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Larry Norton

Publications and source records attributed to Larry Norton.

At least 19 recordsLinked to original sources
PubMed2007

Increased dose density is feasible: a pilot study of adjuvant epirubicin and cyclophosphamide followed by paclitaxel, at 10- or 11-day intervals with filgrastim support in women with breast cancer.

PURPOSE: Because Cancer and Leukemia Group B 9741 trial showed a benefit for every 14-day administration of chemotherapy compared with every 21-day treatment, we hypothesized that even greater dose density would be more effective. We conducted a pilot trial to assess the feasibility of dose-dense chemotherapy consisting of a standard regime at 10- to 11-day intervals in the adjuvant/neoadjuvant setting. A 2-day window was allowed for scheduling logistics. EXPERIMENTAL DESIGN: Thirty-nine women with early-stage breast carcinoma were accrued from April 2004 to October 2004. Median age was 47 years (range, 26-67 years). Patients received therapy with 100 mg/m(2) epirubicin and 600 mg/m(2) cyclophosphamide (EC) q 10 to 11 days for four cycles followed by 175 mg/m(2) paclitaxel q 10 to 11 days for four cycles, all with filgrastim support (300 microg s.c. daily) from day 2 to 24 h before the next treatment. RESULTS: Thirty-five (90%) patients completed all planned therapy. The median intertreatment interval was 10 days (range, 8-28 days). Cycles (80.7%) were delivered at no more than 10- to 11-day intervals. There were five dose reductions of 25% for grade 3 nonhematologic toxicity in five patients. Six (16%) patients developed febrile neutropenia defined as temperature >38 degrees C with absolute neutrophil count <1,000/microL. All febrile neutropenia was during therapy with EC. Other grade 3 toxicities included bone pain, hand and foot syndrome, neuropathy, mucositis, nausea, and vomiting. CONCLUSIONS: Therapy with EC for four cycles followed by paclitaxel for four cycles at 10- to 11-day intervals is feasible. The approximately 30% reduction in intertreatment interval compared with every 14-day treatment could increase the efficacy of adjuvant chemotherapy.

Adult↗
PubMed2006

Pharmacokinetics and toxicity of weekly docetaxel in older patients.

PURPOSE: To evaluate the pharmacokinetics of weekly docetaxel in a cohort of older patients with metastatic cancer and to explore the relationship of pharmacokinetic variables, Erythromycin Breath Test results, age, geriatric assessment variables, and toxicity to therapy. EXPERIMENTAL DESIGN: Twenty patients ages > or = 65 years with metastatic breast, prostate, or lung cancer entered an Institutional Review Board-approved protocol to evaluate the pharmacokinetics of weekly docetaxel administered at 35 mg/m2 i.v. for 3 weeks followed by a 1-week break. The Erythromycin Breath Test and geriatric assessment were done before the first dose. Blood samples were collected for pharmacokinetic analysis with the first dose of docetaxel. RESULTS: Of the 20 patients who entered the study, 19 were evaluable. There were no age-related differences in the pharmacokinetics of weekly docetaxel. Fifty-eight percent (11 of 19) experienced grade > or = 3 toxicity: 16% (3 of 19) grade > or = 3 hematologic toxicity, and 53% (10 of 19) grade > or = 3 nonhematologic toxicity. There was an association between the Erythromycin Breath Test results and docetaxel pharmacokinetic variables; however, there was no association between Erythromycin Breath Test results or docetaxel pharmacokinetics with frequency of grade > or = 3 toxicity. CONCLUSIONS: Despite no statistically significant age-related differences in weekly docetaxel pharmacokinetics, over half of these older patients experienced a grade > or = 3 toxicity at the 35 mg/m2 starting dose. We advocate a starting dose of 26 mg/m2 on this weekly schedule and dose escalating if no toxicity.

Aged↗
PubMed2006

Interleukin-6, multidrug resistance protein-1 expression and response to paclitaxel in women with metastatic breast cancer: results of cancer and leukemia group B trial 159806.

