Oral Endoxan for prostate cancer

Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: a phase II study.

Lord R, Nair S, Schache A, Spicer J, Somaihah N, Khoo V, Pandha H.

Department of Oncology and Urology, St. George's, University of London, London, UK.

PURPOSE: Cyclophosphamide is a bifunctional alkylating agent long associated with immune activation. Continuous, uninterrupted, low (so-called metronomic) doses of cyclophosphamide can lead to enhanced immunity against a variety of antigens possibly by targeting regulatory T cells and/or tumor angiogenesis. In this study we tested the observations from animal models and evaluated the safety and efficacy of continuous low dose oral cyclophosphamide in patients with hormone resistant prostate cancer. MATERIALS AND METHODS: A total of 80 patients were recruited during a 2-year period and 58 received at least 2 cycles (8 weeks) of 50 mg/m(2) oral cyclophosphamide to be included in the safety and intent to treat analysis. RESULTS: Metronomic cyclophosphamide was safe and well tolerated, and although lymphopenia (up to grade 3) was observed in a third of all patients, there were no clinical complications. The response rate was 34.5% inclusive of objective and prostate specific antigen (absolute reduction and reduction in prostate specific antigen velocity). The median duration of response was 7.5 months (range 3 to 18). CONCLUSIONS: Oral cyclophosphamide can be used on a metronomic basis safely in men with hormone resistant prostate cancer. The efficacy, low toxicity, low cost and ease of administration of cyclophosphamide justifies further studies in prostate cancer in combination with other agents

No role for Velcade in castration resistant metastatic prostatic cancer

A phase II trial of bortezomib and prednisone for castration resistant metastatic prostate cancer.

Morris MJ, Kelly WK, Slovin S, Ryan C, Eicher C, Heller G, Scher HI.

Department of Medicine (Genitourinary Oncology Service), Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

PURPOSE: We defined the antitumor effects of bortezomib alone and in combination with prednisone in patients with progressive, castration resistant metastatic prostate cancer. MATERIALS AND METHODS: A total of 30 men with progressive castration resistant disease were treated in 2 groups. Cohort 1 received 1.5 mg/m2 bortezomib intravenously twice weekly for 2 cycles (2 weeks on and 1 week off), followed by 1.6 mg/m2 weekly (4 weeks on and 2 weeks off). Prednisone (10 mg) was given orally throughout. Cohort 2 comprised patients with limited chemotherapy exposure who received a decreased dose of bortezomib (1.3 mg/m2) during the induction period with prednisone added only at disease progression. The primary end point was no evidence of disease progression at 12 weeks, defined as no increase in prostate specific antigen from baseline and no radiographic progression. Interleukin-6 was assessed to correlate with antitumor effects. RESULTS: One of 24 evaluable patients (4%) achieved the primary end point. In cohort 1, 18 patients were treated, 13 were evaluable for response and 4 discontinued treatment due to toxicities, including 3 before attaining the point of being evaluable. No patient achieved the primary end point. In cohort 2, 12 patients were treated and 11 were evaluable for response. Toxicity was slightly mitigated compared with that in cohort 1. One patient achieved the primary end point. Interleukin-6 did not correlate with posttreatment prostate specific antigen changes in either cohort. CONCLUSIONS: Although interleukin-6 and other pathways regulated by nuclear factor-kappa B may be legitimate targets, treatment with bortezomib alone and with prednisone does not appear to have significant antitumor effects in patients with castration resistant metastatic prostate cancer.

For Anthopoulos

Phase I study of bortezomib with weekly paclitaxel in patients with advanced solid tumours.

Cresta S, Sessa C, Catapano CV, Gallerani E, Passalacqua D, Rinaldi A, Bertoni F, Viganò L, Maur M, Capri G, Maccioni E, Tosi D, Gianni L.

Fondazione IRCCS Istituto Nazionale Tumori (INT), Milan, Italy.

