Biomedical subjects
G W Sledge
Publications and source records attributed to G W Sledge.
All therapy is targeted therapy: the future of systemic therapy.
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What do we mean by targeted therapy?
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Gemcitabine, paclitaxel, and trastuzumab in metastatic breast cancer.
A phase II trial evaluated the effectiveness and toxicity of combination paclitaxel (Taxol), gemcitabine (Gemzar), and trastuzumab (Herceptin) as first-line therapy for patients with newly diagnosed HER2-overexpressing metastatic breast cancer. To date, 27 patients have received paclitaxel at 175 mg/m2 over 3 hours on day 1, plus gemcitabine at 1,200 mg/m2 on days 1 and 8, plus trastuzumab at a 4-mg/kg loading dose on day 1, followed by 2 mg/kg weekly. Treatment cycles were repeated every 21 days. Responding or stable patients who had received six cycles of combination therapy continued single-agent trastuzumab weekly until disease progression. Treatment was generally well tolerated with grade 4 toxicity limited to myelosuppression. In all, 12 patients have achieved a partial remission and 1 patient had progressive disease; 14 patients continue treatment and have not yet been evaluated for response. Combination treatment with paclitaxel, gemcitabine, and trastuzumab is well tolerated and appears to be highly active. Accrual will continue to a total enrollment of 46 patients.
Combined anthracycline-taxane regimens in the adjuvant setting.
Within the past decade there has been enormous interest in integrating the taxanes into the adjuvant breast cancer setting. Adjuvant trial designs in the early 1990s were absent of taxanes. By the mid 1990s, the taxanes were included in adjuvant trials, but were mainly limited to trials conducted in node-positive patients. Currently, taxanes are a chemotherapeutic modality in the majority of ongoing adjuvant trials in both node-negative and node-positive patients. These trials are being conducted in thousands of patients worldwide by several of the cooperative research organizations. Most of the adjuvant trials have focused on defining the clinical efficacy and toxicity of the concurrent or sequential use of taxanes with anthracyclines. The collective experience with taxanes over the next 3 to 5 years will make them one of the most intensely studied treatments in the history of patients with breast cancer. The outcome of these trials is greatly anticipated because they have the potential of changing the current standards of care in the adjuvant treatment of patients with breast cancer.
Paclitaxel sensitivity of breast cancer cells with constitutively active NF-kappaB is enhanced by IkappaBalpha super-repressor and parthenolide.
The transcription factor nuclear factor-kappaB (NF-kappaB) regulates genes important for tumor invasion, metastasis and chemoresistance. Normally, NF-kappaB remains sequestered in an inactive state by cytoplasmic inhibitor-of-kappaB (IkappaB) proteins. NF-kappaB translocates to nucleus and activates gene expression upon exposure of cells to growth factors and cytokines. We and others have shown previously that NF-kappaB is constitutively active in a subset of breast cancers. In this study, we show that constitutive activation of NF-kappaB leads to overexpression of the anti-apoptotic genes c-inhibitor of apoptosis 2 (c-IAP2) and manganese superoxide dismutase (Mn-SOD) in breast cancer cells. Furthermore, expression of the anti-apoptotic tumor necrosis factor receptor associated factor 1 (TRAF1) and defender-against cell death (DAD-1) is regulated by NF-kappaB in certain breast cancer cells. We also demonstrate that NF-kappaB-inducible genes protect cancer cells against paclitaxel as MDA-MB-231 breast cancer cells modified to overexpress IkappaBalpha required lower concentrations of paclitaxel to arrest at the G2/M phase of the cell cycle and undergo apoptosis when compared to parental cells. The effect of NF-kappaB on paclitaxel-sensitivity appears to be specific to cancer cells because normal fibroblasts derived from embryos lacking p65 subunit of NF-kappaB and wild type littermate embryos were insensitive to paclitaxel-induced G2/M cell cycle arrest. Parthenolide, an active ingredient of herbal remedies such as feverfew (tanacetum parthenium), mimicked the effects of IkappaBalpha by inhibiting NF-kappaB DNA binding activity and Mn-SOD expression, and increasing paclitaxel-induced apoptosis of breast cancer cells. These results suggest that active ingredients of herbs with anti-inflammatory properties may be useful in increasing the sensitivity of cancers with constitutively active NF-kappaB to chemotherapeutic drugs. Oncogene (2000) 19, 4159 - 4169
Cancer cell-derived interleukin 1alpha contributes to autocrine and paracrine induction of pro-metastatic genes in breast cancer.