Several reports have suggested that breast cancer patients with elevated serum levels of interleukin-6 (IL-6) have a worse prognosis than patients with lower levels. We have studied IL-6 in breast cancer cell lines and have shown that autocrine production of IL-6 can confer multi-drug resistance in vitro by inducing multidrug resistance gene-1 transcription with subsequent overexpression of P-glycoprotein (PGP). Both IL-6 and PGP expression can be measured in malignant cells using immunohistochemical (IHC) techniques. We hypothesized that patients whose tumors expressed higher amounts of IL-6 or PGP would be less likely to respond to paclitaxel, an agent affected by the PGP pathway. If so, then IL-6 could serve as a predictive factor for paclitaxel sensitivity. Both IL-6 and PGP expression were measured in patients treated in a randomized trial that compared three doses of single agent paclitaxel (175, 210, and 250 mg/m(2) over 3 h every 3 weeks) in 469 women with metastatic breast cancer (CALGB 9342). No difference in complete and partial response was found among the three treatment arms. Tissue blocks in this trial were analyzed for IL-6 (154 patients) and PGP (149 patients) in paraffin-embedded sections from tumor samples; clinical characteristics of these patients were similar to the total sample of 469 patients. There were no significant differences among IL-6 or PGP scores whether measured as continuous or dichotomous variables, or by other scoring, and response to paclitaxel. In multivariate analysis neither IL-6 nor PGP was a significant predictor of time to progression or overall survival. IHC expression of IL-6 and PGP levels in tumor cells is not a predictive marker for response to paclitaxel in women with metastatic breast cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer.

CONTEXT: Breast cancer estrogen-receptor (ER) status is useful in predicting benefit from endocrine therapy. It may also help predict which patients benefit from advances in adjuvant chemotherapy. OBJECTIVE: To compare differences in benefits from adjuvant chemotherapy achieved by patients with ER-negative vs ER-positive tumors. DESIGN, SETTING, AND PATIENTS: Trial data from the Cancer and Leukemia Group B and US Breast Cancer Intergroup analyzed; patient outcomes by ER status compared using hazards over time and multivariate models. Randomized trials comparing (1): 3 regimens of cyclophosphamide, doxorubicin, and fluorouracil (January 1985 to April 1991); (2) 3 doses of doxorubicin concurrent with cyclophosphamide, with or without subsequent paclitaxel (May 1994 to April 1997); (3) sequential doxorubicin, paclitaxel, and cyclophosphamide with concurrent doxorubicin and cyclophosphamide followed by paclitaxel, and also 3-week vs 2-week cycles (September 1997 to March 1999). A total of 6644 node-positive breast cancer patients received adjuvant treatment. MAIN OUTCOME MEASURES: Disease-free and overall survival. RESULTS: For ER-negative tumors, chemotherapy improvements reduced the relative risk of recurrence by 21%, 25%, and 23% in the 3 studies, respectively, and 55% comparing the lowest dose in the first study with biweekly cycles in the third study. Corresponding relative risk reductions for ER-positive tumors treated with tamoxifen were 9%, 12%, and 8% in the 3 studies, and 26% overall. The overall mortality rate reductions associated with chemotherapy improvements were 55% and 23% among ER-negative and ER-positive patients, respectively. All individual ER-negative comparisons and no ER-positive comparisons were statistically significant. Absolute benefits due to chemotherapy were greater for patients with ER-negative compared with ER-positive tumors: 22.8% more ER-negative patients survived to 5 years disease-free if receiving chemotherapy vs 7.0% for ER-positive patients; corresponding improvements for overall survival were 16.7% vs 4.0%. CONCLUSION: Among patients with node-positive tumors, ER-negative breast cancer, biweekly doxorubicin/cyclophosphamide plus paclitaxel lowers the rate of recurrence and death by more than 50% in comparison with low-dose cyclophosphamide, doxorubicin, and fluorouracil as used in the first study.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Effect of adjuvant breast cancer chemotherapy on cognitive function from the older patient's perspective.

PURPOSE: This longitudinal prospective study describes the older breast cancer patient's perception of the cognitive impact of adjuvant chemotherapy. METHODS: A total of 50 patients > or =age 65 with stage I to III breast cancer enrolled in this IRB-approved prospective study. Of the 50, 3 refused postchemotherapy testing and 2 had a cerebrovascular accident (CVA) during therapy, leaving 45 evaluable patients. The Squire Memory Self-Rating Questionnaire, given before and 6 months after chemotherapy, measured patients' perceptions of the ability to learn new information, of working memory, and of remote learning capabilities. RESULTS: Mean age was 70 years (range 65-84). Breast cancer stages were: I (33%), II (64%), III (2%). A 51% (23/45) of study participants perceived a decline in memory from before to 6 months after completion of chemotherapy. Patients who perceived a poorer memory than average before chemotherapy were more likely to report further memory deterioration after chemotherapy (19/30, 63%) than patients who perceived that their memory was average or better than average prior to chemotherapy (4/15, 27%). The memory domain most likely to be perceived as affected was the ability to learn new information (22/45, 49%) compared to remote memory (9/45, 20%) or working memory (13/45, 29%) capabilities. CONCLUSION: Approximately half of these older women perceived a decline in cognitive function from before to 6 months after chemotherapy. This perceived decline in cognitive function was most pronounced in patients with preexisting memory complaints. Further prospective study is needed to confirm these observations, correlate perceived memory changes with objective findings, and identify subgroups at special risk.

