Biomedical subjects

L Pusztai

Publications and source records attributed to L Pusztai.

At least 19 recordsLinked to original sources

PubMed2026

Navigating uncertainties and evidence gaps in adjuvant therapy for premenopausal women with HR+/HER2- breast cancer.

Premenopausal women with hormone receptor-positive (HR+)/HER2-negative early breast cancer represent a clinically distinct population, characterized by more aggressive tumor biology, unique survivorship concerns, and complex treatment decision-making. Although evidence from dedicated trials and subgroup analyses is available, management remains challenging because data are heterogeneous, evolving, and often extrapolated from broader populations that include predominantly postmenopausal women. Adjuvant endocrine therapy, with the addition of CDK4/6 inhibitors in selected higher-risk patients, remains the cornerstone of treatment; however major uncertainties persist regarding the optimal use of ovarian function suppression, the interpretation of genomic assays to inform chemotherapy decisions, the selection of candidates for extended endocrine therapy, and the management of adherence, treatment-related toxicities, pregnancy-related issues, and survivorship concerns. Here, we synthesize current evidence across these domains and propose a pragmatic clinical framework to support individualized treatment strategies and optimize care for this population in the contemporary therapeutic landscape.

HR+/HER2- early breast cancer↗

PubMed2006

Bortezomib (VELCADE) in metastatic breast cancer: pharmacodynamics, biological effects, and prediction of clinical benefits.

BACKGROUND: Bortezomib (VELCADE) is a potent inhibitor of the 26S proteasome with broad antitumor activity. We performed a phase II study of bortezomib to evaluate its clinical effects in patients with metastatic breast cancer. PATIENTS AND METHODS: Twelve patients with metastatic breast cancer were treated with bortezomib (VELCADE) at a dosage of 1.5 mg/m(2) administered biweekly for 2 weeks with 1 week of rest in a 21-day cycle. The primary objective was clinical response rate. Toxicity and pharmacodynamics data were also obtained. RESULTS: No objective responses were observed. One patient had stable disease, and 11 others experienced disease progression. The median survival time was 4.3 months (range, 0.9-37 months). The most common grade 3 or 4 toxicities included fatigue (58%; n = 7) and skin rash (33%; n = 4). The mean inhibition of specific chymotryptic activity was 53.1% (+/- 13.33%). A statistically significant reduction in the plasma interleukin-6 level was seen (P = 0.0354). CONCLUSION: Bortezomib was well tolerated but showed limited clinical activity against metastatic breast cancer when used as a single agent. The future development of this agent for the treatment of breast cancer should be guided by in vivo models that optimize activity in combination with other antitumor agents.

Adult↗

PubMed2005

Microtubule Associated Protein (MAP)-Tau: a novel mediator of paclitaxel sensitivity in vitro and in vivo.

Microtubule binding protein Tau was recently identified through gene expression analysis of human breast cancer tissues as a novel marker of response to paclitaxel. This article reviews these recent findings and provides additional information to support the role of Tau as an emerging marker and mediator of paclitaxel sensitivity. Low expression of Tau is associated with increased sensitivity to paclitaxel in human breast cancer as well as in a broad range of cell lines. Down regulation of Tau in cell lines by siRNA increases their sensitivity to paclitaxel but not to anthracycline chemotherapy. We propose that this is due to increased paclitaxel binding to microtubules when microtubules are assembled in the presence of low concentrations (or absence) of Tau compared to microtubules that are formed in the presence of physiological (or higher) levels of Tau.

Alternative Splicing↗

PubMed2005

On the structure of aqueous LiCl solutions.

The structure of highly concentrated aqueous lithium chloride solutions was investigated by the Reverse Monte Carlo method. Two total structure factors, obtained from neutron and x-ray diffraction experiments, were applied as input information. From the resulting particle configurations, partial pair correlation functions, coordination numbers and cosine distributions of bond angles have been determined. It was found that, in accordance with common-sense expectations, the hydrogen bonded network of water molecules is breaking up continuously as the concentration of the electrolyte increases. The hydration shell of the cations becomes more and more distorted as concentration grows whereas the hydration structure of the anions appears to be nearly invariant. Ion-pairing was not detected even at the highest salt concentration.

