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Larry Norton

Publications and source records attributed to Larry Norton.

15 recordsLinked to original sources
PubMed2003

Representational oligonucleotide microarray analysis: a high-resolution method to detect genome copy number variation.

We have developed a methodology we call ROMA (representational oligonucleotide microarray analysis), for the detection of the genomic aberrations in cancer and normal humans. By arraying oligonucleotide probes designed from the human genome sequence, and hybridizing with "representations" from cancer and normal cells, we detect regions of the genome with altered "copy number." We achieve an average resolution of 30 kb throughout the genome, and resolutions as high as a probe every 15 kb are practical. We illustrate the characteristics of probes on the array and accuracy of measurements obtained using ROMA. Using this methodology, we identify variation between cancer and normal genomes, as well as between normal human genomes. In cancer genomes, we readily detect amplifications and large and small homozygous and hemizygous deletions. Between normal human genomes, we frequently detect large (100 kb to 1 Mb) deletions or duplications. Many of these changes encompass known genes. ROMA will assist in the discovery of genes and markers important in cancer, and the discovery of loci that may be important in inherited predispositions to disease.

Aneuploidy↗
PubMed2003

Long-term adjustment of survivors of early-stage breast carcinoma, 20 years after adjuvant chemotherapy.

BACKGROUND: The long-term impact of breast carcinoma and its treatment was assessed in 153 breast carcinoma survivors previously treated on a Phase III randomized trial (Cancer and Leukemia Group B [CALGB 7581]) a median of 20 years after entry to CALGB 7581. METHODS: Survivors were interviewed by telephone using the following standardized measures: Brief Symptom Inventory (BSI), PostTraumatic Stress Disorder Checklist with the trauma defined as survivors' response to having had cancer (PCL-C), Conditioned Nausea, Vomiting and Distress, European Organization for Research and Treatment of Cancer QLQ-C30 (quality of life), Life Experience Survey (stressful events), MOS Social Support Survey, comorbid conditions (Older Americans Resources and Services Questionnaire), and items developed to assess long-term breast carcinoma treatment side effects and their interference with functioning. RESULTS: Only 5% of survivors had scores that were suggestive of clinical levels of distress (BSI), 15% reported 2 or more posttraumatic stress disorder (PTSD) symptoms (PCL-C) that were moderately to extremely bothersome, 1-6% reported conditioned nausea, emesis, and distress as a consequence of sights, smells, and tastes triggered by reminders of their treatment, 29% reported sexual problems attributed to having had cancer, 39% reported lymphedema, and 33%, reported numbness. Survivors who reported greater lymphedema and numbness that interfered with functioning had significantly worse PTSD (PCL-C; P = 0.008) com- pared with survivors who reported less lymphedema and numbness. Survivors with a lower level of education (P = 0.026), less adequate social support (P = 0.0033), more severe negative life events (P = 0.0098), and greater dissatisfaction with their medical care (P = 0.037) had worse PTSD compared with other survivors. CONCLUSIONS: Twenty years after the initial treatment, the impact of breast carcinoma on survivors' adjustment was minimal. However, the higher prevalence of PTSD symptoms in response to having had cancer is indicative of continuing psychologic sequelae long after treatment completion. Findings related to lymphedema and numbness and continued symptoms of PTSD suggest that the long-term psychologic and medical sequelae on adjustment may be underrecognized. To establish in more detail whether survivors' overall psychologic state is any different from that of individuals without cancer, a population of community residents without cancer would need to be studied.

Adaptation, Psychological↗
PubMed2003

Natural history of more than 20 years of node-positive primary breast carcinoma treated with cyclophosphamide, methotrexate, and fluorouracil-based adjuvant chemotherapy: a study by the Cancer and Leukemia Group B.

