Research needs in breast cancer.

New research questions emerge as medical needs continue to evolve and as we improve our understanding of cancer biology and treatment of malignancies. Although significant advances have been made in some areas of breast cancer research resulting in improvements in therapies and outcomes over the last few decades, other areas have not benefited to the same degree and we continue to have many gaps in our knowledge. This article summarizes the 12 short and medium-term clinical research needs in breast cancer deemed as priorities in 2016 by a panel of experts, in an attempt to focus and accelerate future research in the most needed areas: (i) de-escalate breast cancer therapies in early breast cancer without sacrificing outcomes; (ii) explore optimal adjuvant treatment durations; (iii) develop better tools and strategies to identify patients with genetic predisposition; (iv) improve care in young patients with breast cancer; (v) develop tools to speed up drug development in biomarker-defined populations; (vi) identify and validate targets that mediate resistance to chemotherapy, endocrine therapy and anti-HER2 therapies; (vii) evaluate the efficacy of local-regional treatments for metastatic disease; (viii) better define the optimal sequence of treatments in the metastatic setting; (ix) evaluate the clinical impact of intra-patient heterogeneity (intra-tumor, inter-tumor and inter-lesion heterogeneity); (x) better understand the biology and identify new targets in triple-negative breast cancer; (xi) better understand immune surveillance in breast cancer and further develop immunotherapies; and (xii) increase survivorship research efforts including supportive care and quality of life.

Randomized phase II study of high-dose paclitaxel with or without amifostine in patients with metastatic breast cancer.

PURPOSE: To determine whether the neurotoxicity of paclitaxel 250 mg/m(2) given over 3 hours every 3 weeks could be reduced by pretreatment with amifostine 910 mg/m(2). Secondary objectives included comparing myelosuppression, myalgias, and response rates of the two groups. PATIENTS AND METHODS: Forty women with metastatic breast cancer were randomized to receive either paclitaxel alone (arm 1) or paclitaxel preceded by amifostine (arm 2). All were assessable for toxicity, and 37 were assessable for response. At baseline and after each cycle, all patients completed questionnaires for neurologic symptoms and had standardized neurologic examinations, including objective assessments of power and vibration sense. In addition, standard follow-up assessments for other toxicities and tumor response were undertaken. Changes from baseline after courses 1, 2, and 3 were assessed. The sample size was sufficient to detect a 50% improvement in the expected determination in sensory change. RESULTS: There were no differences observed in any of the measures of neurotoxicity. Other toxicity was similar in arms 1 and 2, including hair loss (95% v 90%), neurosensory changes (100% v 100%), fatigue/lethargy (85% v 90%), myalgia (95% v 90%), and grade 4 neutropenia (47% v 60%). Nausea, vomiting, dizziness, hypotension, and sneezing were more common in the amifostine arm. Response rates (22.2% v 36.8%) and paclitaxel pharmacokinetics were not significantly different. CONCLUSION: There was no protection from paclitaxel-related neurotoxicity or hematologic toxicity in this study. These results suggest that the mechanism of action of paclitaxel-related toxic effects is not amenable to the cytoprotective action of amifostine.

1st International consensus guidelines for advanced breast cancer (ABC 1).

The 1st international Consensus Conference for Advanced Breast Cancer (ABC 1) took place on November 2011, in Lisbon. Consensus guidelines for the management of this disease were developed. This manuscript summarizes these international consensus guidelines.

A phase I study of OSI-211 and cisplatin as intravenous infusions given on days 1, 2 and 3 every 3 weeks in patients with solid cancers.

BACKGROUND: OSI-211 (also known as NX211) is a liposomal preparation of the topoisomerase I inhibitor, lurtotecan, which has shown antitumor activity in phase I and II clinical trials. Cisplatin is a widely used antineoplastic agent with activity in a broad range of tumor types. This phase I trial was conducted to determine the recommended doses of these agents, and their pharmacokinetic properties and toxicities in patients with advanced solid malignancies. PATIENTS AND METHODS: Fourteen patients with advanced and/or metastatic solid malignancies were enrolled in this trial. The first planned dose level was OSI-211 0.9 mg/m(2) with cisplatin 25 mg/m(2) administered intravenously daily for the first three consecutive days of a 21-day cycle. Patients were evaluated for hematological and non-hematological toxicities, and pharmacokinetic studies were performed on both agents. RESULTS: The recommended phase II dose was determined to be 0.7 mg/m(2) OSI-211 given with 25 mg/m(2) cisplatin. Dose-limiting neutropenia was seen in two of three patients at the starting dose level. Three of 11 patients at the second (lower) dose level experienced dose-limiting thrombocytopenia; febrile neutropenia was also seen in one patient. Non-hematological toxicities were generally manageable and included fatigue, nausea and vomiting. Considerable variability was seen in both hematological toxicities and pharmacokinetics. One complete response and three partial responses were seen. CONCLUSIONS: The recommended phase II dose for this combination is 0.7 mg/m(2) OSI-211 with 25 mg/m(2) cisplatin given as an intravenous infusion on days 1, 2 and 3 of a 21-day cycle. The main toxicity was myelosuppression. Preliminary evidence of antitumor activity was seen.

A phase II study of ZD0473 given as a short infusion every 3 weeks to patients with advanced or metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group trial, IND 129.

BACKGROUND: ZD0473 is a new generation platinum compound with activity against a wide range of human tumor cell lines and xenografts, including carboplatin- and cisplatin-resistant lines. A phase II study of ZD0473 in advanced breast cancer was initiated by the National Cancer Institute of Canada Clinical Trials Group. PATIENTS AND METHODS: Women with metastatic breast cancer, measurable disease, an Eastern Cooperative Oncology Group performance status of up to two, and a maximum of one prior cytotoxic agent for recurrent disease were enrolled and treated at 120 mg/m(2) every 3 weeks. After 13 patients were enrolled, the dose was increased to 150 mg/m(2) on the basis of emergent data from studies ongoing at the time. RESULTS: Thirty-three women were evaluable for toxicity and 26 patients for response. Toxicity was mainly hematological with grade 3/4 thrombocytopenia in 12 of 20 patients (60%) treated at 150 mg/m(2) and grade 3 thrombocytopenia in three of 13 patients (23%) at 120 mg/m(2). Grade 3/4 neutropenia occurred in 15 patients (75%) at 150 mg/m(2) and two patients (10%) at 120 mg/m(2). Non-hematological toxicities were generally mild or moderate. There was one partial response seen for a response rate of 3.8% (95% confidence interval 0.1% to 19.5%) and stable disease in 15 patients. CONCLUSION: ZD0473 has minor activity as a single agent in metastatic breast cancer. Combinations with other drugs including docetaxel are ongoing and may be of interest.