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The tissue blocks from a large group of women who had participated in a randomized trial of the treatment of node-positive breast cancer were analyzed for the expression of HER2 and the estrogen receptor. A significant interaction was found between HER2 positivity and a benefit from the addition of paclitaxel after adjuvant treatment with doxorubicin plus cyclophosphamide. A significant interaction was found between HER2 positivity and a benefit from the addition of paclitaxel after adjuvant treatment with doxorubicin plus cyclophosphamide. Adjuvant chemotherapy improves disease-free and overall survival in early-stage breast cancer, 1 and anthracyclines and taxanes are two of the most active agents in such treatment. 2 The Cancer and Leukemia Group B (CALGB) 8541 trial showed that increasing the dose of a doxorubicin (Adriamycin)–based regimen from a relatively low dose (30 mg per square meter of body-surface area) to what is now considered to be a standard dose (60 mg per square meter) is highly beneficial. 3 , 4 Subsequently, a randomized trial (CALGB 9344/INT0148) examined the effects of increased doses of doxorubicin, above 60 mg per square meter, when combined with cyclophosphamide . . .

The temporal order in which patients with early-stage invasive breast cancer receive chemotherapy and radiation therapy after breast-conserving surgery may affect the clinical outcome. 1 – 3 To our knowledge, no previous randomized trial has addressed this issue directly, although two trials comparing different chemotherapy schedules may also yield information about the effect of the timing of radiation therapy after surgery. 4 , 5 We conducted a randomized trial to test whether the sequence of administration of chemotherapy and radiation therapy after breast-conserving surgery influences the outcome among patients at substantial risk for systemic metastases. We found that giving chemotherapy first had better overall . . .

Tamoxifen is standard adjuvant treatment for postmenopausal women with hormone-receptor-positive breast cancer. We assessed the benefit of adding chemotherapy to adjuvant tamoxifen and whether tamoxifen should be given concurrently or after chemotherapy. We undertook a phase 3, parallel, randomised trial (SWOG-8814, INT-0100) in postmenopausal women with hormone-receptor-positive, node-positive breast cancer to test two major objectives: whether the primary outcome, disease-free survival, was longer with cyclophosphamide, doxorubicin, and fluorouracil (CAF) given every 4 weeks for six cycles plus 5 years of daily tamoxifen than with tamoxifen alone; and whether disease-free survival was longer with CAF followed by tamoxifen (CAF-T) than with CAF plus concurrent tamoxifen (CAFT). Overall survival and toxicity were predefined, important secondary outcomes for each objective. Patients in this open-label trial were randomly assigned by a computer algorithm in a 2:3:3 ratio (tamoxifen:CAF-T:CAFT) and analysis was by intention to treat of eligible patients. Groups were compared by stratified log-rank tests, followed by Cox regression analyses adjusted for significant prognostic factors. This trial is registered with ClinicalTrials.gov, number NCT00929591. Of 1558 randomised women, 1477 (95%) were eligible for inclusion in the analysis. After a maximum of 13 years of follow-up (median 8·94 years), 637 women had a disease-free survival event (tamoxifen, 179 events in 361 patients; CAF-T, 216 events in 566 patients; CAFT, 242 events in 550 patients). For the first objective, therapy with the CAF plus tamoxifen groups combined (CAFT or CAF-T) was superior to tamoxifen alone for the primary endpoint of disease-free survival (adjusted Cox regression hazard ratio [HR] 0·76, 95% CI 0·64–0·91; p=0·002) but only marginally for the secondary endpoint of overall survival (HR 0·83, 0·68–1·01; p=0·057). For the second objective, the adjusted HRs favoured CAF-T over CAFT but did not reach significance for disease-free survival (HR 0·84, 0·70–1·01; p=0·061) or overall survival (HR 0·90, 0·73–1·10; p=0·30). Neutropenia, stomatitis, thromboembolism, congestive heart failure, and leukaemia were more frequent in the combined CAF plus tamoxifen groups than in the tamoxifen-alone group. Chemotherapy with CAF plus tamoxifen given sequentially is more effective adjuvant therapy for postmenopausal patients with endocrine-responsive, node-positive breast cancer than is tamoxifen alone. However, it might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes. National Cancer Institute (US National Institutes of Health).

In this study, women 70 years of age or older who had early, estrogen-receptor–positive breast cancer underwent lumpectomy and were then randomly assigned to receive tamoxifen alone or with local irradiation. The only significant difference in outcome was in the probability of local recurrence at five years (4 percent in the tamoxifen group and 1 percent in the combined-treatment group). For women 70 years of age or older, lumpectomy plus adjuvant treatment with tamoxifen (without local irradiation) is a reasonable choice. Multiple trials of breast-conserving surgery for breast cancer 1 – 5 have shown that postoperative irradiation decreases the rate of ipsilateral recurrence but offers no survival benefit. However, the high rate of recurrence with surgery alone (10 to 40 percent) has suggested that the only two appropriate treatments are modified radical mastectomy and breast-conserving surgery plus adjuvant radiation therapy. Since tamoxifen, with 3 or without 4 radiation therapy, decreases the risk of recurrence, and given the cost and adverse effects of breast irradiation 5 – 12 and its negative effect on the quality of life, 6 , 7 we designed a trial to determine whether women 70 years . . .