Aged↗
PubMed2006

Duration of letrozole treatment and outcomes in the placebo-controlled NCIC CTG MA.17 extended adjuvant therapy trial.

PURPOSE: MA.17 was a double-blind placebo-controlled trial involving 5187 postmenopausal women that established letrozole to be of value in reducing recurrence of breast cancer when given in the extended adjuvant therapy setting after about 5 years of tamoxifen. Analyses were conducted to examine the relationships between duration of treatment on MA.17 and outcomes. METHODS: The final MA.17 database that included all events up to the date of unblinding of the study was interrogated. A non-parametric kernel smoothing method was used to estimate the hazard rates for disease-free survival (DFS), distant DFS (DDFS) and overall survival (OS) at 6, 12, 24, 36 and 48 months of follow-up and the hazard ratios (HRs) of letrozole to placebo were determined. The trend in HRs over time was tested based on a Cox model with a time-dependent covariate. RESULTS: Considering all patients, HRs for events in DFS and DDFS progressively decreased over time, favoring letrozole, with the trend being significant (p < 0.0001 and p = 0.0013, respectively) whereas the trend for OS was not significant. Considering the 2360 patients with node-positive status, the HRs for DFS, DDFS and OS all decreased over time with tests for trend all showing significance (p = 0.0004, 0.0005 and 0.038, respectively). Considering the 2568 patients with node-negative status, the HRs for DFS decreased over time with the test for trend being significant (p = 0.027) whereas the HRs for DDFS and OS showed no significant change over time. CONCLUSION: These analyses suggest that, at least out to about 48 months, longer duration of letrozole treatment is associated with greater benefit in the extended adjuvant therapy setting.

Aged↗
PubMed2006

Localization of breast cancer susceptibility loci by genome-wide SNP linkage disequilibrium mapping.

We studied the feasibility of a novel approach to localize breast cancer susceptibility genes, using a low-density genome-wide panel of single-nucleotide polymorphisms and taking advantage of large regions of linkage disequilibrium (LD) flanking Jewish disease genes in high-risk cases. With Affymetrix GeneChip arrays, we genotyped 8,576 polymorphisms in three sets of Ashkenazi Jewish breast cancer cases: a "validation" set of 27 breast cancer cases, all of whom carried the BRCA2*6174delT founder mutation; a "field" set of 19 breast cancer cases from male breast cancer kindreds, which simulated conditions for finding new genes; and a "test" set of 57 probands from breast cancer kindreds (4 or more cases/kindred), in which mutations in BRCA1 and BRCA2 had been excluded. To identify associations, we compared the frequency of genotypes and haplotypes in cases vs. controls by the Fisher's exact test and a maximum likelihood ratio test. In the "validation" set, we demonstrated the presence of a region of linkage disequilibrium on BRCA2*6174delT chromosomes that spanned over 5 million bases. In the "field" set, we showed that this large region of linkage disequilibrium flanking BRCA2 was detectable despite the presence of heterogeneity in the sample set. Finally, in the "test" set, at least three regions of interest emerged that could contain novel breast cancer genes, one of which had been identified previously by linkage analysis. While these results demonstrate the feasibility of genome-wide association strategies, further application of this approach will critically depend on optimizing the density and distribution of SNPs and the size and type of study design.

Adult↗
PubMed2006

Novel patterns of genome rearrangement and their association with survival in breast cancer.

Representational Oligonucleotide Microarray Analysis (ROMA) detects genomic amplifications and deletions with boundaries defined at a resolution of approximately 50 kb. We have used this technique to examine 243 breast tumors from two separate studies for which detailed clinical data were available. The very high resolution of this technology has enabled us to identify three characteristic patterns of genomic copy number variation in diploid tumors and to measure correlations with patient survival. One of these patterns is characterized by multiple closely spaced amplicons, or "firestorms," limited to single chromosome arms. These multiple amplifications are highly correlated with aggressive disease and poor survival even when the rest of the genome is relatively quiet. Analysis of a selected subset of clinical material suggests that a simple genomic calculation, based on the number and proximity of genomic alterations, correlates with life-table estimates of the probability of overall survival in patients with primary breast cancer. Based on this sample, we generate the working hypothesis that copy number profiling might provide information useful in making clinical decisions, especially regarding the use or not of systemic therapies (hormonal therapy, chemotherapy), in the management of operable primary breast cancer with ostensibly good prognosis, for example, small, node-negative, hormone-receptor-positive diploid cases.

