Search PubMed⌕ Search

Biomedical subjects

K Dhingra

Publications and source records attributed to K Dhingra.

At least 19 recordsLinked to original sources
PubMed1999

Interobserver reproducibility of the Lagios nuclear grading system for ductal carcinoma in situ.

Several studies have shown an association between high nuclear grade or necrosis of ductal carcinoma in situ (DCIS) lesions and the risk of local disease recurrence in patients with DCIS treated surgically with less than mastectomy. Although criteria for separating low from high nuclear grade lesions have been published, no information exists regarding interobserver reproducibility (IR). To assess IR in the classification of DCIS, six surgical pathologists from four institutions used the Lagios grading system to grade 125 DCIS lesions. Before meeting to evaluate the cases, a training set of 12 glass slides, including cases chosen to present conflicting cues for classification, was mailed to the participants with a written criteria summary. This was followed by a working session in which criteria were reviewed and agreed on. The pathologists then graded the lesions independently. The area of interest was marked on each slide before grading. After initial grading, the pathologists met again to resolve discrepant lesion classifications. A complete agreement among raters was achieved in 43 (35%) cases, with five of six raters agreeing in another 45 (36%) cases. In no case did two raters differ by more than one grade. The pairwise kappa agreement values ranged from fair to substantial (0.30 to 0.61). Generalized kappa value indicated moderate agreement (0.46, standard error = 0.02). Kappa statistics for the distinction between grades 1 and 2 and 2 and 3 were 0.29 and 0.48, respectively, (standard error = 0.02). Only one of the six raters differed significantly in scoring. With adherence to specific criteria, IR in the classification of DCIS cases can be obtained in most cases. Although these pathologists made a few grading system modifications, further refinements are needed, especially if grading will influence future therapy.

Breast Neoplasms↗
PubMed1999

Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy.

PURPOSE: To assess patient and tumor characteristics associated with a complete pathologic response (pCR) in both the breast and axillary lymph node specimens and the outcome of patients found to have a pCR after neoadjuvant chemotherapy for locally advanced breast cancer (LABC). PATIENTS AND METHODS: Three hundred seventy-two LABC patients received treatment in two prospective neoadjuvant trials using four cycles of doxorubicin-containing chemotherapy. Patients had a total mastectomy with axillary dissection or segmental mastectomy and axillary dissection followed by four or more cycles of additional chemotherapy. Patients then received irradiation treatment of the chest-wall or breast and regional lymphatics. Median follow-up was 58 months (range, 8 to 99 months). RESULTS: The initial nodal status, age, and stage distribution of patients with a pCR were not significantly different from those of patients with less than a pCR (P>.05). Patients with a pCR had initial tumors that were more likely to be estrogen receptor (ER)-negative (P<.01), and anaplastic (P = .01) but of smaller size (P<.01) than those of patients with less than a pCR. Upon multivariate analysis, the effects of ER status and nuclear grade were independent of initial tumor size. Sixteen percent of the patients in this study (n = 60) had a pathologic complete primary tumor response. Twelve percent of patients (n = 43) had no microscopic evidence of invasive cancer in their breast and axillary specimens. A pathologic complete primary tumor response was predictive of a complete axillary lymph node response (P<.01 ). The 5-year overall and disease-free survival rates were significantly higher in the group who had a pCR (89% and 87%, respectively) than in the group who had less than a pCR (64% and 58%, respectively; P<.01). CONCLUSION: Neoadjuvant chemotherapy has the capacity to completely clear the breast and axillary lymph nodes of invasive tumor before surgery. Patients with LABC who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival rate. However, a pCR does not entirely eliminate recurrence. Further efforts should focus on elucidating the molecular mechanisms associated with this response.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Role of axillary lymph node dissection after tumor downstaging with induction chemotherapy for locally advanced breast cancer.