Journal Article↗

PubMed2005

A single-gene biomarker identifies breast cancers associated with immature cell type and short duration of prior breastfeeding.

The pathogenesis of breast cancers that do not express estrogen receptors or Her-2/neu receptors (ER-/HER2- phenotype) is incompletely understood. We had observed markedly elevated gene expression of gamma-aminobutyric acid type A (GABA(A)) receptor subunit pi (GABApi, GABRP) in some breast cancers with ER-/HER2- phenotype. In this study, transcriptional profiles (TxPs) were obtained from 82 primary invasive breast cancers by oligonucleotide microarrays. Real-time reverse transcription-polymerase chain reaction (RT-PCR) was used to measure GABApi gene expression in a separate cohort of 121 invasive breast cancers. GABApi gene expression values from TxP and RT-PCR were standardized and compared with clinicopathologic characteristics in the 203 patients. GABApi gene expression was increased in 16% of breast cancers (13/82 TxP, 20/ 121 RT-PCR), particularly in breast cancers with ER-/HER2- phenotype (60%), and breast cancers with basal-like genomic profile (60%). The profile of genes coexpressed with GABApi in these tumors was consistent with an immature cell type. In multivariate linear regression analysis, the level of GABApi gene expression was associated with ER-/HER2- phenotype (P < 0.0001), younger age at diagnosis (P = 0.0003), and shorter lifetime duration of breastfeeding (< or = 6 months) in all women (P = 0.017) and specifically in parous women (P = 0.013). GABApi gene expression was also associated with combinations of high grade with ER-/HER2- phenotype (P = 0.002), and with Hispanic ethnicity (P = 0.036). GABApi gene expression is increased in breast cancers of immature (undifferentiated) cell type and is significantly associated with shorter lifetime history of breastfeeding and with high-grade breast cancer in Hispanic women.

Biomarkers, Tumor↗

PubMed2005

Adjuvant therapy for breast cancer.

Significant progress has been made in the last 30 years in the adjuvant hormonal and chemo-therapeutic treatments of breast cancer. Currently, several cytotoxic agents are available for use including anthracyclines, taxanes, and cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and a new class of hormonal agents, aromatase inhibitors were introduced. A greater than 50% improvement in risk of relapse and 25% absolute overall survival advantage is presently realistic for many women with lymph node-positive breast cancer who receive adjuvant therapy. Aromatase inhibitors (AI) now constitute a superior alternative to tamoxifen as adjuvant hormonal therapy in postmenopausal women with hormone receptor-positive breast cancer. Extended hormonal therapy with letrozole after completion of five-years of tamoxifen has been shown to improve survival and reduce late relapses. It has also been established that anthracycline containing combination chemotherapy is superior to CMF if the number of cycles is kept the same. Inclusion of a taxane in an anthracycline-based regimen has further improved efficacy. The schedule of administration of drugs, particularly of paclitaxel, also appears to have an impact on efficacy. On the other hand, increasing the dose of cyclophosphamide or anthracyclines above the standard dose do not appear to improve the efficacy of these regimens, whereas substandard dose are clearly inferior. Currently there are several highly effective adjuvant chemotherapy regimens, however there is no single best treatment, let alone a universally effective one. Tamoxifen was the first truly molecularly targeted agent to be used in the treatment of cancer though it took some time to understand that its benefits are restricted to hormone receptor-positive cancers only. Clinical experience shows that similar principals apply to adjuvant chemotherapy as well. Only a subset of patients with micro-metastatic disease benefit from cytotoxic therapy. A major current research effort is focused on the discovery of molecular markers that could predict who will benefit from what particular type of chemotherapy. In the near future, important clinical advances will come from the incorporation of trastuzumab into adjuvant chemotherapy regimens for patients with HER-2 amplified tumors. Results from several large randomized studies are expected shortly and will define the use of trastuzumab in this clinical setting.