Breast Neoplasms↗
PubMed2006

A phase I study of cetuximab/paclitaxel in patients with advanced-stage breast cancer.

BACKGROUND: The epidermal growth factor receptor (EGFR) is part of the ErbB family of receptor tyrosine kinases and is known to be variably expressed in breast cancers. Cetuximab is a humanized monoclonal antibody directed against the EGFR that works by blocking the downstream signaling function of this protein and thereby interfering with cancer cell proliferation. Preclinical studies have indicated a synergistic effect for the combination of anti-EGFR therapy plus paclitaxel in breast cancer models. PATIENTS AND METHODS: Hence, we conducted a dose-escalation phase I trial using cetuximab/paclitaxel in patients with metastatic breast cancer to evaluate the feasibility of this combination. Patients with EGFR-positive metastatic breast cancer treated with <or= 1 previous therapy, excluding taxanes, were eligible. Treatment consisted of weekly cetuximab therapy and every-3-week paclitaxel, with dose escalation of cetuximab until the maximum tolerated dose was reached. RESULTS: Twelve patients were enrolled to 3 treatment cohorts. Two of 6 patients on the second cohort (cetuximab 100 mg/m2) developed dose-limiting toxicities, presenting as grade 3 rash. The third cohort was amended to allow the same cetuximab dose but to modify the paclitaxel to a weekly schedule. Despite this, 1 of 3 patients in this group also developed grade 3 skin toxicity as a dose-limiting toxicity; thus, the trial was stopped. Ten of the 12 patients were evaluable for response, and of these, 2 patients experienced stable disease, and 8 patients experienced disease progression. CONCLUSION: Because of prohibitive dermatologic toxicity and disappointing preliminary efficacy, the combination of paclitaxel/cetuximab was not considered promising in this population, although further study of this regimen might be warranted.

Adult↗
PubMed2005

Incidence of chemotherapy-induced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane.

BACKGROUND: Twenty-five percent of all women with breast carcinoma are premenopausal and are at risk for chemotherapy-induced menopause with long-term side effects. Although there is considerable documentation of the rates of chemotherapy-induced amenorrhea with classic adjuvant regimens, there are inadequate data that address the impact of taxanes on menstrual function in this setting. The objective of this analysis was to determine the incidence of long-term amenorrhea (> or = 12 mos) in women with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane-based chemotherapy, with or without subsequent tamoxifen. METHODS: The authors identified 235 premenopausal women with breast carcinoma age 40 years or younger who were treated with adjuvant anthracycline and taxane-based chemotherapy at Memorial Sloan-Kettering Cancer Center from January 1997 to June 2003. RESULTS: One hundred sixty-six patients met all eligibility criteria and had sufficient follow-up for evaluation. The median age of patients at diagnosis was 36 years (range, 27-40 yrs). All patients had regular pretreatment menses, 25 patients (15%) developed long-term amenorrhea, and 141 patients (85%) resumed menstruation. Eighty-two patients (49%) also received tamoxifen: The incidence of amenorrhea among them was 17%. There was a statistically significant association between age and the development of amenorrhea, with older women at higher risk (P < 0.01). CONCLUSIONS: The sequential addition of a taxane to standard adjuvant anthracycline-based chemotherapy did not appear to produce a high rate of chemotherapy-related amenorrhea compared with historic controls. To increase the information available to assist young patients who are considering adjuvant therapy, prospective studies should incorporate menstrual function ascertainment by patient-reported history and assays of ovarian function.

Adult↗
PubMed2005

Risk of ovarian cancer in BRCA1 and BRCA2 mutation-negative hereditary breast cancer families.

Women from site-specific hereditary breast cancer families who carry a BRCA1 or BRCA2 mutation are at increased risk for ovarian cancer. It is less clear, however, whether individuals from hereditary breast cancer families who do not carry such a mutation are also at increased ovarian cancer risk. To determine whether women from BRCA mutation-negative hereditary breast cancer families are at increased risk for ovarian cancer, 199 probands from BRCA mutation-negative, site-specific breast cancer kindreds who consented to prospective follow-up at the time of genetic testing were identified. The incidence of new breast and ovarian cancers in probands and their families since receipt of their genetic test results was determined by questionnaire. The expected number of cancers and standardized incidence ratios (SIRs) were determined from age-specific cancer incidence rates from the Surveillance, Epidemiology, and End Results (SEER) program by using the method of Byar. All statistical tests were two-sided. During 2534 women-years of follow-up in 165 kindreds, 19 new cases of breast cancer were diagnosed, whereas only 6.07 were expected (SIR = 3.13, 95% confidence interval [CI] = 1.88 to 4.89; P < .001), and one case of ovarian cancer was diagnosed, whereas only 0.66 was expected (SIR = 1.52, 95% CI = 0.02 to 8.46; P = .48). These results suggest that women from BRCA mutation-negative, site-specific breast cancer families are not at increased risk for ovarian cancer.