BACKGROUND: Induction chemotherapy has become the standard of care for patients with locally advanced breast cancer (LABC) and currently is being evaluated in prospective clinical trials in patients with earlier-stage disease. To better gauge the role of axillary lymph node dissection in patients with LABC this study was performed to assess initial axillary status on physical and ultrasound examination, axillary tumor downstaging following induction chemotherapy, and the accuracy of physical examination compared with axillary sonography in predicting which patients will have axillary lymph node metastases found on pathologic examination. METHODS: Between 1992 and 1996, 147 consecutive patients with LABC were registered in a prospective trial of induction chemotherapy using 5-fluorouracil, doxorubicin, and cyclophosphamide. Physical and ultrasound examinations of the axilla were performed at diagnosis and after induction chemotherapy. Segmental resection with axillary lymph node dissection or modified radical mastectomy was performed, followed by postoperative chemotherapy and irradiation of the breast or chest wall and regional lymphatics. RESULTS: Following induction chemotherapy, 43 (32%) of the 133 patients with clinically positive lymph nodes on initial examination had axillary tumor downstaging as assessed by physical and ultrasound examination. The sensitivity of axillary sonography in identifying axillary metastases was significantly higher than that of physical examination (62% vs. 45%, P=.012). The specificity of physical examination (84%) was higher than that of sonography (70%), but the difference did not reach statistical significance. Among the 55 patients in whom the findings of both physical and ultrasound examination of the axilla were negative following induction chemotherapy, 29 patients (53%) were found to have axillary lymph node metastases on pathologic examination of the axillary contents. However, 28 (97%) of these patients had either 1 to 3 positive lymph nodes or only micrometastases 2 to 5 mm in diameter. CONCLUSIONS: Preoperative clinical assessment of the axilla by physical examination combined with ultrasound examination is not completely accurate in predicting metastases in patients with LABC following tumor downstaging. However, patients with negative findings on both physical and ultrasound examinations of the axilla may be potential candidates for omission of axillary dissection if the axilla will be irradiated because minimal axillary disease remains. Patients who have positive findings on preoperative physical or ultrasound examinations should receive axillary dissection to ensure local control. A prospective randomized trial of axillary dissection versus axillary radiotherapy in patients with a clinically negative axilla following induction chemotherapy is currently underway.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy predict disease-free survival in patients with locally advanced breast cancer.

BACKGROUND: This study was performed to validate the prognostic significance of residual axillary lymph node metastases in patients with locally advanced breast cancer (LABC) treated with neoadjuvant chemotherapy and to analyze other clinicopathologic factors that might be independent predictors of disease-free survival (DFS) in an attempt to identify patients in whom axillary dissection might be omitted. METHODS: One hundred sixty-five assessable patients with LABC were treated in a prospective trial of neoadjuvant chemotherapy utilizing four cycles of 5-fluorouracil, doxorubicin, and cyclophosphamide. Responding patients were treated with segmental mastectomy and axillary dissection or modified radical mastectomy. Patients subsequently received additional chemotherapy followed by irradiation of the breast or chest wall and draining lymphatics. The median follow-up was 35 months. RESULTS: Clinical tumor response to neoadjuvant chemotherapy (P = 0.046) and the number of residual metastatic axillary lymph nodes found at axillary dissection (P = 0.05) were the only independent predictors of DFS. Patients with a complete clinical response had a predictably excellent DFS and those with no change or progressive disease had a poor DFS. In patients with a partial response, the number of residual metastatic lymph nodes further stratified patients with respect to DFS (P = 0.006). CONCLUSIONS: Clinical response and residual metastatic axillary lymph nodes following neoadjuvant chemotherapy are important predictors of DFS. Patients with a clinically positive axilla following neoadjuvant chemotherapy should undergo axillary dissection to ensure local control. However, the benefit of axillary dissection in patients with a clinically negative axilla may be minimal if the axilla will be irradiated, and histologic staging does not affect subsequent systemic treatment. A prospective randomized trial of axillary dissection versus axillary radiotherapy in patients with a clinically negative axilla following neoadjuvant chemotherapy is presently under way to evaluate this hypothesis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Expression of leukemia inhibitory factor and its receptor in breast cancer: a potential autocrine and paracrine growth regulatory mechanism.