PURPOSE: Breast cancer heterogeneity dictates lengthy follow-up to assess outcomes. Efficacy differences for three regimens that are based on adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) are presented in this article, but cancer recurrence sites, time of relapse, subsequent primary cancers, and causes of death in the natural history of node-positive breast cancer are emphasized. PATIENTS AND METHODS: Beginning in 1975, 905 patients with node-positive cancer were randomly assigned to receive CMF or two regimens of CMF plus other agents. Median follow-up is 22.6 years. The natural-history analysis was performed on a subset of 814 patients. RESULTS: Eighty percent of the 599 women known to have died, died of metastatic breast cancer. Only 8.5% of the deceased women died of a cause other than breast cancer, a second or third cancer, or adjuvant chemotherapy toxicity. One hundred five women (12.8%) developed other primary cancers, with 49 (46.6%) occurring in the contralateral breast. Therapeutic efficacy differences of the CMF regimens reported earlier have been maintained more than 20 years later. For certain subsets, the five-drug regimen had advantages over CMF. Bone was the most common recurrence site. The longest interval to relapse has been 23.5 years, and 18% of those who relapsed did so more than 10 years later. CONCLUSION: Despite adjuvant chemotherapy, a large majority (80%) of women with node-positive breast cancer die of the disease, and many recurrences develop more than 10 years later. CMF plus vincristine and prednisone provides a benefit compared with CMF, but the magnitude varies with the number of involved nodes. Outcome trends in earlier analyses of this study were maintained even years later.

Adult↗
PubMed2003

Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer.

PURPOSE: This study was designed to determine whether increasing the dose of doxorubicin in or adding paclitaxel to a standard adjuvant chemotherapy regimen for breast cancer patients would prolong time to recurrence and survival. PATIENTS AND METHODS: After surgical treatment, 3,121 women with operable breast cancer and involved lymph nodes were randomly assigned to receive a combination of cyclophosphamide (C), 600 mg/m(2), with one of three doses of doxorubicin (A), 60, 75, or 90 mg/m(2), for four cycles followed by either no further therapy or four cycles of paclitaxel at 175 mg/m(2). Tamoxifen was given to 94% of patients with hormone receptor-positive tumors. RESULTS: There was no evidence of a doxorubicin dose effect. At 5 years, disease-free survival was 69%, 66%, and 67% for patients randomly assigned to 60, 75, and 90 mg/m(2), respectively. The hazard reductions from adding paclitaxel to CA were 17% for recurrence (adjusted Wald chi(2) P =.0023; unadjusted Wilcoxon P =.0011) and 18% for death (adjusted P =.0064; unadjusted P =.0098). At 5 years, the disease-free survival (+/- SE) was 65% (+/- 1) and 70% (+/- 1), and overall survival was 77% (+/- 1) and 80% (+/- 1) after CA alone or CA plus paclitaxel, respectively. The effects of adding paclitaxel were not significantly different in subsets defined by the protocol, but in an unplanned subset analysis, the hazard ratio of CA plus paclitaxel versus CA alone was 0.72 (95% confidence interval, 0.59 to 0.86) for those with estrogen receptor-negative tumors and only 0.91 (95% confidence interval, 0.78 to 1.07) for patients with estrogen receptor-positive tumors, almost all of whom received adjuvant tamoxifen. The additional toxicity from adding four cycles of paclitaxel was generally modest. CONCLUSION: The addition of four cycles of paclitaxel after the completion of a standard course of CA improves the disease-free and overall survival of patients with early breast cancer.

Adult↗
PubMed2003

Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741.

PURPOSE: Using a 2 x 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node-positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities. PATIENTS AND METHODS: A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A x 4 (doses) --> T x 4 --> C x 4 with doses every 3 weeks, (II) sequential A x 4 --> T x 4 --> C x 4 every 2 weeks with filgrastim, (III) concurrent AC x 4 --> T x 4 every 3 weeks, or (IV) concurrent AC x 4 --> T x 4 every 2 weeks with filgrastim. RESULTS: A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P =.010), and OS (RR = 0.69; P =.013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens. CONCLUSION: Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.

Adult↗
PubMed2003

Factors influencing treatment patterns of breast cancer patients age 75 and older.

