Older-Patient-Specific Cancer Trials: A Pooled Analysis of 2,277 Patients (A151715).

BACKGROUND: Less than 3% of older patients with cancer are enrolled in clinical trials. To reverse this underrepresentation, we compared older patients enrolled with older-patient-specific trials, defined as those designed for older patients with cancer, with those enrolled in age-unspecified trials. MATERIALS AND METHODS: We focused on individual patient data from those ≥65 years (younger patients excluded) and included all Alliance phase III adjuvant breast cancer trials from 1985-2012. RESULTS: Among 2,277 patients, 1,014 had been enrolled to older-patient-specific and 1,263 to age-unspecified trials. The median age (range) in the older-patient-specific trials was 72 (65-89) years compared with 68 (65-84) years in the cohort of older patients in age-unspecified trials; p < .0001. A greater percentage of patients 75 years or older had enrolled in older-patient-specific trials compared with the cohort of age-unspecified trials: 26% versus 6% (p < .0001). Median overall survival (OS) was 12.8 years (95% confidence interval [CI], 11.9-13.7) and 13.5 years (95% CI, 12.9-14.1) for older-patient-specific and age-unspecified trials, respectively. OS was comparable (hazard ratio [HR], 1.08; 95% CI, 0.92-1.28; p = .34; referent: age-unspecified trials), after adjusting for age, estrogen receptor status, tumor size, and lymph node status. Similar findings were reached for recurrence-free survival. A lower rate of grade 3-5 adverse events (hematologic and nonhematologic) was reported in older-patient-specific trials (43% vs. 58%; p < .0001). Sensitivity analysis with chemotherapy only trials and subset analysis, adjusted for performance score, yielded similar OS results. CONCLUSION: Older-patient-specific trials appear to address this underrepresentation of older patients with ostensibly comparable outcomes. Clinical trial identification numbers. NCT00003088 (CALGB 9741); NCT00024102 (CALGB 49907); NCT00068601 (CALGB 40401); NCT00005970 (NCCTG N9831) IMPLICATIONS FOR PRACTICE: This work underscores the importance of clinical trials that focus on the recruitment of older patients with cancer.

Bi-specific and tri-specific antibodies- the next big thing in solid tumor therapeutics.

Antibody-based therapy has revitalized the world of cancer therapeutics since rituximab was first approved for the treatment of Non-Hodgkin's Lymphoma. Monoclonal antibodies against cancer antigens have been successful strategies for only a handful of cancer types due to many reasons including lack of antibody specificity and complex nature of tumor milieu which interfere with antibody efficacy. Polyspecific antibodies are promising class of anti-cancer agents which can be directed at multiple tumor antigens to eradicate tumor cells more precisely and effectively. They may overcome some of these limitations and have already changed treatment landscape for some malignancies such as B cell acute lymphoblastic leukemia. Pre-clinical studies and early phase clinical trials have demonstrated that this approach may be an effective strategy even for solid tumors. This review focuses on the development of bispecific and trispecific antibody therapy for the treatment of solid tumor malignancies and highlights the potential they hold for future therapies to come.

Adjuvant ovarian function suppression and cognitive function in women with breast cancer.

BACKGROUND: To examine the effect on cognitive function of adjuvant ovarian function suppression (OFS) for breast cancer. METHODS: The Suppression of Ovarian Function (SOFT) trial randomised premenopausal women with hormone receptor-positive breast cancer to 5 years adjuvant endocrine therapy with tamoxifen+OFS, exemestane+OFS or tamoxifen alone. The Co-SOFT substudy assessed objective cognitive function and patient reported outcomes at randomisation (T0), and 1 year later (T1); the primary endpoint was change in global cognitive function, measured by the composite objective cognitive function score. Data were compared for the pooled tamoxifen+OFS and exemestane+OFS groups vs the tamoxifen alone group using the Wilcoxon rank-sum test. RESULTS: Of 86 participants, 74 underwent both T0 and T1 cognitive testing; 54 randomised to OFS+ either tamoxifen (28) or exemestane (26) and 20 randomised to tamoxifen alone. There was no significant difference in the changes in the composite cognitive function scores between the OFS+ tamoxifen or exemestane groups and the tamoxifen group (mean±s.d., -0.21±0.92 vs -0.04±0.49, respectively, P=0.71, effect size=-0.20), regardless of prior chemotherapy status, and adjusting for baseline characteristics. CONCLUSIONS: The Co-SOFT study, although limited by small samples size, provides no evidence that adding OFS to adjuvant oral endocrine therapy substantially affects global cognitive function.