Leukemia inhibitory factor (LIF) is a pluripotent cytokine which has a diverse array of effects on hematopoietic and epithelial cells. Depending on the nature of the target cells, these effects can be growth-stimulatory or growth-inhibitory. Receptors for leukemia inhibitory factor (LIFR) have been identified on a variety of hematopoietic and epithelial cells. We have recently demonstrated in vitro growth stimulation of human breast cancer cells, both primary tumors and cultured cell lines, by LIF. To begin to understand the in vivo relevance of these observations, we investigated the expression of LIF and LIFR in human breast cancer specimens. Specimens from 50 cases were immunostained with mouse monoclonal antibodies D62.3 and M1 (to stain for LIF and LIFR, respectively). LIF expression was observed in 78% of the specimens and correlated with favorable biological features, i.e. low S-phase fraction (SPF) (P = 0.001) and diploidy (P = 0.08). LIFR expression was observed in 80% of the tumors and correlated with the presence of estrogen receptor (ER) (P = 0.04) and diploidy (P = 0.07). Coexpression of LIF and LIFR was associated with diploidy (P = 0.02) and low SPF (P = 0.05). LIF staining was primarily cytoplasmic whereas LIFR staining was cytoplasmic in the majority of cases and membranous in a minority of cases. The presence of LIFR in the primary tumor specimens correlated with the growth stimulation of tumor cells (derived from the same specimens) by exogenous LIF in methylcellulose colony assays. The findings support a widespread but probably complex role for LIF and LIFR in breast tumor growth regulation which should be investigated in greater detail in larger cohorts of tumors.

Breast Neoplasms↗
PubMed1997

The prognostic significance of sialyl-Tn antigen in women treated with breast carcinoma treated with adjuvant chemotherapy.

BACKGROUND: Sialyl-Tn (STn) represents an aberrantly glycosylated mucin epitope that is expressed in breast carcinoma and other adenocarcinomas and is an important factor in the development of novel immunotherapeutic approaches. The primary aim of the current study was to investigate the influence of STn expression on the prognoses of patients with breast carcinoma. METHODS: A cohort of 207 women diagnosed with invasive breast carcinoma who were treated with anthracycline-containing adjuvant chemotherapy and were enrolled in a randomized clinical trial were studied. Expression of STn was determined by an immunohistochemical procedure in which the B72.3 monoclonal antibody was used. Kaplan-Meier and Cox proportional regression survival analyses were used to compare low STn and high STn patients. RESULTS: Forty-eight (23%) of the 207 specimens demonstrated high STn staining (>25% cells were immunoreactive). During a median follow-up of 5 years, high STn patients had worse disease free survival than low STn patients (55% vs. 74%, respectively; P = 0.03). High STn expression was significantly associated with age (P = 0.04) but not with other conventional prognostic markers. In multivariate analysis using the Cox regression model, high STn emerged as an independent prognostic indicator for disease free survival (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.09-3.73) and for overall survival (HR, 2.16; 95% CI, 0.95-4.92). CONCLUSIONS: The results of this study suggest that STn may be a valuable marker for identifying women at high risk of developing recurrent breast carcinoma who may be candidates for trials investigating new therapies in combination with standard adjuvant therapy.

Adult↗
PubMed1997

Progressive decrease in nuclear retinoic acid receptor beta messenger RNA level during breast carcinogenesis.

Some of the nuclear retinoic acid receptors (RARs) alpha, beta, and gamma and retinoid X receptors (RXRs) alpha, beta, and gamma are thought to mediate the effects of retinoids on cell growth, differentiation, and apoptosis and thereby prevent breast carcinogenesis. We analyzed the expression of mRNAs for the three RARs and RXR-alpha in histological sections of specimens from 70 breast cancer patients, which included adjacent normal tissue, ductal carcinoma in situ, and invasive cancer, using in situ hybridization. RARs alpha, beta, and gamma and RXR-alpha were expressed in 98.1, 98.0, 93.0, and 100% of the adjacent normal tissues. Significant decreases in the number of cases expressing RAR-beta were observed among ductal carcinoma in situ (83.1%) and invasive carcinomas (51.6%), especially among the poorly differentiated cases (77.4 and 35.7 %, respectively). No relationship was found between the expression of estrogen receptor and RAR-beta. These results implicate decreases in RAR-beta expression in breast cancer development and suggest that they are independent of estrogen receptor status.

Breast↗
PubMed1996

Aromatic DNA adducts in adjacent tissues of breast cancer patients: clues to breast cancer etiology.