BACKGROUND: The combination of a proteasome inhibitor with a taxane has potential clinical synergism that prompted a clinical test. PATIENTS AND METHODS: The maximum tolerated dose (MTD) and recommended dose (RD) of intravenous (i.v.) Bortezomib (B) (days 1, 4, 8, 11) and i.v. Paclitaxel (PTX) (days 1, 8) every 3 weeks was evaluated in patients with advanced solid tumours. The RD was tested in patients with breast, ovarian and prostate cancer. At the RD, microarray analysis of transcriptional profiles was carried out before and after the first dosing in peripheral blood mononuclear cells (PBMC). RESULTS: Thirty-one patients were enrolled and 22 were treated at the RD that corresponded to B 1.3mg/m(2) and PTX 100mg/m(2). The main toxicity was cumulative peripheral neuropathy (76% of patients; grade 3-4 in 9%) that required treatment discontinuation in six patients, followed by diarrhoea (55%) and fatigue (41%). Nine partial responses (30%) were observed (three breast cancer, four ovary, two prostate patients). Significant (p<0.05)>70% of patients) in transcriptome were observed. CONCLUSIONS: The incidence of peripheral neuropathy and the anti-tumour activity comparable to that of single-agent PTX do not support further development of this regimen.

ERBITUX in NSCLC

Merck: Erbitux Phase III Study - FLEX Increases Overall Survival In First-line Treatment Of Non-Small Cell Lung Cancer

Safe Effective & Lasting Treatment That Saved Terminally Ill Patients

Merck KGaA announced that Erbitux® (cetuximab) combined with vinorelbine plus cisplatin met the primary endpoint of increasing overall survival compared with chemotherapy alone in a Phase III study initiated by Merck Serono in patients with advanced non-small cell lung cancer (NSCLC).

This randomized multinational trial, known as FLEX (First-Line Treatment for Patients with EGFR-EXpressing Advanced NSCLC), involved patients with Stage IIIB or Stage IV non-small cell lung cancer who were randomized to treatment with chemotherapy and Erbitux or with chemotherapy alone and who had not previously received chemotherapy.

"Non-small cell lung cancer that has spread from the primary site is extremely difficult to treat so we are delighted with these results," said Dr. Wolfgang Wein, Senior Executive Vice President, Oncology, Merck Serono - the division for innovative small molecules and biopharmaceuticals of Merck. "Erbitux is the first targeted agent that when combined with platinum-based chemotherapy has demonstrated a therapeutic benefit in a first-line NSCLC study that included all histological subtypes. These are important results given that recent trials involving other targeted therapies such as Tyrosine Kinase Inhibitors have failed to demonstrate a benefit for patients in this setting."

Detailed results from this study are expected to be submitted for presentation at an upcoming medical conference.

In Europe, there are approximately 400,000 new cases of lung cancer each year, accounting for 22% of all new cancer diagnoses.1 The incidence is higher among men in eastern than western countries..2 Non-small cell lung cancer accounts for around 80% of cancers of the lung.3 The five-year survival for patients with Stage III NSCLC who have radiotherapy and chemotherapy is 7-17%; for Stage IV disease, overall five-year survival is 2%.4 In Europe, lung cancer is the principal cause of cancer deaths in men (22%) and the third-leading cause in women (9%).5

About the study

FLEX is a randomized Phase III study of Erbitux® plus chemotherapy (cisplatin plus vinorelbine) or chemotherapy alone in previously untreated patients with histologically or cytologically confirmed Stage IIIB with documented malignant pleural effusion or Stage IV non-small cell lung cancer, plus immunohistochemical evidence of EGFR-expression on tumor tissue, and the presence of at least one bidimensionally measurable index lesion not lying within an irradiated area. The primary endpoint was overall survival time. Other secondary endpoints included progression free survival time, response rate, safety and quality of life.