Immune checkpoint inhibitors in lung cancer: past, present and future.

Inhibitory ligands on tumor cells and their corresponding receptors on T cells are collectively called immune checkpoint molecules and have emerged as druggable targets that harness endogenous immunity to fight cancer. Immune checkpoint inhibitors targeting CTLA-4, PD-1 and PD-L1 have been developed for the treatment of patients with non-small-cell lung cancer and other malignancies, with impressive clinical activity, durable responses and a favorable toxicity profile. This article reviews the development, current status and future directions for some of these agents. The efficacy and safety data for drugs such as ipilimumab, nivolumab, pembrolizumab, atezolizumab and durvalumab are reviewed, along with combination strategies and response evaluation criteria. The toxicity profiles and predictive biomarkers of response are also discussed.

Trastuzumab-DM1: a clinical update of the novel antibody-drug conjugate for HER2-overexpressing breast cancer.

Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Although trastuzumab is a very active agent in HER2-overexpressing breast cancer, the majority of patients with metastatic HER2-overexpressing breast cancer who initially respond to trastuzumab develop resistance within 1 year of initiation of treatment and, in the adjuvant setting, progress despite trastuzumab-based therapy. The antibody-drug conjugate trastuzumab-DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1 (N-methyl-N-[3-mercapto-1-oxopropyl]-l-alanine ester of maytansinol), a maytansine derivative, to HER2-overexpressing breast cancer cells. T-DM1 is the first antibody-drug conjugate with a nonreducible thioether linker in clinical trials. Phase I and II clinical trials of T-DM1 as a single agent and in combination with paclitaxel, docetaxel and pertuzumab have shown clinical activity and a favorable safety profile in patients with HER2-positive metastatic breast cancer. Two randomized phase III trials of T-DM1 are awaiting final results; the EMILIA trial is evaluating T-DM1 compared with lapatinib plus capecitabine, and early positive results have been reported. The MARIANNE trial is evaluating T-DM1 plus placebo versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane. Here, we summarize evidence from clinical studies and discuss the potential clinical implications of T-DM1.

The evolving use of arsenic in pharmacotherapy of malignant disease.

For more than 2,000 years, arsenic and its derivatives have shown medical utility. Owing to the toxicities and potential carcinogenicity of arsenicals, their popularity has fluctuated. The exact mechanism of action of therapeutic arsenic is not well characterized but likely to involve apoptosis, generation of reactive oxygen species, inhibition of intracellular transduction pathways, and cell functions. Arsenic trioxide has received approval for use in patients with relapsed acute promyelocytic leukemia for remission induction. Arsenic has additionally shown activity in a range of solid tumors, myelodysplastic syndrome, multiple myeloma, and in autoimmune diseases. The following is a review of the history of arsenic, its cellular metabolism, pharmacology, genetic basis of disposition, associated toxicities, and clinical efficacy.

Identification of unique synergistic drug combinations associated with downexpression of survivin in a preclinical breast cancer model system.

An in-vitro 72-h assay using median effect analysis and curve shift analysis was used to evaluate the utility of potentially clinically useful combinations of agents for synergism or antagonism. Six human breast cancer cell lines, both receptor rich and receptor poor, were studied.Panobinostat (LBH-589), a pan histone deacetylase inhibitor with a multitude of biological effects, exhibits time-dependent synergistic effects in breast cancer cell lines with docetaxel, doxorubicin, or gemcitabine in clinically relevant concentrations. Survivin expression was markedly downregulated in the presence of panobinostat with gemcitabine. Bortezomib, a proteasome inhibitor,markedly enhanced the cytotoxic effects of panobinostat combined with gemcitabine. Panobinostat did not demonstrate universal enhancement of cytotoxic drugs,and therefore, synergy was dependent on the second agent selected. No synergy was noted with anti-Her2 agents in Her2 overexpressing cell lines. Metformin combined with panobinostat demonstrated no synergy in this test system. These effects were confirmed by an apoptosis assay and caspase-3 production. A positive drug interaction was identified. The triplet of panobinostat with either doxorubicin/carboplatin or gemcitabine/carboplatin was especially potent in all cell lines. As all these agents are clinically available, further studies of the potent combinations are warranted.

Investigating the benefit of adding a vena cava filter to anticoagulation with fondaparinux sodium in patients with cancer and venous thromboembolism in a prospective randomized clinical trial.

