Amye Tevaarwerk

Cytotoxicity of Paclitaxel in Breast Cancer Is due to Chromosome Missegregation on Multipolar Spindles

The chemotherapy drug paclitaxel causes tumor regression and cell death by inducing high rates of chromosome missegregation on multipolar spindles. The Secret Life of Paclitaxel The classic chemotherapy drug paclitaxel is a standard part of treatment for breast cancer and other malignancies. Although it is commonly understood to act as a microtubule poison and lead to mitotic arrest, this knowledge is largely based on studies of cells in culture, with drug concentrations that may not be realistic. Now, Zasadil and coauthors measured the concentration of paclitaxel in real patients undergoing treatment with the drug, and then investigated the response of cancer cells to paclitaxel at these lower and more realistic concentrations. Unexpectedly, the cells treated under these conditions did not undergo mitotic arrest, but instead proceeded through mitosis with abnormal spindles, resulting in chromosome missegregation, which leads to tumor cell death. This intriguing discovery demonstrates that we may not know as much as we thought about the effects of one of our most common chemotherapy drugs. In addition, the findings from this study may lead to clinical applications both in optimizing the selection of chemotherapy drug combinations and in determining which patients are likely to respond to paclitaxel treatment. The blockbuster chemotherapy drug paclitaxel is widely presumed to cause cell death in tumors as a consequence of mitotic arrest, as it does at concentrations routinely used in cell culture. However, we determine here that paclitaxel levels in primary breast tumors are well below those required to elicit sustained mitotic arrest. Instead, cells in these lower concentrations of drug proceed through mitosis without substantial delay and divide their chromosomes on multipolar spindles, resulting in chromosome missegregation and cell death. Consistent with these cell culture data, most mitotic cells in primary human breast cancers contain multipolar spindles after paclitaxel treatment. Contrary to the previous hypothesis, we find that mitotic arrest is dispensable for tumor regression in patients. These results demonstrate that mitotic arrest is not responsible for the efficacy of paclitaxel, which occurs because of chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future antimitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel.

Phase I Trial of 2-Methoxyestradiol NanoCrystal Dispersion in Advanced Solid Malignancies

Purpose: 2-Methoxyestradiol (2ME2; Panzem) is an endogenous, estradiol-17β metabolite that at pharmacologic doses exerts antimitotic and antiangiogenic activities. Studies with a 2ME2 capsule formulation showed limited oral bioavailability. We report the results of a phase I study using a NanoCrystal Dispersion formulation of 2ME2 (2ME2 NCD). Experimental Design: Patients with refractory solid tumors received 2ME2 NCD orally. Patients received drug either every 6 hours (part A) or every 8 hours (part B). Doses were escalated in successive cohorts until the maximum tolerated dose (MTD) was identified. The primary objective was identifying the MTD. Secondary objectives were to evaluate the plasma pharmacokinetics of 2ME2 and efficacy. Results: In part A, 16 patients received a median of 4 cycles of 2ME2 NCD. Dose-limiting toxicities (DLT) included fatigue (2), hypophosphatemia (2), increased alanine aminotransferase (1), and muscle weakness (1). Trough levels at steady-state reached the minimum effective concentration in all cohorts. The MTD was determined to be 1,000 mg orally every 6 hours. In part B, 10 patients received a median of 1 cycle. DLTs included elevated γ-glutamyltransferase (1), hyponatremia (1), fatigue (1), and anorexia (1). An MTD could not be defined for part B because 4 of 10 patients had DLTs at the initial dose level and dose reduction was not pursued. Thirteen patients had stable disease (A, 11; B, 2); there were no confirmed responses. Conclusion: For 2ME2 NCD, the MTD and recommended phase II regimen is 1,000 mg orally every 6 hours. Treatment was generally well-tolerated.

Phase III Comparison of Tamoxifen Versus Tamoxifen Plus Ovarian Function Suppression in Premenopausal Women With Node-Negative, Hormone Receptor–Positive Breast Cancer (E-3193, INT-0142): A Trial of the Eastern Cooperative Oncology Group

PURPOSE The effects of ovarian function suppression (OFS) on survival and patient-reported outcomes were evaluated in a phase III trial in which premenopausal women were randomly assigned to tamoxifen with or without OFS. PATIENTS AND METHODS Premenopausal women with axillary node-negative, hormone receptor-positive breast cancer tumors measuring ≤ 3 cm were randomly assigned to tamoxifen alone versus tamoxifen plus OFS; adjuvant chemotherapy was not permitted. Primary end points were disease-free survival (DFS) and overall survival (OS). Secondary end points included toxicity and patient-reported outcomes. Patient-reported outcome data included health-related quality of life, menopausal symptoms, and sexual function. These were evaluated at baseline, 6 months, 12 months, and then annually for up to 5 years after registration. RESULTS In all, 345 premenopausal women were enrolled: 171 on tamoxifen alone and 174 on tamoxifen plus OFS. With a median follow-up of 9.9 years, there was no significant difference between arms for DFS (5-year rate: 87.9% v 89.7%; log-rank P = .62) or OS (5-year rate: 95.2% v 97.6%; log-rank P = .67). Grade 3 or higher toxicity was more common in the tamoxifen plus OFS arm (22.4% v 12.3%; P = .004). Patients treated with tamoxifen plus OFS had more menopausal symptoms, lower sexual activity, and inferior health-related quality of life at 3-year follow-up (P < .01 for all). Differences diminished with further follow-up. CONCLUSION When added to tamoxifen, OFS results in more menopausal symptoms and sexual dysfunction, which contributes to inferior self-reported health-related quality of life. Because of early closure, this study is underpowered for drawing conclusions about the impact on survival when adding OFS to tamoxifen.

