The 21-gene Recurrence Score® assay predicts distant recurrence in lymph node-positive, hormone receptor-positive, breast cancer patients treated with adjuvant sequential epirubicin- and docetaxel-based or epirubicin-based chemotherapy (PACS-01 trial).

BACKGROUND: The 21-gene Recurrence Score (RS) result predicts outcome and chemotherapy benefit in node-negative and node-positive (N+), estrogen receptor-positive (ER+) patients treated with endocrine therapy. The purpose of this study was to evaluate the prognostic impact of RS results in N+, hormone receptor-positive (HR+) patients treated with adjuvant chemotherapy (6 cycles of FEC100 vs. 3 cycles of FEC100 followed by 3 cycles of docetaxel 100 mg/m2) plus endocrine therapy (ET) in the PACS-01 trial (J Clin Oncol 2006;24:5664-5671). METHODS: The current study included 530 HR+/N+ patients from the PACS-01 parent trial for whom specimens were available. The primary objective was to evaluate the relationship between the RS result and distant recurrence (DR). RESULTS: There were 209 (39.4%) patients with low RS (< 18), 159 (30%) with intermediate RS (18-30) and 162 (30.6%) with high RS (≥ 31). The continuous RS result was associated with DR (hazard ratio = 4.14; 95% confidence interval: 2.67-6.43; p <  0.001), adjusting for treatment. In multivariable analysis, the RS result remained a significant predictor of DR (p <  0.001) after adjustment for number of positive nodes, tumor size, tumor grade, Ki-67 (immunohistochemical status), and chemotherapy regimen. There was no statistically significant interaction between RS result and treatment in predicting DR (p = 0.79). CONCLUSIONS: After adjustment for clinical covariates, the 21-gene RS result is a significant prognostic factor in N+/HR+ patients receiving adjuvant chemoendocrine therapy. TRIAL REGISTRATION: Not applicable.

The Impact of the Oncotype DX Breast Cancer Assay on Treatment Decisions for Women With Estrogen Receptor-Positive, Node-Negative Breast Carcinoma in Hong Kong.

BACKGROUND: The Oncotype DX Breast Cancer Assay is validated to assess risk of distant recurrence and likelihood of chemotherapy (CT) benefit in estrogen receptor-positive ESBC in various populations. In Hong Kong, > 80% of breast cancers are early stage breast cancer (ESBC) and > 60% of these women receive CT. This prospective study measured changes in CT type and recommendations, as well as physician impression of assay impact in a homogenous Chinese population. METHODS: Consecutive patients with estrogen receptor-positive, T1-3 N0-1mi M0 ESBC were offered enrollment. After surgery, physicians discussed treatment options with patients, then ordered the assay, then reassessed treatment recommendation considering assay results. Changes in treatment recommendation, CT utilization, physician confidence, and physician rating of influence on their treatment recommendations were measured. RESULTS: A total of 146 evaluable patients received pre- and post-testing treatment recommendations. CT recommendations (including changes in intensity of CT) were changed for 34 of 146 patients (23.3%; 95% confidence interval, 16.7%-31.0%); change in intensity occurred in 7 of 146 (4.8%). There were 27 changes in treatment recommendations of adding or removing CT altogether (18.5% change; 95% confidence interval, 12.6%-25.8%). CT recommendations decreased from 52.1% to 37.7%, a net absolute reduction of 14.4% (P < .001; 27.6% net relative reduction). Pre-assay, 96% of physicians agreed/strongly agreed that they were confident in their treatment recommendation; post-assay, 90% of physicians agreed/strongly agreed with the same statement. Thirty percent of physicians agreed/strongly agreed that the test had influenced their recommendation, similar to the proportion of changed recommendations. CONCLUSIONS: The Oncotype DX Assay appears to influence physician ESBC adjuvant treatment recommendations in Hong Kong.

Quantitative Gene Expression by Recurrence Score in ER-Positive Breast Cancer, by Age.

