This study was undertaken to determine whether overexpression of the oncogene HER-2 is associated with an increase in local recurrence in women with early stage breast cancer treated with breast-conserving therapy (BCT). A retrospective review of the medical records of all women treated with stage I-II invasive breast cancer from 1991 through 2001 was performed. Of 596 eligible patients treated in that time period, immunohistochemical testing for HER-2 expression was performed in 352 patients (59%): 266 patients (76%) were HER-2 negative and 86 patients (24%) were HER-2 positive. Median follow-up was 5.4 years. The patient characteristics for the two groups were compared for age, pathologic T and N stage, number of positive nodes, estrogen receptor (ER) and progesterone receptor (PR) status, radiation treatment, and use of hormonal therapy or chemotherapy. There were no significant differences in any of these parameters between the two groups (all p > or = 0.10). Local recurrence at 5 years was 2% in the HER-2-negative group and 0% in the HER-2-positive group (p = 0.15). There was no difference in local recurrence after BCT between HER-2-positive and negative breast cancers at 5 years. Therefore HER-2 overexpression does not appear to be a contraindication to BCT.
Drugs that disrupt microtubule dynamics include some of the most important of cancer chemotherapies. While these drugs, which include paclitaxel (Taxol), are known to invoke the mitotic checkpoint, the factors that determine cancer cell killing remain incompletely characterized. Cells that are relatively resistant to killing by these drugs block robustly in mitosis, whereas cells sensitive to killing block only transiently in mitosis before undergoing nuclear fragmentation and death. Passage through mitosis was an absolute requirement of drug-induced death, because death was markedly reduced in cells blocked at both G1-S and G2. Cell killing was at least in part linked to the absence or inactivation of BubR1, a kinetochore-associated phosphoprotein that mediates the mitotic checkpoint. Sensitivity to paclitaxel correlated with decreased BubR1 protein expression in human cancer cell lines, including those derived from breast and ovarian cancers. Silencing of BubR1 via RNA interference inactivated the mitotic checkpoint in drug-resistant cells, and reversed resistance to paclitaxel and nocodazole. Together, these results suggest that the mitotic checkpoint is an important determinant of the efficacy of microtubule-targeting drugs in killing cancer cells, potentially providing novel targets for increasing treatment efficacy.
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