Nonheritable Cellular Variability Accelerates the Evolutionary Processes of Cancer

Heritable genetic or epigenetic changes in cells are thought to drive tumor development, metastasis, and drug resistance. This essay discusses the possibility that nonheritable phenotypic variability contributes to the evolution of cancer, suggesting new approaches to treatment

Safety and efficacy of using a single agent or a phase II agent before instituting standard combination chemotherapy in previously untreated metastatic breast cancer patients: report of a randomized study--Cancer and Leukemia Group B 8642

PURPOSE: We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients. PATIENTS AND METHODS: A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF. RESULTS: The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm. CONCLUSION: The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer

Molecular chess? Hallmarks of anti-cancer drug resistance

Background The development of resistance is a problem shared by both classical chemotherapy and targeted therapy. Patients may respond well at first, but relapse is inevitable for many cancer patients, despite many improvements in drugs and their use over the last 40 years. Review Resistance to anti-cancer drugs can be acquired by several mechanisms within neoplastic cells, defined as (1) alteration of drug targets, (2) expression of drug pumps, (3) expression of detoxification mechanisms, (4) reduced susceptibility to apoptosis, (5) increased ability to repair DNA damage, and (6) altered proliferation. It is clear, however, that changes in stroma and tumour microenvironment, and local immunity can also contribute to the development of resistance. Cancer cells can and do use several of these mechanisms at one time, and there is considerable heterogeneity between tumours, necessitating an individualised approach to cancer treatment. As tumours are heterogeneous, positive selection of a drug-resistant population could help drive resistance, although acquired resistance cannot simply be viewed as overgrowth of a resistant cancer cell population. The development of such resistance mechanisms can be predicted from pre-existing genomic and proteomic profiles, and there are increasingly sophisticated methods to measure and then tackle these mechanisms in patients. Conclusion The oncologist is now required to be at least one step ahead of the cancer, a process that can be likened to ‘molecular chess’. Thus, as well as an increasing role for predictive biomarkers to clinically stratify patients, it is becoming clear that personalised strategies are required to obtain best results