Adult↗

PubMed2004

Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer.

PURPOSE: The goal of this study was to examine the feasibility of developing a multigene predictor of pathologic complete response (pCR) to sequential weekly paclitaxel and fluorouracil + doxorubicin + cyclophosphamide (T/FAC) neoadjuvant chemotherapy regimen for breast cancer. PATIENTS AND METHODS: All patients underwent one-time pretreatment fine-needle aspiration to obtain RNA from the cancer for transcriptional profiling using cDNA arrays containing 30721 human sequence clones. Analysis was performed after profiling, and 42 patients' clinical results were available, 24 of which were used for predictive marker discovery; 18 patients' results were used as an independent validation set. RESULTS: Thirty-one percent of patients had pCR (six discovery and seven validation), defined as disappearance of all invasive cancer in the breast after completion of chemotherapy. We could identify no single marker that was sufficiently associated with pCR to be used as an individual predictor. A multigene model with 74 markers (P <or=.09) was built using data from the discovery samples and tested on the validation samples. Overall, a 78% (14 of 18) predictive accuracy was observed, with a 100% (three of three) positive predictive value for pCR, a 73% (11 of 15) negative predictive value, a sensitivity of 43% (three of seven), and a specificity of 100% (11 of 11). The expected response rate to T/FAC neoadjuvant therapy in unselected patients is 28%. CONCLUSION: Our results suggest that transcriptional profiling has the potential to identify a gene expression pattern in breast cancer that may lead to clinically useful predictors of pCR to T/FAC neoadjuvant therapy.

Adult↗

PubMed2004

Expression of sigma 1 receptor in human breast cancer.

The sigma 1 receptor (S1R) represents a unique drug-binding site that is distinct from any other receptors. We examined S1R expression in human breast cancer and assessed the activity of S1R ligands in breast cancer cell lines. One-hundred nine breast specimens from normal breast, benign breast disease and cancer were examined with immunohistochemistry or RT-PCR and six different cell lines were also evaluated. S1R mRNA overexpression was detected in 64% of breast cancers compared to normal breast tissue. Immunohistochemistry showed positive epithelial cell staining in 60% of invasive and 41% of in situ cancers, 75% of ductal hyperplasia and in 33% of normal breast. The pattern of expression was more diffuse in invasive breast carcinoma compared to other conditions (p = 0.02). S1R expression was neither a prognostic nor a predictive factor for efficacy of adjuvant chemotherapy but the study only included 58 cancer patients and therefore the statistical power is limited. MDA-MB-361, MDA-MB-435, BT20 and MCF7 cells all expressed S1R protein by Western blot. The non-specific S1R ligands haloperidol, reduced haloperidol and progesterone produced a dose-dependent inhibition of the growth at high (>10 microM) concentrations. Reduced haloperidol also showed additive cytotoxic effects when combined with doxorubicin, vinorelbine , paclitaxel and docetaxel in vitro. The S1R-specific ligand, SKF 10047 demonstrated the least growth inhibitory activity and showed no interaction with chemotherapy. These results demonstrate that some normal and most neoplastic breast epithelial cells and cell lines commonly express S1R. High concentrations of haloperidol inhibit the growth of these cells and potentiate the effect of chemotherapy in vitro.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Clinical trial design for microarray predictive marker discovery and assessment.