BACKGROUND: The benefit of adding a vena cava filter to anticoagulation in treating cancer patients with venous thromboembolism remains controversial. We initiated this study as the first prospectively randomized trial to evaluate the addition of a vena cava filter placement to anticoagulation with the factor Xa inhibitor fondaparinux sodium in patients with cancer. METHODS: Sixty-four patients with deep vein thrombosis (86 %) and/or pulmonary embolism (55 %) were randomly assigned to receive anticoagulation with fondaparinux sodium with or without a vena cava filter. Endpoints included rates of complications by treatment arm, recurrent thromboembolism, complete resolution of thromboembolism, and survival rates. RESULTS: No patient had a recurrent deep vein thrombosis; two (3 %) patients had new pulmonary emboli, one in each randomized cohort. Major bleeding occurred in three patients (5 %). Two patients on the vena cava filter arm (7 %) had complications from the filter. Median survivals were 493 days in the anticoagulation only arm and 266 days for anticoagulation + vena cava filter (p < 0.57). Complete resolution of venous thromboembolism occurred in 51 % of patients within 8 weeks of initiating anticoagulation. CONCLUSIONS: No advantage was found for placement of a vena cava filter in addition to anticoagulation with fondaparinux sodium in terms of safety, recurrent thrombosis, recurrent pulmonary embolism, or survival in this prospective randomized trial evaluating anticoagulation plus a vena cava filter in cancer patients. Favorable complete resolution rates of thrombosis were observed on both study arms.

The pharmacokinetics of therapeutic arsenic trioxide in acute promyelocytic leukemia patients.

Arsenic trioxide (ATO) treats Acute Promyelocytic Leukemia (APL). ATO is converted from inorganic arsenic (iAs) to methylated (MAs) and dimethylated (DMAs) metabolites, which are excreted in the urine. Methylation of iAs is important in detoxification, as iAs exposure is deleterious to health. We examined ATO metabolism in 25 APL patients, measuring iAs, MAs, and DMAs. Plasma total iAs increased after ATO administration, followed by a rapid decline, reaching trough levels by 4-6 h. We identified two patterns of iAs metabolism between 6 and 24 h after infusion: in Group 1, iAs increased and were slowly converted to MAs and DMAs, whereas in Group 2, iAs was rapidly metabolized. These patterns were associated with smoking and different treatments: ATO with all-trans retinoic acid (ATRA) alone vs. ATO preceded by ATRA and chemotherapy. Our data suggest that smoking and prior chemotherapy exposure may be associated with ATO metabolism stimulation, thus lowering the effective blood ATO dose.

Poly(ADP-ribose) polymerase-1 inhibition: preclinical and clinical development of synthetic lethality.

The hereditary forms of breast cancer identified by BRCA1 and BRCA2 genes have a defect in homologous DNA repair and demonstrate a dependence on alternate DNA repair processes by base excision repair, which requires poly(ADP-ribose) polymerase 1 (PARP-1). siRNA and deletion mutations demonstrate that interference with PARP-1 function results in enhanced cell death when the malignancy has a defect in homologous recombination. These findings resulted in a plethora of agents in clinical trials that interfere with DNA repair, and these agents offer the potential of being more selective in their effects than classic chemotherapeutic drugs. An electronic search of the National Library of Medicine for published articles written in English used the terms "PARP inhibitors" and "breast cancer" to find prospective, retrospective and review articles. Additional searches were done for articles dealing with mechanism of action. A total of 152 articles dealing with breast cancer and PARP inhibition were identified. PARP inhibition not only affects nonhomologous repair, but also has several other nongenomic functions. Mutational resistance to these agents was seen in preclinical studies. To date, PARP-1 inhibitors were shown to enhance cytotoxic effects of some chemotherapy agents. This new class of agents may offer more therapeutic specificity by exploiting a DNA repair defect seen in some human tumors with initial clinical trials demonstrating antitumor activity. Although PARP inhibitors may offer a therapeutic option for selected malignancies, the long-term effects of these agents have not yet been defined.

The histone deacetylase inhibitor panobinostat demonstrates marked synergy with conventional chemotherapeutic agents in human ovarian cancer cell lines.

Although platinum based therapy has improved short term survival of patients with metastatic ovarian cancer, the majority of patients continue to relapse and eventually die of their disease. Currently, a plethora of agents are in development, but how to combine them to enhance efficacy remains largely empiric. We have used short in vitro culture of defined cell lines with application of promising agents and analysis for cell death using a MTT assay to identify potentially useful combinations. Using median effect analysis, curve shift analysis and apoptosis assays, we can identify when agents are synergistic or antagonistic when applied together. Up to three agents can be studied in combination. Using three cell lines: SK-OV3, CaOV-3, and ES-2 (a clear cell tumor), we have identified that panobinostat (LBH-589), a broad histone deacetylase inhibitor in clinical trials, demonstrates global synergy with gemcitabine, with paclitaxel, and additive to synergistic effects with 5'DFUR. The triplet of panobinostat, doxorubicin, and carboplatin is especially synergistic in these cell lines. These effects are cytotoxic and not cytostatic. As all these agents are used clinically, we have identified combinations which warrant further investigation.