Lapatinib: A small-molecule inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor—2 tyrosine kinases used in the treatment of breast cancer

BACKGROUND Lapatinib is an oral, small-molecule, reversible inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor-2 (HER2) tyrosine kinases. In March 2007, the US Food and Drug Administration approved lapatinib for use in combination with capecitabine in the treatment of advanced breast cancer overexpressing HER2 (HER2+). OBJECTIVES The goals of this review were to summarize the pharmacology, pharmacokinetics, efficacy, and tolerability of lapatinib, and to review studies of the approved and investigational uses of lapatinib. METHODS English-language reports of clinical trials of lapatinib in patients with cancer were identified through searches of PubMed/MEDLINE (1990-October 2009) and the American Society of Clinical Oncology abstracts database (2003-2008). Search terms included lapatinib, Tykerb, HER2, EGFR, breast cancer, dual tyrosine kinase inhibitor, and GW572016. RESULTS Lapatinib was well tolerated in a Phase II monotherapy trial in patients with advanced breast cancer; however, the response was minimal in HER2+ patients, and no HER2- patients achieved an objective tumor response. A Phase II trial of lapatinib monotherapy in 39 HER2+ patients with breast cancer and brain metastases yielded 1 partial response, although 15.4% of patients had stable disease for > or =16 weeks. In a Phase III trial comparing lapatinib plus capecitabine with capecitabine alone in HER2+ patients with advanced breast cancer that had progressed after trastuzumab therapy, the median time to progression was 8.4 months with combination therapy, compared with 4.4 months with capecitabine alone (P < 0.001). There were no significant differences between combination therapy and capecitabine alone in terms of the overall response rate (22% and 14%, respectively) or overall survival. CONCLUSIONS Lapatinib monotherapy was well tolerated, although the response rate was low in patients with advanced breast cancer. Lapatinib combined with capecitabine was associated with significant improvements in the time to progression and response rate compared with capecitabine alone. The available evidence suggests that clinical efficacy in breast cancer is limited to HER2+ disease.

Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy: Little evidence of improvement over the past 30 years

Population‐based studies have shown improved survival for patients diagnosed with metastatic breast cancer over time, presumably because of the availability of new and more effective therapies. The objective of the current study was to determine whether survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy.

Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy

Population‐based studies have shown improved survival for patients diagnosed with metastatic breast cancer over time, presumably because of the availability of new and more effective therapies. The objective of the current study was to determine whether survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy.

Adjuvant Therapy With Zoledronic Acid in Patients With Breast Cancer: A Systematic Review and Meta-Analysis

BACKGROUND The purpose of the study was to estimate the impact on survival and fracture rates of the use of zoledronic acid versus no use (or delayed use) in the adjuvant treatment of patients with early-stage (stages I-III) breast cancer. MATERIALS AND METHODS We performed a systematic review and meta-analysis of randomized clinical trials. Trials were located through PubMed, ISI, Cochrane Library, and major cancer scientific meeting searches. All trials that randomized patients with primary breast cancer to undergo adjuvant treatment with zoledronic acid versus nonuse, placebo, or delayed use of zoledronic acid as treatment to individuals who develop osteoporosis were considered eligible. Standard meta-analytic procedures were used to analyze the study outcomes. RESULTS Fifteen studies were considered eligible and were further analyzed. The use of zoledronic acid resulted in a statistically significant better overall survival outcome (five studies, 6,414 patients; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.70-0.94). No significant differences were found for the disease-free survival outcome (seven studies, 7,541 patients; HR, 0.86; 95% CI, 0.70-1.06) or incidence of bone metastases (seven studies, 7,543 patients; odds ratio [OR], 0.94; 95% CI, 0.64-1.37). Treatment with zoledronic acid led to a significantly lower overall fracture rate (OR, 0.78; 95% CI, 0.63-0.96). Finally, the rate of osteonecrosis of the jaw was 0.52%. CONCLUSION Zoledronic acid as adjuvant therapy in breast cancer patients appears to not only reduce the fracture risk but also offer a survival benefit over placebo or no treatment.