INTRODUCTION: Breast cancer in young women (<50 years) has been associated with an increased risk of recurrence and decreased survival compared with patients older than 50. The objective of this analysis was to determine, from a large database of patients with early-stage breast cancer, if the Recurrence Score(®) result (Oncotype DX(®), Genomic Health, Inc, Redwood City, CA, USA) provided clinically meaningful differences in predicted risk of recurrence in younger-compared with older-patients. METHODS: Tumor samples from patients with estrogen receptor (ER)-positive breast cancers that were successfully processed in the Genomic Health central lab between June 2004 and December 2013 for Recurrence Score and quantitative gene expression of ER, progesterone receptor (PR), and Her/2neu, were included. Descriptive statistics were used to describe the distribution of scores by age group: <40, 40-49, 50-59, 60-69, and ≥70 years, nodal status, and histologic subtype. RESULTS: Specimens from 394,031 patients [3.3% (n = 13,029) aged <40 years; 15.6% (n = 61,643) aged ≥70 years] were included; 81.6% of patients had invasive ductal carcinoma. Nodal status was specified for 362,001 patients (87.0% negative). Median Recurrence Score results were similar across risk groups. Low (<18)- and high (≥31)- risk Recurrence Score results were seen in 58.5% and 8.5% of patients, respectively. A greater proportion of patients aged <40 (14.1%) than ≥70 (8.8%) years had a high-risk score. ER expression increased as a function of age and PR single-gene and invasion gene group expression were similar across age groups. CONCLUSION: These data indicate that in patients with ER-positive breast cancer, age alone does not reflect the underlying individual tumor biology, suggesting that the Recurrence Score result may add potentially useful information for personalized treatment decisions. FUNDING: Genomic Health, Inc.

A phase II trial of ixabepilone and cyclophosphamide as neoadjuvant therapy for patients with HER2-negative breast cancer: correlation of pathologic complete response with the 21-gene recurrence score.

Ixabepilone and the taxanes have similar activity in the first-line treatment of metastatic breast cancer, and ixabepilone is sometimes effective in taxane-refractory patients. We conducted a phase 2 trial to evaluate ixabepilone in combination with cyclophosphamide as neoadjuvant treatment for patients with locally advanced HER2-negative breast cancer. Response to neoadjuvant treatment was correlated with the baseline 21-gene Recurrence Score® (Oncotype DX; Genomic Health Inc, Redwood City, CA). Eligible women with HER2-negative locally advanced breast cancer received ixabepilone 40 mg/m(2) plus cyclophosphamide 600 mg/m(2) on day 1 of each 21-day cycle. Following 6 cycles, patients underwent definitive surgery. Primary endpoint was rate of pathologic complete response (pCR). Breast biopsy tumor samples were obtained at pretreatment and at surgery in patients with residual disease. Tumor specimens were analyzed using the 21-gene assay. One hundred sixty-eight patients (median age 52 years; 45 % triple-negative) were enrolled; 161 (96 %) underwent definitive surgery following neoadjuvant ixabepilone/cyclophosphamide. Overall, 27 patients (17 %) achieved pCR, including 19 of 73 (26 %) triple-negative patients. The most frequently occurring grade 3/4 toxicity was neutropenia (98 patients; 58 %). Recurrence Scores were highly correlated with achievement of pCR (0/36 with low or intermediate Recurrence Scores vs. 19/72 with high Recurrence Scores; p = 0.002). There was high concordance between baseline and post-treatment Recurrence Scores in the 72 patients with paired samples. The combination of ixabepilone and cyclophosphamide yielded a pCR rate of 17 %, similar to other neoadjuvant chemotherapy regimens. Pathologic complete responses occurred only in patients with high-risk baseline Recurrence Scores.

The relationship between quantitative human epidermal growth factor receptor 2 gene expression by the 21-gene reverse transcriptase polymerase chain reaction assay and adjuvant trastuzumab benefit in Alliance N9831.