PURPOSES: To retrospectively determine the factors influencing treatment decisions in older breast cancer patients at a single center. EXPERIMENTAL DESIGN: 216 patients age > or = 75 seen in post-treatment follow-up between January, 1997 and June, 2000 were identified in the Memorial Sloan-Kettering breast cancer database. Eligible patients were > or = 75 years old at diagnosis, had a diagnosis of stage I, II, or III breast cancer, and received their follow-up care at Memorial Sloan Kettering Cancer Center. A retrospective chart review was performed. Patients were stratified by: (1) prognostic factors (age (75-79 or > or = 80), Charlson comorbidity score, tumor size, nodal status, stage, ER, PR, creatinine, albumin, hemoglobin, and liver function tests), (2) local treatment (lumpectomy, axillary lymph node dissection (AxLND), radiation (XRT), modified radical mastectomy (MRM)) and (3) systemic treatment (tamoxifen, chemotherapy). Combined local treatment was defined as (a) lumpectomy, AxLND, XRT or (b) MRM, AxLND, XRT (if tumor > or = 5 cm or > or = 4+ lymph nodes). RESULTS: 96 patients were eligible for this study: 46 patients (75-79 years); 50 patients (> or = 80 years). The majority of patients (74%) were treated with lumpectomy but those > or = 80 were less likely to receive XRT (94% age 75-80; 45% age >80; P<0.01). Patients > or = 80 were also less likely to receive AxLND (94% age 75-79; 62% age > or = 80; P<0.01). A logistic regression model identified two independent prognostic variables for not receiving combined local treatment: increased age (P<0.01) and increased comorbidity score (P=0.01). Increased age did not correlate with increased comorbidity (P=0.48). 5.2% of patients received adjuvant chemotherapy (all age <80). 83% of ER positive patients received tamoxifen (89% age 75-79; 79% age >80). CONCLUSION: We hypothesize that both comorbidity and age play a significant role in influencing treatment decisions in the older breast cancer patient but these two variables are not necessarily correlated. Prospective studies are needed to determine the relative impact of these variables.

Age Factors↗
PubMed2002

Prospective exploratory analysis of the association between tumor response, quality of life, and expenditures among patients receiving paclitaxel monotherapy for refractory metastatic breast cancer.

PURPOSE: To prospectively evaluate the association between tumor response, change in quality of life (QoL), and hospital expenditures in patients with metastatic breast cancer (MBC) receiving single-agent paclitaxel. PATIENTS AND METHODS: Eligible patients had bidimensionally measurable MBC and any number of previous therapies, excluding taxane chemotherapy. Paclitaxel was administered by various different infusion schedules. QoL measures were evaluated for each patient at baseline and serially using the Memorial Symptom Assessment Scale (MSAS)-Global Distress Index (GDI) and Functional Assessment of Cancer Therapy-Breast (FACT-B) instruments. Patients were assessed for early (first 6 weeks) and ever changes in QoL parameters. Charges were monitored through the hospital's centralized computer billing system and converted to cost ratios for the analysis. Correlations between response and improvement in QoL were assessed by Fisher's exact test statistic. Associations between improvements in QoL with cost ratios were assessed by logistic regression and likewise between response and cost ratios. RESULTS: Of the 59 patients treated, 50 had sufficient data for comparative analyses. The overall response rate was 24% (all partial responses). Minor responses were observed in 17% of patients, 25% had stable disease, and 29% had progression. Responding patients had significant improvement in QoL as assessed by MSAS-GDI (P =.004) and FACT-B (P =.028). The mean total cost/month ratios for patients experiencing improved GDI QoL scores was 1.31 versus 1.56 for those without QoL benefit (P =.52) and 1.05 versus 1.76 for responders versus nonresponders, respectively (P =.07). CONCLUSION: Patients with evidence of tumor response on paclitaxel had a QoL benefit not observed in nonresponders, and this response was associated with a trend for lower overall costs.

Adult↗
PubMed2002

Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation.