Hypersensitivity to oxaliplatin: an investigation of incidence and risk factors, and literature review.

BACKGROUND: Hypersensitivity is a well-known complication of the platinum agents cisplatin and carboplatin. Although hypersensitivity to oxaliplatin has been noted, the incidence varies significantly in reports. Risk factors for developing reactions specifically to oxaliplatin have not been evaluated. We report the 5-year incidence of hypersensitivity to oxaliplatin in our clinical program, the patient and disease characteristics associated with its occurrence, and review the literature. METHODS: Clinical information on all patients treated with oxaliplatin between September 2002 and August 2007 was retrospectively reviewed. Data from patients who experienced hypersensitivity were compared to patients treated with this agent who did not. Risk factors investigated included age, sex, diagnosis, disease stage, presence of preexisting allergies, chemotherapy received, and use of oxaliplatin in front-line versus salvage therapy. RESULTS: 247 patients received oxaliplatin, with 29 experiencing hypersensitivity, for an incidence of 11.7% (95% CI 7.7-15.8). Grade 3/4 events occurred in 1.6%. Hypersensitivity was associated with younger mean age (54.9 +/- 12.5 vs. 60.4 +/- 12.4 years with reactions vs. those without, p = 0.02), female gender (17.2% of females vs. 6.4% of males, p = 0.01) and with use of oxaliplatin as salvage therapy (23.9% second-line or higher vs. 9.1% front-line, p = 0.01). CONCLUSIONS: Our data demonstrate an incidence of hypersensitivity to oxaliplatin of 11.7%, with grade 3/4 events in 1.6%. As use of this agent becomes more widespread, increased vigilance for this potentially serious complication should be high, especially amongst younger patients, females, and with the use of oxaliplatin as salvage therapy; three newly recognized potential risk factors.

Adjuvant chemotherapy for early breast cancer in the elderly.

The use of cytotoxic therapy in the fit elderly breast cancer patient has been tempered with concerns of age, physical function, and co-morbid illness. In the appropriate patient with biologically aggressive disease, such as receptor poor breast cancer, it is reasonable to consider combination chemotherapy as part of an adjuvant program. If this approach is to be employed, the physician must also consider the patient's co-morbid conditions and status of function in society as potential indicators of toxicity or lack of benefit. In this case, a formal geriatric assessment is of value. A Cancer and Leukemia Group B (CALGB) trial of monotherapy vs combination cytotoxic therapy as adjuvant treatment for localized breast cancer patients over 65 years of age has determined that the combination approach is superior to single agent therapy. In an unplanned analysis of receptor rich and receptor poor tumors, the patients with receptor poor tumors seemed to achieve the greatest benefit from combination cytotoxic therapy. Adjuvant chemotherapy can also be considered for patients with high-risk receptor rich breast cancers. However, the use of chemotherapy in the elderly patient with breast cancer is largely based upon data emerging from trials in younger patients. Studies specifically for patients over 65 years of age are urgently needed in this population to provide evidence-based proof of the current approach.

Need for inferior vena cava filters in cancer patients: a surrogate marker for poor outcome.

BACKGROUND: Cancer patients have an increased incidence of venous thromboembolism (VTE). Inferior vena cava (IVC) filters are used extensively in the US, and more than 40 000 are inserted annually. The impact on survival of cancer patients receiving IVC filters has not been studied. METHODS: A retrospective study examined 206 consecutive cancer patients with VTE to compare the effects of IVC filter placement with anticoagulation (AC) therapy on overall survival (OS), as measured from the time of VTE. Patients were classified into 3 treatment groups: AC (n = 62), IVC filter (77), or combination IVC filter + AC (67). RESULTS: Treatment groups did not differ with respect to age, sex, or albumin levels. Median OS was significantly greater in patients treated with AC (13 months) compared with those treated with IVC filters (2 months) or IVC + AC (3.25 months; P < .0002). IVC patients were 1.9 times more at risk of death than AC only (hazard ratio = .528; 95% confidence interval = .374 to .745). Multivariate analysis revealed that performance status and type of thrombus were not confounders and had no effect on OS. CONCLUSION: The need for the insertion of an IVC filter projected markedly reduced survival. Patients requiring an IVC filter rather than AC as initial therapy face a 2-fold increase in risk of death. Whether or not this therapeutic procedure has a positive impact on outcome in cancer patients is uncertain. Complications resulting from thrombosis were also analyzed in this cohort. A prospective randomized trial at our institution is addressing this issue.