INTRODUCTION: The N9831 trial demonstrated the efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) locally positive tumors by protein or gene analysis. We used the 21-gene assay to examine the association of quantitative HER2 messenger RNA (mRNA) gene expression and benefit from trastuzumab. METHODS: N9831 tested the addition of trastuzumab to chemotherapy in stage I-III HER2-positive breast cancer. For two of the arms of the trial, doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) and doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab concurrent chemotherapy-trastuzumab (AC-TH), recurrence score (RS) and HER2 mRNA expression were determined by the 21-gene assay (Oncotype DX®) (negative <10.7, equivocal 10.7 to <11.5, and positive ≥11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with trastuzumab benefit in preventing distant recurrence. RESULTS: Median follow-up was 7.4 years. Of 1,940 total patients, 901 had consent and sufficient tissue. HER2 by reverse transcriptase polymerase chain reaction (RT-PCR) was negative in 130 (14 %), equivocal in 85 (9 %), and positive in 686 (76 %) patients. Concordance between HER2 assessments was 95 % for RT-PCR versus central immunohistochemistry (IHC) (>10 % positive cells = positive), 91 % for RT-PCR versus central fluorescence in situ hybridization (FISH) (≥2.0 = positive) and 94 % for central IHC versus central FISH. In the primary analysis, the association of HER2 expression by 21-gene assay with trastuzumab benefit was marginally nonsignificant (nonlinear p = 0.057). In hormone receptor-positive patients (local IHC) the association was significant (p = 0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 expression levels. CONCLUSIONS: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR were similar and high. Association of HER2 mRNA expression with trastuzumab benefit as measured by time to distant recurrence was nonsignificant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in patients with either IHC-positive or FISH-positive tumors. Trend for benefit was observed also for the small groups of patients with negative results by any or all of the central assays. TRIAL REGISTRATION: Clinicaltrials.gov NCT00005970 . Registered 5 July 2000.

A study of the impact of the 21-gene breast cancer assay on the use of adjuvant chemotherapy in women with breast cancer in a Mexican public hospital.

BACKGROUND: The majority of breast cancer patients in Mexico are treated through the public health system and >80% receive adjuvant chemotherapy. The aim of this prospective study was to characterize the impact of the Oncotype DX assay on adjuvant therapy decision making and the confidence in those decisions amongst public sector physicians in Mexico. METHODS: Ninety-eight consecutive patients with ER+, HER2-, stage I-IIIa, N0/N1-3 node-positive breast cancer from the Instituto Nacional de Cancerología were eligible for the study. The primary endpoint was the overall change in treatment recommendations after receiving the assay results. RESULTS: Of 96 patients, 48% received a chemohormonal therapy recommendation prior to testing. Following receipt of results, treatment decisions changed for 31/96 (32%) patients, including 17/62 (27%) node-negative patients and 14/34 (41%) node-positive patients. The proportion of patients with a chemotherapy-based recommendation decreased from 48% pre- to 34% post-assay (P=0.024). 92% of physicians agreed that they were more confident in their treatment recommendation after ordering the assay. CONCLUSIONS: These results suggest that use of the 21-gene assay in the Mexican public health system has a meaningful impact on adjuvant treatment recommendations that may reduce the overall use of chemotherapy.

Societal cost-effectiveness analysis of the 21-gene assay in estrogen-receptor-positive, lymph-node-negative early-stage breast cancer in Japan.

