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, the majority of 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 due to chromosome missegregation on highly abnormal, multipolar spindles. This mechanistic insight may be used to improve selection of future anti-mitotic drugs and to identify a biomarker with which to select patients likely to benefit from paclitaxel.

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Purpose Population-based studies have shown improved survival for patients diagnosed with metastatic breast cancer (MBC) over time, presumably due to the availability of new and more effective therapies. The objective of this analysis was to determine if survival improved for patients who developed distant recurrence of breast cancer after receiving adjuvant therapy. Methods Adjuvant chemotherapy trials coordinated by the Eastern Cooperative Oncology Group (ECOG) that accrued patients between 1978–2002 were reviewed. Survival following distant recurrence was estimated for progressive time periods, and adjusted for baseline covariates in a Cox proportional hazards model. Results Of the 13,785 patients who received adjuvant chemotherapy in 11 trials, 3447 (24.4%) developed distant recurrence; median survival following recurrence was 20 months (95% confidence intervals: 19, 21). Factors associated with inferior survival included shorter distant recurrence free interval (DRFI), ER- and PR-negative disease number of positive axillary nodes at diagnosis and black race (p<0.0001 for all). When time-period of recurrence was added to the model, it was not significantly associated with survival for the general population with recurrence. Survival improved over time only in hormone-receptor negative patients with a DRFI ≤ 3 years, both among the 5 recent and entire trial datasets (p=0.01 and p=0.05 respectively). Conclusions In contrast to reports from population-based studies, we did not observe general improvement in survival over the last three decades for patients who developed distant recurrence after adjuvant chemotherapy after adjusting for DRFI. Improved survival for hormone-receptor negative patients with a short DRFI suggests benefit from trastuzumab.