevacizumab 10 mg/kg Q2W (Arm A: n = 46); ixabepilone 40 mg/m(2) Q3W (reduced to 32 mg/m(2) after four cycles of treatment) plus bevacizumab 15 mg/kg Q3W (Arm B: n = 45); or paclitaxel 90 mg/m(2) weekly plus bevacizumab 10 mg/kg intravenous infusion Q2W (Arm C: n = 32). Of 123 randomized patients, 122 were treated. All were followed for ≥19 months; 5 % of patients remained on study treatment at the time of this analysis. Grade 3 or 4 neutropenia was more common in Arm B (60 %) than Arms A (16 %) or C (22 %); other adverse events were similar. The investigator-assessed ORR was 48, 71, and 63 % for Arms A, B, and C, respectively. Median progression-free survival (randomized patients) was 9.6 months in Arm A, 11.9 months in Arm B, and 13.5 months in Arm C. In conclusion, ixabepilone Q3W plus bevacizumab has clinical activity as first-line therapy for MBC relative to paclitaxel plus bevacizumab, but with significantly greater risk of grade 3 or 4 neutropenia. In addition, these data suggest that weekly dosing of ixabepilone may be less active than Q3W dosing, but with less neutropenia.

An exploratory study of sunitinib in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive metastatic breast cancer.

BACKGROUND: This exploratory study assessed the safety, pharmacokinetics, and antitumor activity of sunitinib combined with docetaxel and trastuzumab. METHODS: Patients with unresectable, locally recurrent or metastatic human epidermal growth factor receptor 2 (HER2)+ breast cancer received sunitinib plus docetaxel and trastuzumab. Sunitinib was administered at 37.5 mg/day for 2 weeks on treatment followed by 1 week off (Schedule 2/1). The primary endpoint was safety; secondary endpoints included pharmacokinetics and antitumor activity. RESULTS: Twenty-six patients enrolled; 24 received at least one dose of sunitinib plus docetaxel and trastuzumab, and one patient received one dose of docetaxel and trastuzumab only. These 25 treated patients were evaluable for safety. Twenty-three patients discontinued the study, primarily due to disease progression. The planned dose of sunitinib was maintained in 10 patients and reduced at least once to 25 mg/day in 14 patients. The most common grade 3/4 non-hematologic adverse events were fatigue/asthenia (28%), diarrhea (16%), stomatitis (12%), vomiting (8%) and dyspnea (8%). Neutropenia was reported in all 24 evaluable patients; most events were grade 4. Three grade 1-3 cardiac adverse events occurred. Sunitinib and docetaxel levels were consistent with known single-agent levels, suggesting that there were no clinically relevant drug-drug interactions. Of 22 evaluable patients, 16 (73%) experienced an objective response (all confirmed partial responses). CONCLUSIONS: Sunitinib combined with docetaxel and trastuzumab had an acceptable toxicity profile and showed preliminary antitumor activity as first-line treatment for metastatic HER2+ breast cancer.

Antiangiogenic strategies in breast cancer management.

Angiogenesis is considered one of the key mechanisms of tumour growth and survival. Therefore it represents an ideal pharmaceutical target. Many antiangiogenic agents have been developed so far in several solid tumours and also in breast cancer. Vascular endothelial growth factor (VEFG) is the main target and both monoclonal antibodies and small molecules belonging to the tyrosine kinase inhibitors directed against VEGF(R) have been developed. Some other therapeutic approaches have shown to exert some antiangiogenic activity, such as hormonal agents, metronomic chemotherapy, bisphosphonates and others. In this paper we provide an introduction of the current data supporting the angiogenesis in breast cancer and a review of the most relevant antiagiogenic therapies which have been investigated so far.

Switching to an aromatase inhibitor provides mortality benefit in early breast carcinoma: pooled analysis of 2 consecutive trials.

BACKGROUND: The superiority of new generation aromatase inhibitors over tamoxifen in the adjuvant treatment of early breast carcinoma has emerged from several randomized trials. However, until now not all previous studies have shown a mortality benefit. METHODS: A pooled analysis of 2 prospective multicentric trials, sharing the same study design and nearly identical inclusion criteria, was performed. In both trials, women treated previously with tamoxifen for 2 or 3 years were randomly assigned to either continuing tamoxifen for an additional 2 or 3 years or to having their treatment switched to aminoglutethimide or anastrozole for a comparable time period. Mortality was analyzed according to allocated treatment and other patient and tumor variables. RESULTS: In all, 828 postmenopausal women, mostly with estrogen receptor (ER)-positive and node-positive tumors who had been monitored for a median time of 78 months (range, 6-141 months) were analyzed. Of these women, 415 were randomly selected to continue tamoxifen and 413 switched to aminoglutethimide or anastrozole. All-cause mortality and breast cancer-specific mortality were significantly improved by the switch: all-cause mortality: hazard ratio (HR) = 0.61 (0.42-0.88) P = .007; breast cancer-specific mortality: HR = 0.61 (0.39-0.94) P = .025. No increase was recorded in breast cancer-unrelated mortality in women after switching. Multivariate analysis showed that patient age, tumor size, allocated treatment, and nodal status, in that order, were independent mortality predictors. CONCLUSIONS: Switching to an aromatase inhibitor after 2 or 3 years of tamoxifen therapy significantly improves survival compared with continuing 2 or 3 years of additional tamoxifen treatment.

Concomitant versus sequential administration of epirubicin and paclitaxel as first-line therapy in metastatic breast carcinoma: results for the Gruppo Oncologico Nord Ovest randomized trial.

BACKGROUND: The authors performed a randomized trial comprising patients with metastatic breast carcinoma (MBC). They used a noninferiority design to evaluate whether the results of sequential administration of epirubicin and paclitaxel were not markedly worse than the concomitant administration in terms of objective response rates (ORRs). Toxicity profile, quality of life (QOL), and pharmacoeconomic evaluations were evaluated as well. METHODS: In the current study, 202 patients with MBC were randomized to receive either the combination of epirubicin at a dose of 90 mg/m2 plus paclitaxel at a dose of 200 mg/m2 for 8 cycles (concomitant arm, n = 108) or epirubicin at a dose of 120 mg/m2 for 4 cycles followed by paclitaxel at a dose of 250 mg/m2 over 3 hours for 4 cycles every 21 days (sequential arm, n = 94). RESULTS: The authors rejected the null hypothesis that the sequential treatment is less active than the standard concomitant regimen (ORRs: concomitant = 58.5%, sequential = 57.6%). The median progression-free and overall survival periods were 11.0 months (95% confidence interval [95% CI], 9.7-12.3) and 20.0 months (95% CI, 17.2-22.6), respectively, in the concomitant arm and 10.8 months (95% CI, 7.9-13.6) and 26 months (95% CI, 18.1-33.8), respectively, in the sequential arm (P = not significant). Patients who received the sequential regimen experienced a higher incidence of Grade 3/4 (according to the World Health Organization grading system) neutropenia (62.2% of courses vs. 50.62%; P = 0.003) and Grade > or = 2 neuropathy (45.5% vs. 30.4% of patients; P = 0.03), whereas 6 patients who received the concomitant regimen developed Grade II cardiotoxicity according to New York Heart Association criteria. QOL analyses failed to provide clear differences. CONCLUSIONS: The sequential administration of epirubicin and paclitaxel at full doses was found to be as active as their association. Therefore, both the sequential and the combined administration were acceptable options.