BACKGROUND: Breast-cancer incidence and mortality have been increasing in Japan. Japanese-specific clinical validity and utility data for the 21-gene assay (Oncotype DX® Breast Cancer Assay; Genomic Health, Inc., Redwood City, USA) are now available. The objective of this study was to evaluate the cost-effectiveness of the 21-gene assay for the guidance of adjuvant chemotherapy decisions in estrogen-receptor-positive, lymph-node-negative, early-stage breast cancer patients, from the Japanese societal perspective. METHODS: The recurrence risk group distribution by the 21-gene assay result and the assay's influence on adjuvant chemotherapy recommendations were obtained from a study of 104 patients. A state-transition cohort (Markov) model tracked time from surgery until distant recurrence and from distant recurrence to death. Adjuvant chemotherapy benefit by 21-gene assay risk group was based on published clinical validation studies. Direct and indirect medical costs were obtained from the referral centers. Utilities associated with progression and chemotherapy-related adverse events were extracted from literature. Sensitivity analyses assessed the key drivers and robustness of the primary outcomes. RESULTS: The 21-gene assay identified 48% of patients as low-risk, 36% as intermediate-risk, and 16% as high-risk. Total acute chemotherapy-related costs decreased by ¥154,066 due to less adjuvant chemotherapy usage. In the high-risk group, adjuvant chemotherapy use increased 18%, leading to survival benefits. Chemotherapy use overall decreased by 19%. Monitoring costs increased by ¥3,744 but recurrence costs declined by ¥46,113 per patient. Use of the 21-gene assay increased quality-adjusted-life-years (QALYs) by 0.241 per patient on average; the net cost per QALY gained was ¥636,752 ($6,368). CONCLUSIONS: The 21-gene assay for women with estrogen-receptor-positive, lymph-node-negative, early-stage breast cancer is projected to be cost-effective in Japan.

Prospective study of the effect of the 21-gene assay on adjuvant clinical decision-making in Japanese women with estrogen receptor-positive, node-negative, and node-positive breast cancer.

BACKGROUND: In this study we investigated if the 21-gene assay result affects adjuvant decision-making in Japanese women with ER+ invasive EBC. PATIENTS AND METHODS: A total of 124 consecutive eligible patients with ER+, HER2-negative EBC and 0 to 3 positive lymph nodes were enrolled. Treatment recommendations, physicians' confidence and patients' decisional conflict before and after knowledge of the Recurrence Score results of the 21-gene assay were recorded. RESULTS: One-hundred four patients (84%) had N0 disease, including micrometastases, and 20 (16%) had N+ disease. Overall, recommendations changed in 33% (95% CI, 24%-43%) of N0 and 65% (95% CI, 41%-85%) of N+ patients. In 27 of 48 (56%) of N0 and 13 of 15 (87%) of N+ patients an initial recommendation for chemohormonal therapy was revised to only hormonal therapy after assay results, and in 7 of 56 (13%) of N0 and 0 of 5 N+ patients from only hormonal to combined chemohormonal therapy. Decisions appeared to follow the Recurrence Score results for low and high values. For patients with intermediate Recurrence Score values, overall recommendations for chemohormonal treatment tended to decrease after assay results. Physicians' confidence increased in 106 of 124 (85.5%; 95% CI, 78%-91%) cases. Patients' decisional conflict significantly improved as indicated by changes in the total score and the 5 defined subscores (P = .014 for Informed Subscore; P < .001 for all others). CONCLUSION: Results from this prospective study in a Japanese population confirm an effect of the 21-gene assay results on adjuvant treatment decision-making, consistent with reported experiences from the United States and Europe.

The impact of a genomic assay (Oncotype DX) on adjuvant treatment recommendations in early breast cancer.

OBJECTIVES: To assess how the recurrence score of the Oncotype DX breast cancer assay influences adjuvant systemic treatment decisions in the multidisciplinary meeting (MDM) for patients with early breast cancer (EBC) in Australia. DESIGN, SETTING AND PARTICIPANTS: A before-and-after study at three academic medical centres in Melbourne with patients and physicians serving as their own controls. Paired systemic adjuvant treatment recommendations were made in multidisciplinary meetings (MDMs) before and after Oncotype DX testing. Medical oncologists and surgeons, treating patients with unifocal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-negative or node-positive early breast cancer. MAIN OUTCOME MEASURES: Changes in physician treatment recommendations. RESULTS: This study enrolled 151 eligible patients between 1 November 2010 and 30 September 2011. Of these, 101 patients (67%) had node-negative and 50 (33%) had node-positive tumours. Recurrence score information resulted in treatment recommendation changes for 24 patients with node-negative tumours (24%) and for 13 patients with node-positive tumours (26%). The proportional change from chemo-hormonal therapy (CHT) to hormonal therapy (HT) was significantly greater than from HT to CHT for patients with node-negative tumours (23% difference in proportions; P= 0.02), and of similar magnitude for patients with node-positive tumours (25% difference in proportions; P = 0.14). CONCLUSION: The Oncotype DX recurrence score has a major impact on adjuvant treatment decision making in the MDM setting.