Transcriptional profiling technologies that simultaneously measure the expression of thousands of mRNA species represent a powerful new clinical research tool. Similar to previous laboratory analytical methods including immunohistochemistry, PCR and in situ hybridization, this new technology may also find its niche in routine diagnostics. Outcome predictors discovered by these methods may be quite different from previous single-gene markers. These novel tests will probably combine the information embedded in the expression of multiple genes with mathematical prediction algorithms to formulate classification rules and predict outcome. The performance of machine learning-algorithm-based diagnostic tests may improve as they are trained on larger and larger sets of samples, and several generations of tests with improving accuracy may be introduced sequentially. Several gene-expression profiling-technology platforms are mature enough for clinical testing. The most important next step that is needed for further progress is the development and validation of multigene predictors in prospectively designed clinical trials to determine the true accuracy and clinical value of this new technology. This manuscript reviews methodological and statistical issues relevant to clinical trial design to discover and validate multigene predictors of response to therapy.

Clinical Trials as Topic↗

PubMed2001

Expression of erbB/HER receptors, heregulin and P38 in primary breast cancer using quantitative immunohistochemistry.

The purpose of this study was to investigate the frequency of expression of the erbB/HER family of growth factor receptors, their ligand heregulin, and the two different signaling pathways p38 and mitogen-activated protein kinase (MAPK), as well as the status of HER-2 phosphorylation in tumor specimens from patients with primary breast cancer. The level of expression of these proteins was measured by quantitative immunohistochemistry combined with microscope-based image analysis in paraffin-embedded breast cancer tissue from 35 patients. The frequency of expression was: EGFR (51%), HER-2 (54%), P-HER-2 (48%), HER-3 (48%), HER-4 (57%), heregulin (48%), p38 (17%), MAPK (48%). There was evidence of associations among the coexpression of heregulin, EGFR, HER-2, and HER-3. Also, there was evidence of a positive association between P-MAPK and HER-4. HER-3 was expressed at high levels in patients younger than 50 years of age. There was a trend for expression of higher levels of HER-4 in tumors larger than 2 cm. The expression of EGFR, HER-2, heregulin, p38 and MAPK was independent of age, tumor size, number of lymph nodes involved or hormone receptor status. The HER family of growth factor receptors appear to be regulated independently in invasive breast cancer. Assessing the expression of multiple tumor markers by quantitative immuno-histochemistry is feasible. Further research is needed to determine the prognostic and predictive roles of the various associations between HER receptors, their ligands and signal transduction molecules in patients with early-stage breast cancer.

Breast Neoplasms↗

PubMed2001

Surgical conservation planning after neoadjuvant chemotherapy for stage II and operable stage III breast carcinoma.

BACKGROUND: This study was performed to investigate the extent of tumor downstaging achieved in women with operable breast cancer treated with neoadjuvant chemotherapy and breast-conservation surgery, develop recommendations for effective surgical planning, and report local-regional recurrence rates with this approach. METHODS: One hundred nine patients with stage II or III (T3N1) breast cancer were treated in three prospective trials utilizing four cycles of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC, n = 72) or paclitaxel (n = 37) followed by segmental resection (n = 109) and axillary node dissection (n = 94). Postoperatively, patients received 4 additional cycles of FAC followed by irradiation of the breast. The median follow-up was 53 months. RESULTS: The median tumor size was 4 cm (range 1.1 to 9 cm) at presentation and only 1 cm (range 0 to 4.5 cm) after four cycles of chemotherapy. The primary tumor could not be palpated after chemotherapy in 55% of 104 patients presenting with a palpable mass and therefore required needle localization or ultrasound guidance for surgical resection. Of the 34 patients clinically deemed to have no residual carcinoma in the breast after chemotherapy and before surgery, only 50% of these patients were found to have no residual carcinoma on pathologic examination after surgery. Patients with primary tumors < or =2 cm were significantly more likely than patients with larger tumors to have complete eradication of the primary tumor prior to surgery (P <0.001). The 5-year local-regional recurrence rate was 5%. CONCLUSIONS: Tumor downstaging is marked in patients with operable breast cancer and requires close monitoring during chemotherapy. We recommend placement of metallic tumor markers when the primary tumor is < or =2 cm to facilitate adequate resection and pathologic processing. Resection of the tumor bed remains necessary in women deemed to have a complete clinical response to ensure low rates of recurrence.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2001

Chemotherapy-induced histologic changes in mastectomy specimens and their potential significance.