The etiology of the majority of human breast cancers is unknown. Environmental factors have long been suspected to play a role, but no specific causative agent has been identified. If the hypothesis that environmental carcinogen exposure contributes to human breast cancer is true, carcinogen-DNA adducts would be expected to be present in human breast tissues. To address this possibility, aromatic DNA adducts were measured in 87 surgical specimens of normal human breast tissues from 87 breast cancer patients undergoing mastectomy using the nuclease P1-enhanced version of the 32P postlabeling assay. Breast tissue samples from 29 noncancer patients undergoing reduction mammoplasty served as controls. Whereas aromatic DNA adducts were detected in all tissue samples examined, the total adduct levels in cancer patients were significantly higher than that in noncancer controls [mean +/- SEM, 97.4 +/- 23.4/10(9) nucleotides (range, 3.8-1737.1) versus 18.1 +/- 11.6/10(9) nucleotides (range, 5.6-56.7), respectively; P < 0.01, t test and Mann-Whitney test]. This difference was not affected by the age distribution of the two groups. The typical smoking-related DNA adduct pattern (i.e., a diagonal radioactive zone) was observed in 29 of 87 tissues (17 of 17 current smokers, 5 of 8 former smokers, 4 of 52 nonsmokers, and 3 of 10 patients with unknown smoking status) and in 2 of 10 control tissues. It was of interest that a benzo(a)pyrene (BP)-like DNA adduct was observed in 36 normal adjacent breast tissues (41%), 27 of which were from nonsmokers. Levels of this BP-like adduct were extremely high (> 100/10(9) nucleotides) in 5 patients (4 nonsmokers and 1 smoker) and moderately high (> 10/10(9) nucleotides) in 13 other patients (8 nonsmokers and 5 smokers). One patient exhibited this adduct at a level of 1500/10(9) nucleotides, which is comparable to the highest level of total adducts reported in human tissues related to carcinogen exposure (e.g., cigarette smoking). In contrast, this adduct was absent (< 1/10(9) nucleotides) in all of the control tissues. Cochromatography and rechromatography analysis of DNA samples from human breast tissues and from MCF-7 cells treated with BP revealed that this adduct could be generated by BP exposure but is not the major BP 7,8-diol-9,10-epoxide-deoxyguanine adduct detected previously in animal tissues and human mammary epithelial cells. These findings support the hypothesis that environmental carcinogen exposure, in addition to cigarette smoking, may be associated with the etiology of human breast cancer.

Adult↗
PubMed1996

Technical approach for the study of the genetic evolution of breast cancer from paraffin-embedded tissue sections.

We have optimized a technique that allows the study of numerous chromosomal loci (n = 20-50) from single paraffin-embedded tissue sections by microsatellite length polymorphism analysis. DNA samples from normal and breast cancerous tissue can be obtained from the same section by means of microdissection. This technique was further improved by subjecting DNA to several cycles of amplification with a degenerate (universal) primer and then with specific microsatellite primers. This amplified DNA was also used to screen for mutations in the p53 gene by means of PCR-SSCP. In addition adjacent tissue sections were used to assess specific chromosome copy number by interphase cytogenetic analyses (chromosome in situ hybridization) and to analyze expression of specific genes such as p53 and ERBB2. As an example of the use of our approach we performed a detailed chromosome 17 allelotypic analysis in 22 breast tumors (5 ductal carcinomas in situ, 13 invasive ductal carcinomas, and 4 invasive lobular carcinomas). We detected mutations in the p53 gene by PCR-SSCP in 36% of the samples. Samples with significant levels of p53 protein accumulation detected by immunohistochemistry were also positive for mobility shifts in the SSCP analysis. We observed that chromosome 17 allelic losses and imbalance occurred at as early a stage as ductal carcinoma in situ (DCIS). Although in some cases we observed allelic losses or imbalance affecting the 17p13 region, close to the p53 locus, several of the tumors showed dissociation between such loss or imbalance and p53 mutation. Lobular carcinomas were predominantly disomic for chromosome 17 in contrast with ductal tumors, which often showed polysomy for chromosome 17. This comprehensive approach correlating the tumor subtype, its allelotype, with specific chromosome copy number and specific gene mutations and expression in preinvasive or early invasive breast cancer lesions will potentially provide information of relevance for a better understanding of the multistep mechanisms of breast carcinogenesis.

Alleles↗
PubMed1996

Paclitaxel: severe mucocutaneous toxicity in a patient with hyperbilirubinemia.