Biomarker modulation following short-term vorinostat in women with newly diagnosed primary breast cancer.

PURPOSE: Agents that target the epigenome show activity in breast cancer models. In preclinical studies, the histone deacetylase inhibitor vorinostat induces cell-cycle arrest, apoptosis, and differentiation. We evaluated biomarker modulation in breast cancer tissues obtained from women with newly diagnosed invasive disease who received vorinostat and those who did not. EXPERIMENTAL DESIGN: Tumor specimens were collected from 25 women who received up to 6 doses of oral vorinostat 300 mg twice daily and from 25 untreated controls in a nonrandomized study. Candidate gene expression was analyzed by reverse transcription PCR (RT-PCR) using the Oncotype DX 21-gene assay, and by immunohistochemistry for Ki-67 and cleaved caspase-3. Matched samples from treated women were analyzed for gene methylation by quantitative multiplex methylation-specific PCR (QM-MSP). Wilcoxon nonparametric tests were used to compare changes in quantitative gene expression levels pre- and post-vorinostat with changes in expression in untreated controls, and changes in gene methylation between pre- and post-vorinostat samples. RESULTS: Vorinostat was well tolerated and there were no study-related delays in treatment. Compared with untreated controls, there were statistically significant decreases in the expression of proliferation-associated genes Ki-67 (P = 0.003), STK15 (P = 0.005), and Cyclin B1 (P = 0.03) following vorinostat, but not in other genes by the Oncotype DX assay, or in expression of Ki-67 or cleaved caspase-3 by immunohistochemistry. Changes in methylation were not observed. CONCLUSIONS: Short-term vorinostat administration is associated with a significant decrease in expression of proliferation-associated genes in untreated breast cancers. This demonstration of biologic activity supports investigation of vorinostat in combination with other agents for the management of breast cancer.

A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast.

BACKGROUND: For women with ductal carcinoma in situ (DCIS) of the breast, the risk of developing an ipsilateral breast event (IBE; defined as local recurrence of DCIS or invasive carcinoma) after surgical excision without radiation is not well defined by clinical and pathologic characteristics. METHODS: The Oncotype DX breast cancer assay was performed for patients with DCIS treated with surgical excision without radiation in the Eastern Cooperative Oncology Group (ECOG) E5194 study. The association of the prospectively defined DCIS Score (calculated from seven cancer-related genes and five reference genes) with the risk of developing an IBE was analyzed using Cox regression. All statistical tests were two-sided. RESULTS: There were 327 patients with adequate tissue for analysis. The continuous DCIS Score was statistically significantly associated with the risk of developing an IBE (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.15 to 4.49; P = .02) when adjusted for tamoxifen use (prespecified primary analysis) and with invasive IBE (unadjusted HR = 3.68, 95% CI = 1.34 to 9.62; P = .01). For the prespecified DCIS risk groups of low, intermediate, and high, the 10-year risks of developing an IBE were 10.6%, 26.7%, and 25.9%, respectively, and for an invasive IBE, 3.7%, 12.3%, and 19.2%, respectively (both log rank P ≤ .006). In multivariable analyses, factors associated with IBE risk were DCIS Score, tumor size, and menopausal status (all P ≤ .02). CONCLUSIONS: The DCIS Score quantifies IBE risk and invasive IBE risk, complements traditional clinical and pathologic factors, and provides a new clinical tool to improve selecting individualized treatment for women with DCIS who meet the ECOG E5194 criteria.

Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer.