Adult↗
PubMed2005

Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17.

BACKGROUND: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. METHODS: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan-Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. RESULTS: After a median follow-up of 30 months (range = 1.5-61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio [HR] for recurrence or contralateral breast cancer = 0.58, 95% confidence interval [CI] = 0.45 to 0.76; P < .001; distant DFS: HR = 0.60, 95% CI = 0.43 to 0.84; P = .002). Overall survival was the same in both arms (HR for death from any cause = 0.82, 95% CI = 0.57 to 1.19; P = .3). However, among lymph node-positive patients, overall survival was statistically significantly improved with letrozole (HR = 0.61, 95% CI = 0.38 to 0.98; P = .04). The incidence of contralateral breast cancer was lower in women receiving letrozole, but the difference was not statistically significant. Women receiving letrozole experienced more hormonally related side effects than those receiving placebo, but the incidences of bone fractures and cardiovascular events were the same. CONCLUSION: Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease-free survival but not overall survival, except in node-positive patients.

Aged↗
PubMed2005

Comparison of HER2 status by fluorescence in situ hybridization and immunohistochemistry to predict benefit from dose escalation of adjuvant doxorubicin-based therapy in node-positive breast cancer patients.

PURPOSE: HER2 is a clinically important tumor marker in breast cancer; however, there is controversy regarding which method reliably measures HER2 status. We compared three HER2 laboratory methods: immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR), to predict disease-free survival (DFS) and overall survival (OS) after adjuvant doxorubicin-based therapy in node-positive breast cancer patients. METHODS: This is a Cancer and Leukemia Group B (CALGB) study, using 524 tumor blocks collected from breast cancer patients registered to clinical trial CALGB 8541. IHC employed CB11 and AO-11-854 monoclonal antibodies; FISH used PathVysion HER2 DNA Probe kit; PCR utilized differential PCR (D-PCR) methodology. RESULTS: Cases HER2 positive by IHC, FISH and D-PCR were 24%, 17%, and 18%, respectively. FISH and IHC were clearly related (kappa = 64.8%). All three methods demonstrated a similar relationship for DFS and OS. By any method, for patients with HER2-negative tumors, there was little or no effect of dose of adjuvant doxorubicin-based therapy. For patients with HER2-positive tumors, all three methods predicted a benefit from dose-intense (high-dose) compared with low- or moderate-dose adjuvant doxorubicin-based therapy. CONCLUSION: FISH is a reliable method to predict clinical outcome following adjuvant doxorubicin-based therapy for stage II breast cancer patients. There is a moderate level of concordance among the three methods (IHC, FISH, PCR). None of the methods is clearly superior. Although IHC-positive/FISH-positive tumors yielded the greatest interaction with dose of therapy in predicting outcome, no combination of assays tested was statistically superior.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Prospective, randomized comparison of high-dose chemotherapy with stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, and NCIC MA-13.

PURPOSE: The prognosis for women with primary breast cancer involving multiple axillary nodes remains poor. High-dose chemotherapy with stem-cell support produced promising results in initial clinical trials conducted at single institutions. PATIENTS AND METHODS: Seven hundred eighty-five women aged 22 to 66 years with stage IIA, IIB, or IIIA breast cancer involving 10 or more axillary lymph nodes were randomized after surgery and standard adjuvant chemotherapy to either high-dose cyclophosphamide, cisplatin, and carmustine (HD-CPB) with stem-cell support or intermediate-dose cyclophosphamide, cisplatin, and carmustine (ID-CPB) with G-CSF support but without stem cells. Planned treatment for all patients included locoregional radiation therapy. Hormone-receptor-positive patients were to receive 5 years of tamoxifen. Event-free survival (EFS) was the primary end point. RESULTS: Median follow-up was 7.3 years. Event-free survival was not significantly different between the two treatment groups (P = .24). The probability of being free of an event at 5 years with HD-CPB was 61% (95% CI, 56% to 65%), and was 58% (95% CI, 53% to 63%) for ID-CPB. Thirty-three patients died of causes attributed to HD-CPB, compared with no therapy-related deaths among women treated with ID-CPB. Overall survival for the two arms was identical at 71% at 5 years (P = .75). CONCLUSION: HD-CPB with stem-cell support was not superior to ID-CPB for event-free or overall survival among all randomized women with high-risk primary breast cancer.

Adult↗