Paclitaxel is a novel anticancer drug that is being increasingly used to treat cancer of the breast and other organs. We describe a patient with metastatic breast cancer and liver dysfunction who had severe mucocutaneous toxicity after administration of a standard dose of paclitaxel. Another interesting finding in this patient was that the administration of paclitaxel led to a prompt resolution of parathyroid hormone-related protein (PTHrP)-mediated hypercalcemia, which had previously proven to be refractory to multiple conventional antihypercalcemic agents as well as anthracycline-containing chemotherapy combination. The need for definitive guidelines for paclitaxel administration in the setting of hepatic dysfunction and the potentially unique sensitivity of PTHrP--producing cells to paclitaxel are discussed.

Anthracyclines↗
PubMed1996

Critical evaluation of prognostic factors.

The ability to predict the biological behavior of breast tumors can allow selection of the optimum treatment and follow-up strategies. Conventionally, tumor size, lymph node metastases, and histopathologic features have been used to determine the risk of systemic relapse. The discovery of a number of specific genetic and biochemical alterations in breast tumors has led to the molecular era of prognostic factors. Many of these molecular changes are determinants of relevant biological characteristics of malignancy, ie, dyregulated proliferation, invasion, and metastases. Preliminary data suggest that they may provide a better determination of the risk of relapse than can be ascertained by conventional prognostic factors alone. For example, amplification/overexpression of HER-2/neu oncogene has been shown to be a marker of increased risk of relapse after locoregional therapy of breast cancer. More recent studies have shown that it may also play a role in determining sensitivity to chemo-therapeutic drugs. It is expected that a greater understanding of the molecular basis of breast cancer growth regulation will allow a better identification of subjects who should receive systemic therapy and will also allow a better selection of the appropriate systemic therapy regimen.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Lipid peroxidation-induced putative malondialdehyde-DNA adducts in human breast tissues.

The etiology of the majority of human breast cancers is unknown; however, oxidative stress and lipid peroxidation have been suggested to play a role in breast carcinogenesis. To address this possibility, DNA adducts induced by malondialdehyde (MDA), an end product of lipid peroxidation, were analyzed in surgical specimens of normal breast tissues of 51 breast cancer patients using the nuclease P1-enhanced version of the 32P-postlabeling assay. Normal breast tissue samples from 28 noncancer patients receiving reduction mammoplasty served as controls. Two previously characterized putative MDA-deoxyadenosine (dA) and one MDA-deoxyguanosine adduct were detected in all tissue samples examined. Normal breast tissues from cancer patients exhibited significantly higher levels of the putative MDA adducts [median (42.5) and range (2.2-202.8) of relative adduct labeling x 10(9) values] than those found in noncancer controls (median, 15.67; range, 2.4-382.1; P = 0.0001, Mann-Whitney U test). Ten of the 51 cancer patients and 1 of the 28 controls were found to contain the putative MDA adducts at the level of > 1/10(7) nucleotides, a frequency comparable to that found in human liver. Age and body mass did not significantly influence the levels of these adducts. However, the presence of a previously detected benzo(a)pyrene-like DNA adduct in the breast tissues was associated with higher levels of the putative MDA-dA adducts in cancer patients (P = 0.012). The level of the putative MDA-dA adducts was significantly lower in smokers and former smokers compared to nonsmokers among cases after adjusting for age, body mass index, and status of the benzo(a)pyrene-like adduct (P = 0.009). Tumor tissues (n = 11) displayed significantly lower levels of the putative MDA adducts (median, 10.2; range, 5.3-20.6) than their corresponding normal adjacent tissues (median, 25.5; range, 10.5-138; P < 0.01). These findings provide evidence that lipid peroxidation products can accumulate in human breast tissues and reach relatively high levels in the breast tissues of women with breast cancer. There seems to be an interaction between these endogenous DNA modifications and carcinogen exposure-induced DNA adducts. Detection and quantitation of the putative MDA-DNA adducts may potentially be a useful tool in the understanding of breast cancer etiology.

Adult↗
PubMed1995

The effects of anaemia on heart, placenta and body weight, and blood pressure in fetal and neonatal rats.