The aim was to assess chemotherapy-induced histologic changes in breast cancer and to evaluate their relationship with tumour response, to treatment and patient survival. We examined paired pre- and post-chemotherapy tumour specimens from 57 patients with stages II and III breast cancers. All patients received three to four courses of anthracycline-containing preoperative treatment and subsequently underwent modified radical mastectomy 3-5 months after diagnosis. Histologic parameters evaluated included extent of residual disease and cytologic changes in residual tumour and in non-neoplastic breast tissue and lymph nodes. Correlation of pathologic changes with disease-free and overall survival was evaluated. Clinical evaluation indicated that 24% (n=14) of patients had a complete response, 53% (n=30) had a partial response, and 22% (n=13) had stable disease. Pathologic assessment revealed a complete response in 14% (n=8) of patients. Clinical and histologic complete responses were discordant in 35% of patients. Sixty-eight percent of tumours demonstrated moderate to severe cytologic changes in the cytoplasm and nucleus of neoplastic cells. These were characterized by increased overall cell size, cytoplasmic vacuolization, nuclear enlargement, multinucleation, and vesiculation of chromatin. Chemotherapy-induced histologic changes varied within a tumour and between patients. Tumour cytologic changes were significantly associated with histologic (p=0.03) as well as clinical (p=0.02) tumour response. Pathologic tumour response, but not histologic changes, was also a powerful predictor of overall survival and relapse-free survival. In the non-neoplastic glandular tissue, periductal and perilobular fibrosis and atrophy of lobular acini similar to those seen in postmenopausal breast tissue were noted. Changes in lymph nodes were characterized by lymphoid depletion and fibrosis with and without tumour metastasis. Chemotherapy-induced cytologic changes are frequently seen in neoplastic breast epithelium and correlate with response to treatment. Histologic confirmation of clinical tumour response to preoperative chemotherapy is necessary for accurate characterization of patients', response to treatment.

Journal Article↗

PubMed2001

Chemotherapy of metastatic breast cancer: what to expect in 2001 and beyond.

Chemotherapy plays an important role in the management of metastatic breast cancer. The anthracyclines (doxorubicin, epirubicin) and the taxanes (paclitaxel, docetaxel) are considered the most active agents for patients with advanced breast cancer. Traditionally, the anthracyclines have been used in combination with cyclophosphamide and 5-fluorouracil (FAC, FEC). The taxanes have single-agent activity similar to older combination chemotherapy treatments. There is great interest in developing anthracycline/taxane combinations. Capecitabine is indicated for patients who progress after anthracycline and taxane therapy. Vinorelbine and gemcitabine have activity in patients with metastatic breast cancer and are commonly used as third- and fourth-line palliative therapy. The role of high-dose chemotherapy is not well-defined and remains experimental. Novel cytotoxic therapy strategies include the development of anthracycline, taxane, and oral fluoropyrimidine analogues; antifolates; topoisomerase I inhibitors, and multidrug resistance inhibitors. A better understanding of the biology of breast cancer is providing novel treatment approaches. Oncogenes and tumor-supressor genes are emerging as important targets for therapy. Trastuzumab, a monoclonal antibody directed against the Her-2/neu protein, has been shown to prolong survival in patients with metastatic breast cancer. Other novel biologic therapies interfere with signal transduction pathways and angiogenesis. The challenge for the next decade will be to integrate these promising agents in the management of metastatic and primary breast cancer.

Antibodies, Monoclonal↗

PubMed2000

Novel marine-derived anticancer agents: a phase I clinical, pharmacological, and pharmacodynamic study of dolastatin 10 (NSC 376128) in patients with advanced solid tumors.