Invasion and metastasis of cancer cells is a complex process requiring the activity of proteins that promote extracellular matrix degradation, motility of cancer cells, and angiogenesis. Although exclusively the cancer cells make several of these proteins, few key proteins are derived from stromal cells in response to cancer cell-stromal cell interaction. In this report, we show that the breast cancer cell-derived interleukin-1alpha (IL-1alpha) plays an important role in expression of pro-metastatic genes in cancer as well as in stromal cells. Neutralizing antibody against IL-1alpha inhibited IL-6, and IL-8 expression in IL-1alpha-expressing cancer cells. In addition, this antibody also prevented induction of IL-6, IL-8, and matrix metalloproteinase 3 (MMP3) but not vascular endothelial growth factor (VEGF) in fibroblasts by conditioned medium (CM) from IL-1alpha-expressing breast cancer cells. These results suggest that inhibition of IL-1alpha activity by either neutralizing antibody against IL-1alpha or chemical inhibitor of IL-1alpha processing may prevent invasion and metastasis of breast cancer.
Effects of tetracyclines on angiogenesis in vitro.
Most tumors kill their hosts by the process of metastasis rather than by local growth of the primary mass. A significant factor contributing to the distant invasion of cancer cells is the ability of tumors to produce large numbers of new blood vessels in their midst, known as angiogenesis. This both provides access to nourishment for the primary cancer and enables the cells to escape from the tumor and enter the bloodstream. We have been examining agents that appear to inhibit metastasis and, in particular, angiogenesis. We now report on the ability of the synthetic tetracycline, doxycycline, and the chemically-modified tetracycline, COL-3, to inhibit angiogenesis in a quantitative in vitro assay of angiogenesis, using human umbilical vascular endothelial cells (HUVECs) attached to microcarrier beads.
Effects of high dose raloxifene in selected patients with advanced breast carcinoma.
BACKGROUND: An earlier trial of raloxifene, conducted in women with metastatic breast carcinoma who initially had responded to tamoxifen and subsequently developed disease progression, suggested no antitumor activity for raloxifene in tamoxifen-refractory disease. However, preclinical studies and preliminary clinical data in healthy women suggest that raloxifene antagonizes growth of estrogen-dependent neoplasia. METHODS: Raloxifene HCl 150 mg twice daily was given to 22 postmenopausal women with metastatic (American Joint Committee on Cancer Stage IV) or locoregionally recurrent, initially estrogen receptor positive breast carcinoma. Prior systemic treatment of metastatic disease was not allowed. Prior adjuvant chemotherapy or hormonal therapy was required to have been completed at least 1 year before study entry. Tumor response was evaluated every other month either radiographically or by physical examination. Evaluable disease was defined as bidimensionally measurable lesions. RESULTS: Twenty-one patients were eligible for efficacy analysis; 6 had been treated previously with tamoxifen. There were no complete tumor responses. Four patients (19%; 95% confidence interval [95% CI], 2.2%, 36%) had partial tumor responses lasting 6.3, 17.5, 23.9, and 28.1 months, respectively. Prolonged stable disease (i.e., tumor size stable for > or = 6 months) was observed in 3 patients (14%; 95% CI, 0.0%, 29%) and lasted 7.9, 12.2, and 25.1 months, respectively. Combining partial responses and prolonged stable disease yielded an overall clinical benefit rate of 33% (95% CI, 13%, 53%). Adverse events generally were consistent with the disease state; there were no serious adverse events or laboratory changes believed to be therapy-related. CONCLUSIONS: Raloxifene HCl, 150 mg, administered twice daily was safe, well tolerated, and modestly effective in highly selected postmenopausal women with advanced breast carcinoma. Further study of high dose raloxifene as monotherapy for advanced breast carcinoma most likely is unwarranted.