1. Reports that maternal anaemia in pregnancy is associated with a greater placental: birth weight ratio, which predisposes towards high postnatal blood pressure in the human, led us to examine the effects of maternal anaemia during pregnancy on placental size, fetal and neonatal growth, and blood pressure development in the rat. 2. Nutritional anaemia was induced in female rats prior to mating and maintained throughout pregnancy and up until weaning of the pups. Fetuses were studied at 20 days of gestation (E20). Pups were studied on postnatal days 20 (P20) and 40 (P40), having been weaned onto normal rat chow at 21 days. 3. In the anaemic group placental: fetal body weight ratios were lower compared with controls. Body weights at all ages were lower in the anaemic group than in controls, despite a greater rate of growth in the anaemic group between P20 and P40. 4. At P20 heart weights of the anaemic group were almost twice that of controls, suggesting an alteration in their cardiovascular development. However, paradoxically, the systolic blood pressure of the anaemic group was lower than that of controls. 5. By P40 the systolic blood pressure of the anaemic group (136 +/- 3 mmHg) had increased and was greater than that in control pups (126 +/- 3 mmHg). 6. In conclusion, we have shown that there is a pronounced postnatal rise in systolic blood pressure associated with maternal anaemia during pregnancy, which is not related to a greater placental: birth weight ratio. Before weaning, anaemic pups have a lower systolic blood pressure than controls and there is an important association between the rate of postnatal growth and blood pressure.

Anemia↗
PubMed1995

Phase I clinical and pharmacological study of suppression of human antimouse antibody response to monoclonal antibody L6 by deoxyspergualin.

Development of human antimouse antibody (HAMA) is a major limiting factor in the application of murine mAb for clinical use. A novel immunomodulatory drug, deoxyspergualin (DSG), has shown potential to suppress antimouse antibody response in preclinical model systems. We conducted a Phase I trial to determine the effect of DSG on HAMA response to murine mAb L6 administered to patients with advanced cancers (in previous trials, this antibody elicited HAMA in two-thirds of the treated patients). L6 mAb was administered at a fixed dose of 200 mg/m2 on days 1-5. DSG was administered at doses of 50 mg/m2 [dose level (dl) 1] or 150 mg/m2 (dls II and III) on days 1-7. Treatment courses were repeated every 6 weeks (dls I and II) or every 3 weeks (dl III). HAMAs were quantitated by a commercially available ELISA assay (ImmuSTRIP; anti-isotypic antibodies) and a radiometric assay (antiisotypic and anti-idiotypic antibodies). Pharmacokinetics of L6 and DSG was also studied in all consenting patients. Among 24 evaluable patients, 2 patients developed detectable HAMAs using the ELISA (one each at dls I and II) after a median follow-up of 122 days (P = 0.0001 as compared to historical controls). Even in the two patients who developed HAMA, the HAMA levels were quite low (160 and 181 ng/ml; historical experience, 70-38,744 ng/ml). The radiometric assay detected anti-L6 antibodies in 13 patients (4, 6, and 3 at dls I-III, respectively) after a median of 82 days. The median highest anti-L6 antibody level was 129 ng/ml (range, 21-2150). The highest anti-L6 antibody level at dl III was only 44 ng/ml. The results suggest suppression of anti-idiotypic response also. No clinical antitumor activity was observed, and no significant changes in T4/T8 subsets or immunoglobulins occurred (suggesting a lack of generalized immunosuppression). We conclude that DSG can suppress HAMA response to L6. A starting dose of 150 mg/m2/day is recommended for Phase II trials to confirm this observation.

Adult↗
PubMed1995

Genetic changes in breast cancer--consequences for therapy?

The knowledge of specific genetic changes and their biological consequences is critical to an understanding of the natural history of breast tumors and the development of rational means to prevent and treat them. A number of genetic changes have been identified in breast tumors. Some of these involve specific genetic loci that directly contribute to one or more attributes of transformation, i.e., dysregulated proliferation and invasion, while other changes confer genetic instability that increases the possibility of acquiring subsequent, specific genetic lesions relevant to tumorigenesis. Many of these changes have been correlated with an adverse prognosis and attempts to integrate these in comprehensive multifactorial prognostic models are in progress. Initial clinical trials have also demonstrated the 'proof of concept' of targeting specific genetic lesions for therapeutic purposes. In the not too distant future, we can envision the use of specific therapies for individual (or subgroups of) tumors based on the specific genetic changes that lead to their development, rather than the global approach of multiagent cytotoxic therapy that is in widespread use today.

Breast Neoplasms↗
PubMed1995

A phase II chemoprevention trial design to identify surrogate endpoint biomarkers in breast cancer.