Dolastatin (DOLA)-10 is a pentapeptide isolated from the mollusc Dolabella auricularia with clinically promising antitumor activity documented in various in vitro and in vivo tumor models. The objectives of this Phase I study were to determine the maximum tolerated dose, evaluate toxic effects, and document any antitumor activity of this novel agent. Using an electrospray ionization mass spectroscopy system, we also characterized the clinical pharmacokinetics, pharmacodynamics, and metabolism of DOLA-10. The maximum tolerated dose was reached at 300 microg/m2. Granulocytopenia, the dose-limiting toxicity, was documented in 33% of the patients treated at that dose level. There were no episodes of thrombocytopenia or severe anemia (Hgb < 8), and no major nonhematological toxicity was observed. Stabilization of tumor growth was observed in four patients, but no objective responses were seen. Whereas a two-compartment model described the DOLA-10 plasma concentration-time data reasonably well, a three-compartment model consistently performed better. After a rapid distribution phase, DOLA-10 plasma levels declined with mean beta and gamma half-lives of 0.99 and 18.9 h, respectively. Significant interpatient and intrapatient variability in DOLA-10 plasma clearances was observed. The mean area under the concentration-time curve increased proportionally as the dose was escalated, but there was significant overlap between dose levels. The area under the concentration-time curve and the percentage of decline in neutrophils were correlated. A single DOLA-10 metabolite was detected in five patients. Unlike the in vitro studies of DOLA-10, the principal metabolite detected was an N-demethyl derivative, confirmed by mass spectroscopy. In all five subjects, the concentration of this metabolite never exceeded 2% of the simultaneously measured parent drug concentration. The available preclinical, pharmacological, and clinical data suggest that further study of escalated DOLA-10 dosing with cytokine support is warranted.

Adult↗

PubMed1999

Relative cytotoxic activity of immunotoxins reactive with different epitopes on the extracellular domain of the c-erbB-2 (HER-2/neu) gene product p185.

Different epitopes on the extracellular domain of the HER-2 receptor can serve as distinct targets for immunotoxins. To determine the optimal epitope target for immunotoxin therapy, 7 anti-HER-2 ricin A chain murine monoclonal immunotoxins, each reactive with different epitopes of HER-2 receptor, were tested for cytotoxic activity. The immunotoxins produced 1.2-4.6 logs of cytotoxicity in limiting dilution clonogenic assays with 2 breast cancer cell lines that overexpressed HER-2. Cytotoxicity did not correlate with immunoglobulin isotype, binding affinity, relative position of epitopes or internalization of the anti-HER-2 immunotoxins. Interestingly, the most and least effective immunotoxins bound to epitopes in very close proximity. Competitive binding assays with unconjugated antibodies have previously indicated that our antibodies recognized epitopes that are arranged in a linear array. To orient this relative epitope map, deletions were prepared in the HER-2/neu gene and these mutant constructs were expressed in NIH3T3 cells. Epitope expression was determined by antibody binding and radioimmunoassay. Epitopes targeted by the PB3, 454C11 and NB3 antibodies are localized N-terminal to the epitopes recognized by ID5, BD5, 741F8 and 520C9 antibodies. The 2 non-conformational epitopes PB3 and NB3 were localized to regions corresponding to amino acides 78-242 of the p185(HER-2) protein.

3T3 Cells↗

PubMed1999

Phase II study of mitoxantrone by 14-day continuous infusion with granulocyte colony-stimulating factor (GCSF) support in patients with metastatic breast cancer and limited prior therapy.