A phase II trial of high dose epirubicin in patients with advanced breast carcinoma.
BACKGROUND: Anthracyclines are among the most active drugs in the treatment of breast carcinoma and exhibit a steep dose-response curve in vitro. This trial was performed to determine the efficacy and toxicity of epirubicin in the treatment of patients with advanced breast carcinoma when administered as a single agent in maximal doses. METHODS: Patients with chemotherapy-naïve American Joint Committee on Cancer/International Union Against Cancer Stage IIIB or IV breast carcinoma received epirubicin, 180 mg/m(2), intravenously every 3 weeks for a maximum of 8 cycles of therapy. Hematopoietic growth factors and cardioprotective agents were not used routinely. RESULTS: Twenty-seven patients were entered in the study. Although NCI/CTC criteria Grade 4 neutropenia occurred in 96% of patients, epirubicin was administered at 83.1% of the planned dose intensity. The median fall in left ventricular ejection fraction was 10%; clinical cardiac toxicity was observed in 3 patients. Objective responses were observed in 21 patients, including 6 complete responses. CONCLUSIONS: High dose epirubicin was found to result in substantial hematologic toxicity but was highly active in the treatment of patients with advanced breast carcinoma.
Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: An Eastern Cooperative Oncology Group study.
PURPOSE: Although hormonal therapy represents standard therapy for metastatic hormone-sensitive disease, many patients receive initial chemotherapy because of the location, bulk, or aggressiveness of their disease. It is uncertain whether simultaneous hormonal therapy provides additional benefit compared with chemotherapy alone. Eastern Cooperative Oncology Group trial E3186 was initiated to explore this question. PATIENTS AND METHODS: Between January 1988 and December 1992, 231 patients with estrogen receptor (ER)-positive or ER-unknown metastatic breast cancer were randomized to receive either chemotherapy (cyclophosphamide, doxorubicin, and fluorouracil ¿CAF) or chemohormonal therapy (CAF plus tamoxifen and Halotestin ¿fluoxymesterone; Pharmacia-Upjohn, Kalamazoo, MI ¿CAFTH) as front-line therapy for metastatic breast cancer. Patients who experienced a complete response to induction therapy either received or did not receive maintenance cyclophosphamide, methotrexate, fluorouracil, prednisone, and TH as a secondary randomization. RESULTS: The response rates (complete response and partial response) of patients who received CAF and CAFTH were similar (69.2% v 68.9%, respectively; P =.99). Time to treatment failure (TTF) was slightly longer for patients who received chemohormonal therapy compared with chemotherapy alone patients (13.4 months v 10.3 months, respectively; P =.087), and TTF was significantly longer in ER-positive compared with ER-negative patients (17.4 months v 10.3 months, respectively; P =.048). However, ER status had no effect on overall survival (30.0 months for CAF v 29.3 months for CAFTH). CONCLUSION: In patients with potentially hormone-sensitive metastatic breast cancer, chemohormonal therapy prolongs TTF for ER-positive patients without improving overall survival.
The future of clinical research in breast cancer: opportunities.
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The future of clinical research in breast cancer: challenges.
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Why big lies matter: lessons from the Bezwoda affair.
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The role of chemotherapy for metastatic breast cancer.
Metastatic breast cancer remains a devastating and largely incurable disease. Currently available therapies offer meaningful palliation for many and modest prolongation of survival for some patients. Single-agent hormonal therapy remains the treatment of choice for patients with ER-positive disease, with sequential use of further hormonal agents or cytotoxic chemotherapy at the time of disease progression. Chemotherapy is appropriate as initial therapy for patients with receptor-negative or rapidly progressive visceral disease. Although combination regimens may increase response rates, the lack of survival benefit does not justify the increased toxicity of aggressive combination regimens in most patients. Maintenance chemotherapy deserves consideration in selected well-informed patients, especially those with few therapy-related side effects. High-dose regimens confer substantial toxicity with no clear therapeutic advantage and cannot be recommended outside of ongoing trials. New chemotherapy agents offer the hope of effective salvage therapy with acceptable toxicity to a larger number of patients. Perhaps most promising, the development of targeted, biologically based therapies such as rhuMAbHER2 offers encouragement for the future.