PURPOSE: We developed quantitative gene expression assays to assess recurrence risk and benefits from chemotherapy in patients with stage II colon cancer. PATIENTS AND METHODS: We sought validation by using RNA extracted from fixed paraffin-embedded primary colon tumor blocks from 1,436 patients with stage II colon cancer in the QUASAR (Quick and Simple and Reliable) study of adjuvant fluoropyrimidine chemotherapy versus surgery alone. A recurrence score (RS) and a treatment score (TS) were calculated from gene expression levels of 13 cancer-related genes (n = 7 recurrence genes and n = 6 treatment benefit genes) and from five reference genes with prespecified algorithms. Cox proportional hazards regression models and log-rank methods were used to analyze the relationship between the RS and risk of recurrence in patients treated with surgery alone and between TS and benefits of chemotherapy. RESULTS: Risk of recurrence was significantly associated with RS (hazard ratio [HR] per interquartile range, 1.38; 95% CI, 1.11 to 1.74; P = .004). Recurrence risks at 3 years were 12%, 18%, and 22% for predefined low, intermediate, and high recurrence risk groups, respectively. T stage (HR, 1.94; P < .001) and mismatch repair (MMR) status (HR, 0.31; P < .001) were the strongest histopathologic prognostic factors. The continuous RS was associated with risk of recurrence (P = .006) beyond these and other covariates. There was no trend for increased benefit from chemotherapy at higher TS (P = .95). CONCLUSION: The continuous 12-gene RS has been validated in a prospective study for assessment of recurrence risk in patients with stage II colon cancer after surgery and provides prognostic value that complements T stage and MMR. The TS was not predictive of chemotherapy benefit.

Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial.

BACKGROUND: The 21-gene recurrence score assay is prognostic for women with node-negative, oestrogen-receptor-positive breast cancer treated with tamoxifen. A low recurrence score predicts little benefit of chemotherapy. For node-positive breast cancer, we investigated whether the recurrence score was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher risks of recurrence. METHODS: The phase 3 trial SWOG-8814 for postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer showed that chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) before tamoxifen (CAF-T) added survival benefit to treatment with tamoxifen alone. Optional tumour banking yielded specimens for determination of recurrence score by RT-PCR. In this retrospective analysis, we assessed the effect of recurrence score on disease-free survival by treatment group (tamoxifen vs CAF-T) using Cox regression, adjusting for number of positive nodes. FINDINGS: There were 367 specimens (40% of the 927 patients in the tamoxifen and CAF-T groups) with sufficient RNA for analysis (tamoxifen, n=148; CAF-T, n=219). The recurrence score was prognostic in the tamoxifen-alone group (p=0.006; hazard ratio [HR] 2.64, 95% CI 1.33-5.27, for a 50-point difference in recurrence score). There was no benefit of CAF in patients with a low recurrence score (score <18; log-rank p=0.97; HR 1.02, 0.54-1.93), but an improvement in disease-free survival for those with a high recurrence score (score > or =31; log-rank p=0.033; HR 0.59, 0.35-1.01), after adjustment for number of positive nodes. The recurrence score by treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), although the cumulative benefit remained at 10 years. Results were similar for overall survival and breast-cancer-specific survival. INTERPRETATION: The recurrence score is prognostic for tamoxifen-treated patients with positive nodes and predicts significant benefit of CAF in tumours with a high recurrence score. A low recurrence score identifies women who might not benefit from anthracycline-based chemotherapy, despite positive nodes. FUNDING: National Cancer Institute and Genomic Health.

Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features.