ADJUVANT RADIOTHERAPY FOR T3N0M0 PROSTATE CANCER

Adjuvant Radiotherapy Useful for PT3N0M0 Prostate Cancer

NEW YORK (Reuters Health) Feb 16 - Adjuvant radiotherapy can cut the risk of metastasis and improve survival in men who have undergone radical prostatectomy for pathological T3N0M0 prostate cancer, according to a report in the March issue of The Journal of Urology.

Prior research has shown that roughly a third of men who undergo radical prostatectomy for apparently localized prostate cancer will develop extraprostatic disease. Whether adjuvant radiotherapy may help cut risk of metastatic disease and mortality was unclear.

Dr. Ian M. Thompson, from the University of Texas Health Science Center, San Antonio, and colleagues addressed this topic by assessing the outcomes of 431 men who were randomized to receive adjuvant radiotherapy (60 to 64 Gy) or observation after radical prostatectomy. Seventy of the 211 men randomized to observation later received radiotherapy.

Radiotherapy increased the odds of metastasis-free survival and overall survival. Specifically, the hazard ratio for metastasis in the radiotherapy arm versus the observation arm was 0.71 (p = 0.016), and the corresponding mortality hazard ratio was 0.72 (p = 0.023).

The investigators conclude that "adjuvant radiotherapy within 18 weeks after radical prostatectomy in a man with T3N0M0 prostate cancer significantly reduces the risk of PSA recurrence, metastasis, and the need for hormonal therapy, and significantly increases survival."

ANOTHER GENOMIC TEST FOR BREAST CANCER

New Genomic Test May Improve Management in Breast Cancer

February 19, 2009 — A genomic test may add significant prognostic and predictive information to standard parameters for breast cancer patients. Designed by a multi-institutional team of researchers, the new test is broadly applicable to all women diagnosed with breast cancer, according to report a published online February 9 in the Journal of Clinical Oncology.

"It's an evolution in the testing process," said Matthew Ellis, MD, PhD, a member of the Siteman Cancer Center at Washington University and Barnes-Jewish Hospital, in St. Louis, Missouri, who is one of the study's authors. "The critical issue is targeting the therapy."

Among patients with a poor prognosis, he explained, the goal is to find a way to target the disease effectively. Among those with cancers who have a better prognosis, the goal is to define the minimum amount of therapy.

Dr. Ellis and colleagues investigated the development of a new genomic assay test to improve on current standards for breast cancer prognosis and prediction of chemotherapy benefit. Their model is a 50-gene subtype predictor, developed using microarray and quantitative reverse-transcriptase–PCR data from 189 prototype samples, that incorporates the gene-expression-based "intrinsic" Luminal A, Luminal B, HER2-enriched, and Basal-like subtypes.

Differs From Other Tests

The new assay is different from the genomic tests that are currently available, and may offer a broader array of benefits. "In gene numbers, we fall between the 70-gene MammaPrint microarray assay and the 21-gene OncotypeDx assay," Dr. Ellis told Medscape Oncology, referring to assays that are already commercially available.

The OncotypeDx assay can be used to risk stratify early-stage estrogen-receptor (ER)-positive node-negative disease, whereas the new genomic test can be used in node-positive disease and, thus, is applicable to a much wider range of women diagnosed with breast cancer.

"The MammaPrint is also only applicable for node-negative disease and requires a fresh frozen sample," he said. "Our format allows for retrospective studies, using samples from patients treated a while ago."

Soonmyung Paik, MD, who was not involved in the study or the development of the test, commented to Medscape Oncology that, in essence, this study shows that Luminal A subtype defined by gene expression has good prognosis. "This has been known for a while now, and the investigators developed it into a test format that can be applied to routinely processed biopsy tissue specimens," said Dr. Paik, director, Division of Pathology, National Surgical Adjuvant Breast and Bowel Project, in Pittsburgh, Pennsylvania.

"So it is not a novel finding, but it is a step forward to implement what we already know to a clinical test," he added. "The test is similar to the OncotypeDx test — the only difference is that it was developed purely by academic labs."