BACKGROUND: Risk-reducing salpingo-oophorectomy is often considered by carriers of BRCA mutations who have completed childbearing. However, there are limited data supporting the efficacy of this approach. We prospectively compared the effect of risk-reducing salpingo-oophorectomy with that of surveillance for ovarian cancer on the incidence of subsequent breast cancer and BRCA-related gynecologic cancers in women with BRCA mutations. METHODS: All women with BRCA1 or BRCA2 mutations identified during a six-year period were offered enrollment in a prospective follow-up study. A total of 170 women 35 years of age or older who had not undergone bilateral oophorectomy chose to undergo either surveillance for ovarian cancer or risk-reducing salpingo-oophorectomy. Follow-up involved an annual questionnaire, telephone contact, and reviews of medical records. The time to cancer in the two groups was compared by Kaplan-Meier analysis and a Cox proportional-hazards model. RESULTS: During a mean follow-up of 24.2 months, breast cancer was diagnosed in 3 of the 98 women who chose risk-reducing salpingo-oophorectomy and peritoneal cancer was diagnosed in 1 woman in this group. Among the 72 women who chose surveillance, breast cancer was diagnosed in 8, ovarian cancer in 4, and peritoneal cancer in 1. The time to breast cancer or BRCA-related gynecologic cancer was longer in the salpingo-oophorectomy group, with a hazard ratio for subsequent breast cancer or BRCA-related gynecologic cancer of 0.25 (95 percent confidence interval, 0.08 to 0.74). CONCLUSIONS: Salpingo-oophorectomy in carriers of BRCA mutations can decrease the risk of breast cancer and BRCA-related gynecologic cancer.

Actuarial Analysis↗
PubMed2002

Assessment of molecular markers of clinical sensitivity to single-agent taxane therapy for metastatic breast cancer.

PURPOSE: The taxanes affect tubulin polymerization and interfere with mitotic transition. A checkpoint blockade at the G(1)-S boundary would be expected to promote taxane-induced apoptotic cell death through a mechanism that may involve p27. Other proposed determinants of clinical taxane sensitivity/resistance include p53, members of the epidermal growth factor receptor (EGFR) superfamily (e.g., HER2, EGFR), and estrogen receptors and progesterone receptors. These molecular markers and their correlation with clinical taxane sensitivity are investigated in this retrospective clinicopathologic study. PATIENTS AND METHODS: We performed immunohistochemistry (IHC) for estrogen receptors, progesterone receptors, HER2, EGFR, p53, and p27 on 144 breast tumor specimens from patients treated for metastatic breast cancer on a series of clinical trials of single-agent taxane chemotherapy for correlation with clinical response (complete or partial response). Patient characteristics that could influence response (i.e., performance status, extent of disease, and prior therapy) were also examined. RESULTS: In univariate analysis, Karnofsky performance status > or = 90% and no prior history of anthracycline therapy correlated with a good clinical response to single-agent taxane (P =.003 and P =.041, respectively). None of the IHC variables tested were predictive of clinical response to taxane therapy, although p27 negativity showed a trend toward significance (P =.075). Concordance between the polyclonal antibody with HercepTest (DAKO, Carpinteria, CA) and the monoclonal antibody CB-11 (BioGenex, San Ramon, CA) was noted (kappa = 0.943); however, neither univariate nor multivariate analysis demonstrated an association between HER2 status and response to taxane chemotherapy. CONCLUSION: The IHC biomarkers studied were not predictive of response to single-agent taxane chemotherapy in patients with metastatic breast cancer. Identification of molecular correlates of taxane response remains an important goal.

Antineoplastic Agents, Phytogenic↗
PubMed2002

Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: evidence for involvement of AP-1 and PEA3.