Toward checkmate: biology and breast cancer therapy for the new millennium.
A better understanding of the biology of breast cancer should lead to the rational development of new treatments and the ability to customize therapy for individual patients. Though promising in theory, translating advances in biological knowledge to the clinic has been difficult. Recently several areas of research have produced treatments which have entered clinical trials: three will be reviewed here. The growth of breast cancer is regulated by growth factors and their receptors; amplification or overexpression is associated with poor prognosis. As such inhibition of growth factors and/or growth factor receptors may provide an ideal therapeutic target. Herceptin binds to c-erbB-2, a member of the epidermal growth factor receptor family. Significant responses were seen in patients with c-erbB-2 overexpressing breast cancer with Herceptin administered as a single agent or in combination with chemotherapy. Herceptin was approved by the Food and Drug Administration in late 1998. Breast cancer invasion and metastasis requires degradation of the surrounding basement membrane by matrix metalloproteinases and other proteolytic enzymes. Synthetic inhibitors of these enzymes are now in clinical trials. Breast cancers must stimulate angiogenesis, the growth of new blood vessels, in order to grow beyond a few millimeters in diameter. This nascent vascular network provides another opportunity for therapy. Preclinical models support the critical role of angiogenesis and the therapeutic benefit of angiogenesis inhibition; clinical trials are underway.
Combination versus sequential doxorubicin and docetaxel as primary chemotherapy for breast cancer: A randomized pilot trial of the Hoosier Oncology Group.
PURPOSE: To evaluate the efficacy and toxicity of combination and sequential dose-dense chemotherapy with doxorubicin and docetaxel (Taxotere; Rhône-Poulenc Rorer, Collegeville, PA) as primary chemotherapy of breast cancer. PATIENTS AND METHODS: Patients with newly diagnosed stage II or noninflammatory stage III breast cancer were randomly assigned to receive the same total doses of doxorubicin and docetaxel over a 12-week period before definitive surgery. Patients in arm A received sequential therapy with doxorubicin 75 mg/m(2) every 2 weeks for three cycles followed by docetaxel 100 mg/m(2) every 2 weeks for three cycles. Patients in arm B received combination therapy with doxorubicin 56 mg/m(2) plus docetaxel 75 mg/m(2) every 3 weeks for four cycles. Granulocyte colony-stimulating factor was administered on days 2 to 12 of each cycle in both groups. RESULTS: Forty patients were entered onto the trial. Pretreatment tumor size averaged 5.7 cm with clinically positive axillary lymph nodes in 23 patients (57%). As expected, myelosuppression was severe in both groups; however, >/= 80% of planned dose-intensity was delivered. Hand-foot syndrome was more common after sequential therapy. Clinical responses were similar in both groups, with an overall response rate of 87%, including 20% clinical complete remissions. Pathologic complete remission or residual in situ disease only was confirmed in five patients (12.8%). Patients who received sequential therapy had fewer positive lymph nodes (mean, 2.17 v 4.81; P <.037) at definitive surgery. CONCLUSION: Primary chemotherapy with doxorubicin and docetaxel is well tolerated and highly active. A sequential treatment schedule increases toxicity but may result in more substantial lymph node clearance than combination therapy.
Taxanes in the treatment of breast cancer: a prodigy comes of age.
The taxanes, paclitaxel and docetaxel, are among the most promising new agents in the treatment of breast cancer. Responses are routinely seen in > 30% of patients with metastatic disease, including those who have previously received anthracyclines. Combination therapy has increased response rates but as yet has not improved the overall survival of patients with metastatic disease. Improved survival with the addition of paclitaxel to standard adjuvant therapy reported in a recently completed trial suggests the true impact of the taxanes has not yet been realized.