Predictive of Treatment Response

The intrinsic Luminal A, Luminal B, HER2-enriched, Basal-like, and Normal-like subtypes have been extensively studied by microarray and hierarchical clustering analysis, the researchers note. In this study, they evaluated the utility of these subtypes alone and as part of a risk-for-relapse predictor in 2 cohorts.

In the first cohort, patients received no adjuvant systemic therapy, whereas in the second, women received paclitaxel, 5-fluorouracil, doxorubicin, and cyclophosphamide neoadjuvant chemotherapy. The researchers compared risk-for-relapse models with standard models using pathologic stage, grade, and ER and HER2 status.

A 50-gene subtype predictor was developed using data from 189 prototype samples. Test sets from the 761 patients in the first cohort were evaluated for prognosis, whereas those from the 133 patients in the second cohort were evaluated for prediction of pathologic complete response to a taxane and anthracycline regimen.

The subtype diagnoses demonstrated markedly different distributions, depending on ER or HER2 status, but all subtypes were represented in ER-positive, ER-negative, HER2-positive, and HER2-negative categories. This finding shows that ER and HER2 status alone are not accurate surrogates for true intrinsic subtype status, the researchers observed. Instead, the intrinsic subtypes showed a significant impact on prognosis for relapse-free survival among patients who did not receive systemic therapy and when stratified by ER status.

When evaluating response to chemotherapy, they found that the genetic test was highly sensitive and very predictive for therapeutic response (94% sensitivity and 97% negative predictive value for identifying nonresponders to chemotherapy). Their assay was more predictive than the clinical molecular markers that are typically used, including ER status, progesterone-receptor status, and HER2 gene-expression status.

"The gene test allows for identifying Luminal B tumors, which have a poor prognosis," said Dr. Ellis. "This type is worrisome, because it is not very responsive to current treatments, exemplifying the need for new agents and new approaches for this group."

This test is a potential starting point for a variety of new clinical-trial designs, which will focus on patients with a poorer prognosis. "Unlike the Oncotype trials, which are focused on finding out which groups do not need adjuvant chemotherapy, this test has much more to do with patients with poor-prognosis breast cancer who need entirely new systemic therapy approaches," explained Dr. Ellis.

According to Dr. Ellis, the test should become available later this year. But Dr. Paik pointed out that for this test to be offered to patients, it has to be commercialized. "The cost of the assay should be much lower than, for example, the OncotypeDx assay, but it all depends on their market evaluation, so I cannot speculate at this point."

DO NOT SCREEN AFTER 75 FOR PROSTATE CANCER IF PSA IS BELOW 3 ng/ml

Stop PSA Screening in Men Over 75 � But Only Those With Low PSA, Says New Study

February 20, 2009 — New data that support discontinuing screening for prostate cancer in men older than 75 years are reported in the April issue of The Journal of Urology.

However, the new analysis does not suggest that screening be stopped in all men older than 75 years, but only in men who have low levels of prostate-specific antigen (PSA ≤3 ng/mL).

This group is unlikely to develop aggressive prostate cancer or to die of this disease during their remaining life and, therefore, these men may represent an ideal target group for discontinuation of PSA testing," say the researchers, headed by Edward Schaeffer, MD, PhD, from the Department of Urology at Johns Hopkins University School of Medicine, in Baltimore, Maryland.

Not screening these older men would dramatically cut costs and would eliminate harm from additional evaluations and/or treatment in a population unlikely to experience benefit, they add.

The conclusions tie in with, but differ from, the recent recommendation from the US Preventive Services Task Force (USPSTF), which advised stopping screening in all men who are 75 years or older, as reported by Medscape Oncology

However, as Dr. Schaeffer and colleagues point out, "all men older than 75 years of age may not be equal."

"Indeed, in our cohort, no patient older than 75 years with a PSA of less than 3 ng/mL had high-risk prostate cancer," they write. "However, of those with a PSA greater than 3 ng/mL, there were several subsequent prostate cancer deaths."