Markedly increased levels of cyclooxygenase-2 (COX-2) mRNA, protein, and prostaglandin E(2) synthesis were detected in HER-2/neu-transformed human mammary epithelial cells (184B5/HER) compared with its nontransformed partner cell line (184B5). HER-2/neu stimulated COX-2 transcription via the Ras --> Raf --> MAPK pathway. The inductive effects of HER-2/neu were mediated, in part, by enhanced binding of AP-1 (c-Jun, c-Fos, and ATF-2) to the cyclic AMP-response element (-59/-53) of the COX-2 promoter. The potential contribution of the transcription factor PEA3 was also investigated. Elevated levels of PEA3 were detected in 184B5/HER cells. A PEA3 site (-75/-72) was identified juxtaposed to the cyclic AMP-response element. HER-2/neu-mediated activation of the COX-2 promoter was blocked by mutagenizing the PEA3 site or overexpressing antisense to PEA3. To determine whether HER-2/neu status was also a determinant of COX-2 expression in vivo, we compared levels of COX-2 protein in HER-2/neu-positive and -negative human breast cancers. Increased amounts of COX-2 were detected in HER-2/neu-positive tumors. Taken together, these results suggest that closely spaced PEA3 and cyclic AMP-response elements are required for HER-2/neu-mediated induction of COX-2 transcription. The clear relationship between HER-2/neu status and COX-2 expression in human breast tumors suggests that this mechanism is likely to be operative in vivo.

Base Sequence↗
PubMed2002

Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers.

PURPOSE: To prospectively determine the impact of genetic counseling and testing on risk-reduction strategies and cancer incidence in a cohort of individuals at hereditary risk for breast and ovarian cancer. PATIENTS AND METHODS: Two hundred fifty-one individuals with BRCA mutations were identified at a single comprehensive cancer center from May 1, 1995, through October 31, 2000. Uniform recommendations regarding screening and preventive surgery were provided in the context of genetic counseling. Patients were followed for a mean of 24.8 months (range, 1.6 to 66.0 months) using standardized questionnaires, chart reviews, and contact with primary physicians. RESULTS: Frequency of cancer surveillance by physical examinations and imaging studies increased after genetic counseling and testing. Twenty-one breast, ovarian, primary peritoneal, or fallopian tube cancers were detected after receipt of genetic test results. Among 29 individuals choosing risk-reducing mastectomy after testing, two were found to have occult intraductal breast cancers. Among 90 individuals who underwent risk-reducing salpingo-oophorectomy, one early-stage ovarian neoplasm and one early-stage fallopian tube neoplasm were found. Radiographic or tumor marker-based screening detected six breast cancers, five of which were stage 0/I, one early-stage primary peritoneal cancer, and three stage I or II ovarian cancers. Six additional breast cancers were detected by physical examination between radiographic screening intervals; four of these six tumors were stage I. No stage III or stage IV malignancies were detected after genetic testing. CONCLUSION: This study provides prospective evidence that genetic counseling and testing increased surveillance and led to risk-reducing operations, which resulted in diagnosis of early-stage tumors in patients with BRCA1 and BRCA2 mutations.

Adult↗
PubMed2002

Association of angiogenesis and disease outcome in node-positive breast cancer patients treated with adjuvant cyclophosphamide, doxorubicin, and fluorouracil: a Cancer and Leukemia Group B correlative science study from protocols 8541/8869.

PURPOSE: Increased microvessel density (MVD), a reflection of tumor angiogenesis, is associated with diminished relapse-free and overall survival (OS) in several subsets of breast cancer patients. However, the utility of this assay in node-positive patients treated with adjuvant cyclophosphamide, doxorubicin, and fluorouracil (CAF) has not been well studied. PATIENTS AND METHODS: Immunostaining for factor VIII-related antigen was performed on tissue sections from a subset of node-positive patients who received one of three dose/schedule regimens of CAF during participation in Cancer and Leukemia Group B protocol 8541. Sections from 577 cancers exhibited acceptable tumor and immunostaining quality and were included in the study. Each section was examined quantitatively for MVD as well as non-quantitatively by scoring the presence or absence of a prominent vascular pattern. RESULTS: MVD counts were not associated with relapse-free or OS in univariate analysis. The presence of a prominent plexiform vascular pattern was correlated with decreased OS (P =.0085) in univariate analysis, but this pattern was not an independent prognostic indicator of survival in multivariate analysis. No apparent clinically important interactions between measures of angiogenesis, other prognostic factors, administration of tamoxifen, and chemotherapy dose were observed. CONCLUSION: Assessment of angiogenesis does not provide useful information regarding prognosis in node-positive breast cancer patients treated with adjuvant CAF, nor do these measures predict which patients will benefit from dose intensification or addition of tamoxifen.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