PURPOSE: Adjuvant! is a standardized validated decision aid that projects outcomes in operable breast cancer based on classical clinicopathologic features and therapy. Genomic classifiers offer the potential to more accurately identify individuals who benefit from chemotherapy than clinicopathologic features. PATIENTS AND METHODS: A sample of 465 patients with hormone receptor (HR) -positive breast cancer with zero to three positive axillary nodes who did (n = 99) or did not have recurrence after chemohormonal therapy had tumor tissue evaluated using a 21-gene assay. Histologic grade and HR expression were evaluated locally and in a central laboratory. RESULTS: Recurrence Score (RS) was a highly significant predictor of recurrence, including node-negative and node-positive disease (P < .001 for both) and when adjusted for other clinical variables. RS also predicted recurrence more accurately than clinical variables when integrated by an algorithm modeled after Adjuvant! that was adjusted to 5-year outcomes. The 5-year recurrence rate was only 5% or less for the estimated 46% of patients who have a low RS (< 18). CONCLUSION: The 21-gene assay was a more accurate predictor of relapse than standard clinical features for individual patients with HR-positive operable breast cancer treated with chemohormonal therapy and provides information that is complementary to features typically used in anatomic staging, such as tumor size and lymph node involvement. The 21-gene assay may be used to select low-risk patients for abbreviated chemotherapy regimens similar to those used in our study or high-risk patients for more aggressive regimens or clinical trials evaluating novel treatments.

Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis: results of a pilot randomized controlled clinical trial.

BACKGROUND/AIMS: Insulin-like growth factor I (IGF-I) is an anabolic hormone synthesized in the liver whose levels decrease sharply in liver cirrhosis. METHODS: We conducted a randomized double-blind placebo-controlled clinical trial to evaluate the effect of subcutaneous administration of IGF-I (20 microg/kg/day with dose escalation to 50-100 microg/kg/day) for 4 months in patients with alcoholic or primary biliary cirrhosis (PBC) and subnormal IGF-I levels. Eight alcoholics and one PBC entered the placebo group and seven alcoholics and two PBC the treatment group. Biochemistry, body composition, muscle mass and strength, and resting energy expenditure (REE) were evaluated. RESULTS: Total serum IGF-I and IGF-I/IGFBP-3 ratio (a surrogate marker of IGF-I biovailability) increased in the treatment group but IGF-I values still remained below normal limits in the treated patients. No differences were observed in body composition, muscle strength or muscle mass between groups. However, IGF-I therapy increased significantly serum albumin (P = 0.038) and this improvement correlated positively with variation of IGF-I/IGFBP-3 ratio. IGF-I treatment also tended to increase REE (P = 0.085); this difference was significant (P = 0.049) in the subgroup of alcoholic patients. CONCLUSIONS: A short course of IGF-I increased albumin levels and tended to improve energy metabolism in liver cirrhosis. These findings warrant larger clinical trials to assess the clinical benefit of IGF-I in cirrhotic patients.

A randomized controlled trial evaluating the efficacy and safety of intermittent 3-, 4-, and 5-day cycles of intravenous recombinant human interleukin-2 combined with antiretroviral therapy (ART) versus ART alone in HIV-seropositive patients with 100-300 CD4+ T cells.

The effect of length of therapy on the safety and efficacy profile of continuous intravenous (CIV) interleukin-2 (IL-2) in combination with antiretroviral therapy (ART) was evaluated in 81 HIV-seropositive patients with CD4(+) T-cell counts of 100-300/mm(3). Patients were randomized to CIV IL-2 (12 mIU/day) for 3, 4, or 5 days plus ART every 8 weeks for six cycles, or to ART alone. The mean percent increase in CD4(+) T-cell counts was 24.5% for IL-2 recipients compared with a mean percent decrease of 30.5% for control patients (P = 0.005). Increasing duration of CIV IL-2 therapy resulted in improved CD4(+) T-cell response. The most frequent clinical adverse events and laboratory abnormalities were predominantly of grade 1 or 2 severity. However, grade 3 or 4 events were reported in 57%, 60%, and 84% of the 3-, 4-, and 5-day CIV IL-2 patients, respectively. Serious adverse events, mainly due to the requirement of hospitalization, occurred in 20% of IL-2 recipients, compared with 10% of control patients. Viral load during the course of the study was not different among the treatment groups. IL-2 therapy in cycles of 5 days resulted in an optimal increase in CD4(+) T-cell counts and is the preferred cycle length for IL-2 therapy geared toward increasing CD4(+) T-cell numbers.