Leveraging Electronic Health Record Systems to Create and Provide Electronic Cancer Survivorship Care Plans: A Pilot Study

PURPOSE The Institute of Medicine (IOM) recommends cancer survivors receive survivorship care plans after completing active cancer treatment. However, care plan creation requires significant time and effort, contributing to diminished adoption of this recommendation. Electronic health record (EHR) systems have been proposed as a solution. We assessed the feasibility of creating and delivering care plans within an EHR system. METHODS Thirty-eight breast cancer survivors without existing care plans were recruited during a follow-up visit to their primary oncologist. Using an EHR template, an oncologist created an individualized care plan for each participant. Time spent creating each plan was recorded. Participant use and feedback were collected. RESULTS Participants enrolled a median of 19.7 months after diagnosis (range, 4.3 to 57 months). A minority of IOM-recommended plan elements could be automatically imported without any manual entry. The majority of elements required interpretation and manual import by the clinician. However, with an established infrastructure for importing elements, the time needed to create a care plan electronically was short (median, 3 minutes; range 2 to 12 minutes). Most survivors (n = 36; 95%) successfully accessed their care plans online and spent a median of 12 minutes (range, 0.5 to 61.9 minutes) reviewing them. Survivors perceived the plans as useful and did not generally report difficulty in accessing them online or understanding content. CONCLUSION Rapid care plan creation and delivery within an EHR is possible. Plans were available to all (survivors, oncologists, primary care physicians) via the EHR. Further research is required to explore the barriers to automating data importation into plans as well as the impact of EHR-integrated plans.

Phase I Study of an AKT Inhibitor (MK-2206) Combined with Lapatinib in Adult Solid Tumors Followed by Dose Expansion in Advanced HER2+ Breast Cancer

Purpose: Preclinical data support combining AKT inhibitors with HER2-targeted therapies to overcome resistance to treatment. This phase I study combined the investigational AKT inhibitor, MK-2206, with lapatinib to determine the MTD. Experimental Design: The dose escalation cohort enrolled adults with advanced solid tumors, who received MK-2206 dosed 30 to 60 mg every other day and lapatinib 1,000 to 1,500 mg daily continuously, escalated using a 3+3 design. Cycles were 28 days except cycle 1 (35 days, including an initial 8 days of MK-2206 alone to evaluate pharmacokinetic interactions). The dose expansion cohort enrolled adults with advanced HER2+ breast cancer. Results: Twenty-three participants enrolled in the dose escalation cohort. Dose-limiting toxicities were hyponatremia, fatigue, rash, hypocalcemia, and mucositis. Common toxicities included diarrhea, nausea, and rash. The MTD was reached at MK-2206 45 mg orally every other day and lapatinib 1,500 mg orally daily. Two participants maintained stable disease for >4 months, including a colorectal cancer participant with substantial carcinoembryonic antigen decrease. Of 5 participants in the dose expansion cohort, 2 maintained stable disease for >6 months, including one with prior progression on single-agent lapatinib. Plasma MK-2206 concentrations decreased after addition of lapatinib, but in vitro studies indicate lapatinib increases the intracellular levels of MK-2206. Conclusions: MK-2206 combined with lapatinib can be tolerated with both drugs above biologically active single-agent doses. Overlapping toxicities result in significant diarrhea and rash, which can be managed medically. Antitumor activity was promising and supports evaluation of AKT inhibitors combined with HER2-targeted therapies. Clin Cancer Res; 22(11); 2659–67. ©2016 AACR.

Randomized trial of adjuvant zoledronic acid in postmenopausal women with high-risk breast cancer.

PURPOSE We present the results of a randomized multicenter clinical trial of adjuvant zoledronic acid (ZA) in postmenopausal women with high-risk breast cancer. The primary objective was change in bone mineral density (BMD) at the lumbar spine and femoral neck at 1 year. Secondary objectives included change in calcaneal BMD, disease-free survival (DFS), overall survival (OS), and toxicity. PATIENTS AND METHODS Postmenopausal women with stage II/III breast cancer diagnosed up to 5 years previous were eligible and randomized to either observation or ZA 4 mg intravenous every 3 months. Bone mineral density testing was performed at 0, 6, and 12 months. RESULTS Sixty-eight women were enrolled (36 ZA and 32 observation). The population was a median of 2 years from diagnosis and the majority received tamoxifen during the study. There was a significant difference in the mean change from baseline to 1 year follow-up for lumbar spine (increased by 4.28% ± 0.62%; P = .01), total femur (increased by 1.9% ± 0.4%; P = .03), trochanter (increased by 2.97% ± 0.69%; P = .03), and calcaneal BMD (increased by 2% ± 0.57%; P = .01) in favor of the ZA arm. No significant difference in the mean change for the femoral neck was seen. No significant differences in DFS or OS were observed. CONCLUSION Zoledronic acid significantly improved the BMD at multiple skeletal sites in postmenopausal women largely on tamoxifen. No new safety signals were noted. There were insufficient events to comment on DFS or OS.