Phase I and pharmacokinetic study of LY293111, an orally bioavailable LTB4 receptor antagonist, in patients with advanced solid tumors.

PURPOSE: LY293111, a novel diaryl ether carboxylic acid derivative, is a potent and selective inhibitor of the lipoxygenase pathway either directly through 5'-lipoxygenase or via antagonism of the leukotriene B4 (LTB4) receptor. More recently it has been determined to have peroxisome proliferator activated receptor-gamma agonist (PPARgamma) activity. LY293111 has antineoplastic activity in a variety of preclinical models. The tolerability and pharmacokinetics of LY293111 administered continuously, by mouth, BID for repeat cycles of 21 days was evaluated. PATIENTS AND METHODS: Thirty-eight patients with advanced solid tumors were treated at five dose levels (200 to 800 mg BID) for a total of 102 cycles. RESULTS: The most common toxicity was diarrhea (76%). One patient at 600 mg BID (n = 11) and two at 800 mg BID (n = 8), experienced dose-limiting grade 3 diarrhea. Dose reductions and/or delays were infrequent. Increases in steady-state maximum plasma concentration (Cmax,ss) and area under the steady-state plasma concentration time curve 0 to 12 hours (AUCtau,ss) on day 8 could be considered to be dose-proportional over the four-fold-dose range. Interpatient variability in Cmax,ss and AUCtau,ss was estimated to be 65% and 71% respectively. There was a small increase in AUC (1.37; 90% CI, 0.85 to 2.21) between single and multiple doses. Two patients with progressive chondrosarcoma and melanoma had stable disease lasting approximately 336 and 168 days, respectively. CONCLUSION: LY293111 can be administered safely by continuous oral therapy with mild toxicities. Diarrhea is dose-limiting. The recommended phase II dose will be 600 mg BID. The steady-state concentrations in humans exceed relevant levels observed in preclinical models.

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.

TSP50, a possible protease in human testes, is activated in breast cancer epithelial cells.

Initial studies have identified TSP50 as a human testes-specific gene that is demethylated in breast cancer. In this study, we will present new data related to the TSP50 gene. We have found that the TSP50 gene product shares a similar enzymatic structure with many serine proteases. However, the most critical catalytic site, serine, has been replaced by threonine. Western analysis revealed that in human testes, the TSP50 antibody detected two closely positioned protein bands whose estimated molecular masses were 37 kDa, whereas in a large portion of breast cancer tissues, but not normal control tissues, only one band was present. Immunohistochemistry assays found TSP50 proteins located in the spermatocytes of human testes, whereas in situ hybridization and immunohistochemistry confirmed that gene activation in breast tumors took place in malignant mammary epithelial cells. These results suggested that the normal function of the TSP50 gene was involved in spermatogenesis, whereas the up-regulation of TSP50 in many breast cancer patients not only indicated that it might be a novel biomarker for this disease but also encouraged us to further explore the possibility of whether it was an oncogene.

WTH3, a new member of the Rab6 gene family, and multidrug resistance.

The WTH3 gene was obtained by a DNA fragment isolated by the methylation-sensitive representational difference analysis technique due to its hypermethylation in the human multidrug resistant (MDR) breast cancer cell line MCF7/AdrR. The WTH3 gene product is 89% and 91% identical to the human Rab6 and Rab6c proteins, but possesses an elongated C-terminal region which contains 46 extra amino acids. Nevertheless, we consider the WTH3 gene a new member of the Rab6 gene family. Semi-quantitative reverse transcriptase-polymerase chain reaction results showed that WTH3 was 15 and 4 times downregulated in MCF7/AdrR and MES-SA/Dx5, a human MDR uterine sarcoma cell line, as compared to their non-MDR parental cell lines. Permanent expression of the WTH3 transgene in MDR cell lines increased to varying degrees their sensitivity to several anticancer drugs, which included doxorubicin, taxol, vinblastine, vincristine, and etoposide, as compared to the control sublines transfected with the empty vector. Flow cytometry and fluorescence microscope experiments suggest that the WTH3 transgene stimulated the host's uptake and retention of DOX. Our results imply that the WTH3 gene plays a role(s) in MDR phenotype development in vitro.

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.