High-dose versus standard chemotherapy in metastatic breast cancer: comparison of Cancer and Leukemia Group B trials with data from the Autologous Blood and Marrow Transplant Registry.

PURPOSE: To assess survival of patients with metastatic breast cancer treated with high-dose chemotherapy (HDC) versus standard-dose chemotherapy (SDC). PATIENTS AND METHODS: SDC in four Cancer and Leukemia Group B (CALGB) trials was compared with hematopoietic stem-cell support in patients from the Autologous Blood and Marrow Transplant Registry. Cox proportional hazard regression incorporated potentially confounding effects. A total of 1,509 women were enrolled onto CALGB trials, and 1,188 women received HDC. No significant survival differences existed by CALGB trial or HDC regimen. Consideration was restricted to candidates for both SDC and HDC. The resulting sample included 635 SDC and 441 HDC patients. The outcome of interest was overall survival. RESULTS: The HDC group displayed better performance status. The SDC group had slightly better survival in first year after treatment. The HDC group had lower hazard of death from years 1 to 4 and had somewhat higher probability of 5-year survival (adjusted probabilities [95% confidence intervals], 23% [17% to 29%] v 15% [11% to 19%], P =.03). CONCLUSION: After controlling for known prognostic factors in this nonrandomized analysis of two large independent data sets, women receiving HDC versus SDC for metastatic breast cancer have a similar short-term probability of survival, and might have a modestly higher long-term probability of survival.

Adult↗
PubMed1995

Rapidly cycled courses of high-dose alkylating agents supported by filgrastim and peripheral blood progenitor cells in patients with metastatic breast cancer.

Our purpose was to determine the feasibility of a regimen of multiple, rapidly cycled courses of high-dose alkylating agents, including paired courses of escalating doses of thiotepa, supported by peripheral blood progenitor cells and filgrastim, in patients with responding stage IV breast cancer. The regimen consisted of two courses of cyclophosphamide (3.0 g/m2/course) followed by two courses of thiotepa (500-700 mg/m2/course). All courses were supported by filgrastim. Leukaphereses were performed after each cyclophosphamide course to harvest peripheral blood progenitors (PBPs) for use as rescue following thiotepa administration. The planned interval for all courses was 14 days. Forty-two patients were enrolled. Thirty-eight received all four courses, and four did not receive the second thiotepa cycle due to poor PBP mobilization. The maximum dose of thiotepa that was administered was 700 mg/m2 x 2. At this dose, one patient developed encephalopathy, which resolved over several weeks. The median number of days to an absolute neutrophil count of 0.5 x 10(9)/liter after PBP reinfusion for cycles 1 and 2 of thiotepa were 9 (range, 7-16) and 9 (range, 8-13) days, respectively. The corresponding values for platelet recovery to >20 x 10(9)/liter were 11 (range, 8-39) and 12 (range, 10-28) days, respectively. There were no treatment-related deaths. Hospitalization was required following 28 of 84 cyclophosphamide courses and 76 of 80 thiotepa courses. Four patients developed grade III-IV mucositis. The median interval between courses of treatment was 15 (range, 13-29) days. Of 19 patients who entered the protocol with measurable disease in partial response from prior therapy, 8 (42%) achieved complete response following the high-dose therapy. Nine (21%) of 42 remain progression free at a median follow-up of 28 (range, 20-32) months. Therefore, we concluded that the administration of multiple, rapidly cycled courses of high-dose alkylating agents is feasible.

Adult↗