Surrogate biomarkers for risk assessment and efficacy of potential chemopreventive agents are needed to improve the efficiency and reduce the cost of conducting chemoprevention trials. In addition to criteria of sensitivity, specificity, quantifiability, and reproducibility applicable to most potential biomarkers, there are additional specific constraints in developing biomarkers for specific organ sites. In the case of breast tissue, these difficulties include lack of a consensus on the nature of premalignant lesions and the histologic criteria used to define them; even when such a consensus can be evolved, there are limitations in visualizing such lesions without invasive biopsies. Also, knowledge of specific genetic and biochemical changes in premalignant lesions is limited. In addition, the physiology of breast tissue is cyclic, no proven, relevant markers can be studied in a randomly obtained needle aspirate. The earliest determinate lesion that can be recognized in breast tissue is ductal carcinoma in situ (DCIS). At the University of Texas M.D. Anderson Cancer Center, we have initiated a study to develop biomarkers for tamoxifen and 4-hydroxyphenylretinamide by administering one or both of these drugs to women with DCIS or small invasive lesions in the interval between the initial diagnostic core biopsy and definitive surgery. The treatment is to be administered for 2-4 weeks. Proposed biomarkers to be studied include: (a) markers associated with neoplastic phenotypes, e.g., excessive proliferation, alternations of nuclear morphology and angiogenesis; (b) proteins likely to be required for response to the putative chemopreventive agents, e.g., estrogen receptor, nuclear retinoid receptors; (c) markers indicative of intact downstream response pathways, e.g., progesterone receptors; (d) oncogenes and tumor suppressor genes regulated by the proposed chemopreventive agents, e.g., neu, TGF-beta; and (e) potential novel markers of genetic instability that could be studied in randomly obtained needle aspirates, i.e., random chromosomal gains and losses in high risk mammary epithelium. The experience gained in designing and conducting this trial is expected to facilitate development of future chemoprevention trials of breast, as well as other organ site cancers.

Anticarcinogenic Agents↗
PubMed1995

Phase II clinical and pharmacological study of pirarubicin in combination with 5-fluorouracil and cyclophosphamide in metastatic breast cancer.

Doxorubicin containing combination chemotherapy regimens are widely used for treatment of breast and other cancers. However, these regimens are associated with significant toxicities including myocardial dysfunction and alopecia. Analogues of doxorubicin are being developed to reduce these side effects. We conducted a Phase II trial of an anthracycline analogue, pirarubicin, administered in combination with 5-fluorouracil and cyclophosphamide every 3 weeks, as front-line chemotherapy in women with metastatic breast cancer. Patients who had received prior anthracycline therapy were excluded. The chemotherapy doses were as follows: 5-fluorouracil (500 mg/m2 on days 1 and 8), pirarubicin (50 mg/m2 on day 1), and cyclophosphamide (500 mg/m2 on day 1). Among 40 evaluable patients treated on this protocol, a major response (partial or complete remission) was observed in 26 patients (response rate, 62%; 95% confidence interval, 46-77). The median response duration was 8 months, and median survival was 16 months. Grade III/IV myelosuppression occurred in 81% of the courses. The median cumulative pirarubicin dose was 410 (range, 90-870) mg/m2. A significant decrease in left ventricular ejection fraction occurred in 12 patients (at a median cumulative pirarubicin dose of 460 mg/m2) and led to congestive heart failure in 4 of these patients (cumulative pirarubicin doses of 500, 520, 590, and 730 mg/m2, respectively). Eleven patients underwent endomyocardial biopsy, either because they experienced a drop in left ventricular ejection fraction or because they had received a cumulative pirarubicin dose of 600 mg/m2 and were still responding to the treatment. Of these, only one biopsy was found to be more than grade 1.0 (in an individual who had received a cumulative dose of 705 mg/m2). Severe alopecia occurred in two-thirds of the patients. Pharmacokinetic studies revealed a triphasic elimination of pirarubicin with alpha, beta and gamma half-lives of 0.12, 1.44, and 33.9 h, respectively. Total clearance of drug was 4.2 liters.1 h/kg while the cumulative 24-h urinary excretion was less than 10% of the administered dose. The activity of the combination appears to be similar to doxorubicin-containing regimens, while the incidence of alopecia appears to be lower than the historical experience with doxorubicin. However, cardiotoxicity remains a significant problem.

Adult↗