Safety and tolerability of docetaxel, cyclophosphamide, and trastuzumab compared to standard trastuzumab-based chemotherapy regimens for early-stage human epidermal growth factor receptor 2-positive breast cancer.

PURPOSE: We evaluated the tolerability and cardiac safety of docetaxel, cyclophosphamide, and trastuzumab (TCyH) for the treatment of early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer and compared to the standard trastuzumab-based chemotherapy regimens doxorubicin with cyclophosphamide followed by paclitaxel and trastuzumab (AC-TH) and docetaxel, carboplatin, and trastuzumab (TCaH). METHODS: We retrospectively reviewed early-stage, resectable, HER2-positive breast cancer patients treated with trastuzumab-based chemotherapy at a single comprehensive cancer center between 2004 and 2011. Patient characteristics, comorbidities, relative dose intensity (RDI) of each regimen, tolerability, and cardiac toxicity were evaluated. RESULTS: One hundred seventy-seven patients were included in the study (AC-TH, n=114; TCaH, n=39; TCyH, n=24). TCyH was solely administered in the adjuvant setting, whereas two-thirds of the AC-TH and TCaH groups were administered postoperatively. Patients treated with TCyH tended to have a more significant underlying cardiac history, higher Charlson comorbidity index, and were of an earlier stage. All patients treated with TCyH received granulocyte colony stimulating factor primary prophylaxis. No febrile neutropenia or grade ≥3 hematologic toxicity was observed in the TCyH group as compared to the AC-TH and TCaH groups. There were no significant differences in the rates of early termination, hospitalization, dose reduction, or RDI between the regimens. The symptomatic congestive heart failure rate between AC-TH, TCaH, and TCyH groups was not significantly different (4.4% vs. 2.6% vs. 8.3%, respectively, p=0.57). There was also no significant difference in the rate of early trastuzumab termination between patients treated with each regimen. CONCLUSION: TCyH is well tolerated and should be investigated as an alternative adjuvant chemotherapy option for patients who are not candidates for standard trastuzumab-containing regimens. Larger clinical trials are necessary to support the wider use of TCyH as an adjuvant regimen.

Update on antiangiogenic therapy in colorectal cancer: aflibercept and regorafenib.

Angiogenesis plays an important role in colorectal carcinogenesis and approaches targeting the vascular growth factor receptor (VEGF) signaling such as bevacizumab yielded significant survival improvement for metastatic colorectal cancer patients. Recent evidence demonstrated the benefit of continuing angiogenic suppression after first-progression following bevacizumab-containing cytotoxic regimen though no benefit was observed with the use of bevacizumab in adjuvant setting. Aflibercept, a soluble fusion protein with high affinity for VEGF-A, -B and PlGF, administered in combination with irinotecan-containing regimen improved the survival of metastatic colorectal cancer patients in second-line setting (VELOUR trial). Regorafenib, a small molecule multikinase inhibitor against various pro-angiogenic and -proliferation targets, improved the survival of metastatic colorectal cancer patients who had progressed on all standard therapy. These developments had renewed enthusiasm in the field and the role of aflibercept and regorafenib in other treatment settings will continue to be defined by on-going and future clinical trials. As other anti-angiogenic approaches are being tested clinically, other novel non-angiogenic targets deserve to be evaluated in our effort to improve the outcome of colorectal cancer patients.

Progressive chronic lymphocytic leukemia after allogeneic hematopoietic cell transplantation.

This case report presents a patient with poor-prognosis chronic lymphocytic leukemia (CLL) who was treated with chemotherapy and underwent allogeneic hematopoietic cell transplant (alloHCT) but ultimately progressed. The application of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL and the impact of alloHCT on secondary therapy for progressive CLL are discussed.

Light at night activates IGF-1R/PDK1 signaling and accelerates tumor growth in human breast cancer xenografts.

Regulation of diurnal and circadian rhythms and cell proliferation are coupled in all mammals, including humans. However, the molecular mechanisms by which diurnal and circadian rhythms regulate cell proliferation are relatively poorly understood. In this study, we report that tumor growth in nude rats bearing human steroid receptor-negative MCF-7 breast tumors can be significantly accelerated by exposing the rats to light at night (LAN). Under normal conditions of an alternating light/dark cycle, proliferating cell nuclear antigen (PCNA) levels in tumors were maximal in the early light phase but remained at very low levels throughout the daily 24-hour cycle period monitored. Surprisingly, PCNA was expressed in tumors continually at a high level throughout the entire 24-hour period in LAN-exposed nude rats. Daily fluctuations of Akt and mitogen activated protein kinase activation in tumors were also disrupted by LAN. These fluctuations did not track with PCNA changes, but we found that activation of the Akt stimulatory kinase phosphoinositide-dependent protein kinase 1 (PDK1) directly correlated with PCNA levels. Expression of insulin-like growth factor 1 receptor (IGF-1R), an upstream signaling molecule for PDK1, also correlated with fluctuations of PDK1/PCNA in the LAN group. In addition, circulating IGF-1 concentrations were elevated in LAN-exposed tumor-bearing nude rats. Finally, RNAi-mediated knockdown of PDK1 led to a reduction in PCNA expression and cell proliferation in vitro and tumor growth in vivo, indicating that PDK1 regulates breast cancer growth in a manner correlated with PCNA expression. Taken together, our findings demonstrate that LAN exposure can accelerate tumor growth in vivo, in part through continuous activation of IGF-1R/PDK1 signaling.