PURPOSE: Early phase II evaluation of intravenous bolus mitoxantrone indicated objective response rates of 17 36% in patients with metastatic breast cancer. Subsequently, it has been suggested that continuous infusion may be the optimal way to administer this drug in order to achieve maximal cytotoxic effect with minimal toxicity. We present the results of a phase II study that evaluated the efficacy and side effects of mitoxantrone administered at the maximally tolerated dose by continuous infusion in patients with metastatic breast cancer. METHODS: This study included 16 patients with metastatic breast cancer and limited previous therapy for their metastatic disease. Mitoxantrone, 1.5 mg/m2 per day, was given by continuous intravenous infusion for 14 consecutive days repeated every 21 days with concomitant granulocyte colony-stimulating factor support. Dose escalation was allowed. RESULTS: No complete tumor response was seen. Two patients (13%, CI 0-29%) had a partial response, nine patients (56%) had progressive disease and the remaining five patients (31%) had stable disease on therapy. The major dose-limiting side effect was myelotoxicity. Two of the 16 patients (13%) experienced asymptomatic cardiotoxicity that required discontinuation of therapy. CONCLUSIONS: Our results indicate limited antitumor activity and significant toxicity of mitoxantrone given by continuous infusion as second-line chemotherapy for metastatic breast cancer. The objective response rate documented in this study is inferior to response rates reported with other second-line regimens, particularly the taxanes, now available for this patient population.

Adult↗

PubMed1999

Relapse after complete response to anthracycline-based combination chemotherapy in metastatic breast cancer.

In this study we examined the clinical characteristics of relapse before and after complete clinical response (CR) to anthracycline-based combination chemotherapy in metastatic breast cancer (MBC). Our goal was to determine whether similar clinical trends could be observed during first relapse and relapse after CR. Two hundred and sixty-three patients with MBC were identified who had achieved CR after anthracycline-based combination chemotherapy for first recurrence. From this group, 226 patients had relapse after CR after a minimum follow-up of 13 years. Clinical features of their disease at first relapse and after progression from CR (second relapse) were examined, including disease-free interval (DFI) from diagnosis until first relapse, sites of recurrence, response to subsequent therapy, and survival after progression from CR. There was a significant correlation between duration of CR and survival after progression from CR. Patients who relapsed < 12 months after achieving CR had a median survival of 8.8 months after second relapse, whereas those who relapsed beyond 3 years had a median survival of 21.5 months (p = 0.0034). Neither the duration of CR nor length of survival after second relapse was related to the length of initial DFI. Patients with a short duration of CR (< 12 months) more often experienced second recurrences at multiple sites and in visceral organs (62% and 75%, respectively) than did patients with prolonged CR (> 36 months) (27% and 45%, respectively, p < 0.001). The anatomic location of metastatic disease at the time of first and second relapses was similar within a CR duration group but different among the groups. Short CR duration was associated with more frequent recurrence at visceral sites and also with chemotherapy-resistant second relapse. In conclusion, prolonged CR is associated with long survival after second relapse; however, neither CR duration nor survival after second relapse is related to the length of initial DFI. This suggests that chemotherapy, when it induces CR, may change the pace of disease progression. The tissue pattern of recurrence appears to be similar between first and second relapse, suggesting that the cellular predilection for metastatic sites has been preserved.

Antibiotics, Antineoplastic↗

PubMed1999

Chemo-signal therapy, an emerging new approach to modify drug resistance in breast cancer.

Recent advances in understanding how response or resistance to cytotoxic drugs develops at the cellular level resulted in the development of novel, non-cytotoxic agents that modulate response the chemotherapy. 'Chemo-signal therapy', the combination of chemotherapy with cellular response modifiers, is a very promising new treatment modality that has entered the arena of clinical trials. Clinical experience with the anti-HER-2 antibody, trastuzumab, in breast cancer has demonstrated that manipulation of growth factor signalling can enhance sensitivity to cytotoxic drugs in a clinically meaningful way. Several other agents that were designed to modulate response to chemotherapy are currently in early phases of clinical drug development. It is likely that some of these new molecules will have a major impact on how chemotherapy will be given in the next decade. This paper will review current clinical research with a select group of chemotherapy response modifiers. We will focus on agents that modulate signal transduction, oncogene expression and apoptosis with an emphasis on breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