Taxanes, paclitaxel and docetaxel, are among the most effective agents used to treat breast cancer. Nab-paclitaxel (ABI-007, Abraxane ® ) is paclitaxel encapsulated in albumin. This differs from the more conventional formulation which uses cremophor to increase the solubility of paclitaxel (CrEL-paclitaxel). In a randomized trial that formed the basis of its regulatory approval in the USA, 3-weekly nab-paclitaxel induced a higher response rate and longer time to progression than CrEL-paclitaxel in patients with metastatic breast cancer. Except for grade 3 sensory neuropathy, nab-paclitaxel was also safer. An interim analysis from a more recent randomized Phase II trial suggests that weekly nab-paclitaxel is more effective and safer than either 3-weekly nab-paclitaxel or 3-weekly docetaxel. The superior efficacy of nab-paclitaxel is presumably due to the improved safety profile, which allows for the administration of higher doses, a greater proportion of which actually reaches the tumor. Observations on the development of nab-paclitaxel have important implications for our understanding of dose response in the use of cytotoxic drugs to treat all forms of cancer. Although it is not yet clear whether nab-paclitaxel can be routinely substituted for CrEL-paclitaxel or docetaxel in breast cancer treatment regimens, it seems highly likely that this will occur within the next 5 years.

The discovery of new prognostic factors proceeds at a much more rapid pace than our knowledge of how to properly utilize this information in the management of patients with breast cancer, especially those with early breast cancer that has not metastasized to regional lymph nodes. Prognostic factors provide information on how the patient is likely to do regardless of treatment. Predictive factors provide information on whether a patient is likely to benefit from therapy. Most factors identified to date provide prognostic information, but relatively few provide information that is truly helpful in making a therapeutic decision in the management of individual patients. In large part this is because there has been insufficient study of the factor, especially prospective evaluations of the factor. Unfortunately this has resulted in the premature use of this information under the general rubric that patients with a poor prognosis deserve more treatment in spite of the fact that there may be no benefit from that therapy in the poor prognostic group.

Anthracycline-containing regimens improve disease-free and overall survival of patients with early breast cancer, but the toxicity, especially the cardiotoxicity, of the anthracyclines make them unattractive in the adjuvant setting. Two large, randomized trials, one in unselected patients and one in those with HER2-positive tumors, suggest that a taxane combination without an anthracycline might be just as effective as more traditional regimens. These and other studies also suggest that the anthracyclines might reasonably be used only for those with more aggressive forms of breast cancer, as defined by molecular markers. The results of these studies are provocative but insufficient to justify the conclusion that anthracyclines can be either abandoned or used only for a very select group of patients.

Each of the targeted therapies has been developed for one tumor type and then, in some cases, been evaluated in other tumors only after demonstration of benefit in the first tumor tested. This is illustrated by the HER2 story. Overexpression or amplification of HER2 occurs in many tumor types (Table). However, it has been fully evaluated and Shown tO be Useful in Only tWO Of these: breast, for which the phase II trial was published in 1996[1] and the drug approved by the US Food and Drug Administration (FDA) in 1998; and gastric cancer, for which the phase II trial was published in 20 10 [2] and the drug's new indication approved by the FDA in 2010. Why the long interval? The answers given by investigators have included: \"the number of patients with HER2 overexpression are too few to anticipate an anti-HER2 treatment will have much impact,\" \"the correlative studies fail to demonstrate consistent prognostic value for HER2,\" \"the response rate to trastuzumab was too low to predict success,\" and \"the responses achieved using anti-HER2 therapy in combination are uninterpretable.\" All of these were true for the development of HER2 for both breast and gastric cancer. The remarkable success of trastuzumab in these two tumor types probably represents the continuing efforts of one or a few investigators who were so convinced by preclinical evidence and well developed hypotheses that they persisted in the face of challenges.

The use of adjuvant endocrine therapy in the treatment of hormone receptor-positive, early breast cancer has become important in both pre- and postmenopausal women. Tamoxifen has been the principal adjuvant hormonal therapy in pre- and postmenopausal women with hormone receptor-positive breast cancer for nearly 20 years. Recent data in premenopausal women suggest benefit from ovarian ablation with or without tamoxifen. Early results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial have demonstrated that the third-generation, selective aromatase inhibitor (AI) anastrozole ('Arimidex') is a suitable alternative adjuvant therapy for postmenopausal women with hormone receptor-positive disease. After recurrence or relapse on adjuvant endocrine therapy, responses to the sequential use of additional endocrine agents are common. The increase in the number of options now available for adjuvant therapy will have important implications for the selection of the optimal sequence of endocrine agents in the treatment of recurrent breast cancer. Menopausal status is an important factor in determining the endocrine therapy that a patient receives. For premenopausal women, tamoxifen and/or a luteinizing hormone-releasing hormone agonist such as goserelin ('Zoladex') are both options for adjuvant endocrine treatment. After progression on adjuvant and first-line tamoxifen, ovarian ablation is an appropriate second-line therapy. For premenopausal women who have undergone ovarian ablation, the use of third-line therapy with an AI becomes possible. For postmenopausal women, a wide choice of endocrine treatment options is available and an optimal sequence has yet to be determined. Options for first-line therapy of metastatic disease include an AI for women who have received adjuvant tamoxifen or tamoxifen for patients who have received adjuvant anastrozole. In addition, data suggest that fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist that downregulates the ER protein and has no known agonist effects, is a promising therapeutic option that has shown efficacy in the treatment of postmenopausal women with advanced breast cancer. Other agents that may be used in the sequence include the steroidal AI exemestane and the progestin megestrol acetate. The widening range of adjuvant endocrine options therefore represents an opportunity to prolong patient benefits in the treatment of hormone receptor-positive breast cancer, and will require the further refinement of the optimal sequence of endocrine agents for the treatment of recurrent breast cancer.