The findings come from a new analysis of data collected in the Baltimore Longitudinal Study of Aging, in which investigators collected serial PSA measurements in 849 men, of whom 122 developed prostate cancer.

Questions About the Use of a PSA Cut-Off Level

However, 2 editorial comments that accompany the new study question the conclusion about stopping screening only in older men with low PSA levels.

The implication is that it may not be safe to discontinue testing if PSA is above this level," says Peter Albertsen, MD, from the University of Connecticut Health Center, in Farmington.

But there are still many questions about whether PSA testing identifies clinically significant disease and about how effective treatment is in older patients, he writes. For example, a recent update of the Scandinavian Prostate Cancer Group-4 trial showed no benefit associated with radical prostatectomy for men older than 65 years (J Natl Cancer Inst. 2008;100:1144).

"While we may be able to prevent a few deaths from prostate cancer in patients older than 75 years, this comes at an enormous cost in testing and treatment," Dr. Albertsen comments.

The USPSTF made similar points about men who are 75 years and older. For these men, and others who have a life expectancy of 10 or fewer years, the incremental benefit from treating prostate cancer detected by screening is "small to none." Therefore, harm outweighs benefit, it concludes (Ann Intern Med. 2008;149:185-191).

In another editorial comment, Ruth Etzioni, PhD from the Fred Hutchinson Cancer Research Center, in Seattle, Washington, points out that the conclusions are based on observational data. In particular, the selection of the 3 ng/mL PSA cut-off level is based on a post hoc observation. "Post hoc findings may be valid but generally need to be confirmed in independent datasets," she writes.

DO NOT SCREEN AFTER 75 FOR COLORECTAL CANCER

ACPM 2009: USPSTF Updates Recommendations for Colorectal Cancer Screening

February 17, 2009 (Los Angeles, California) — The US Preventive Services Task Force (USPSTF) no longer recommends colorectal cancer screening for everyone older than 50 years, with no upper age limit.

In 2002, the USPSTF recommended screening for anyone older than 50 years, with no upper limitation on age. That year, the task force also noted that there was, as yet, insufficient evidence to recommend for or against using computed tomography colonography (CTC) as one of the screening modalities.

In the 2009 update, the USPSTF now recommends that adults aged 50 to 74 years be screened in 1 of the following ways: every year with high-sensitivity fecal occult blood testing (FOBT); every 10 years with colonoscopy; or every 5 years with flexible sigmoidoscopy plus interval high-sensitivity FOBT.

The task force also recommended against routine screening of people aged 76 to 85 years, although individual patients might have considerations that support screening. As for CTC, the task force said it is still too early to include it in the screening recommendations.

The recommendation has a rating of A, meaning that the task force urges the clinician to provide the service to eligible patients and that there is good evidence that the service improves health outcomes, with benefits substantially outweighing harms, said USPSTF scientific director Mary Barton, MD, who presented the update here at Preventive Medicine 2009: The Annual Meeting of the American College of Preventive Medicine.

The update was developed based on a review of new data conducted by the Oregon Evidence-Based Practice Center, which analyses clinical studies that federal, state, and private agencies use in making policy and coverage decisions.

To examine the data on CTC, the center analyzed 4 studies it considered to be of good or fair quality, which involved a total of 4312 patients. Depending on whether the scan was read by a gastroenterologist or an experienced radiologist, CTC identified 12 or 13 of a total of 14 colorectal cancers across the 4 studies. Compared with colonoscopy, the sensitivity of CTC ranged from 59% to 94% for detecting adenomas, depending on the size. The specificity ranged from 80% to 96%.

CTC produces "lots of false positives," Dr. Barton said. The result is that doctors might be "sending many people to colonoscopy who [they] were trying to spare colonoscopy," with its "real and moderate-sized procedure-related harms," such as perforation and major bleeding. Noting that Medicare is announcing that it will not cover CTC for colorectal screening, Dr. Barton said that the currently available studies on CTC vary widely in quality, making it hard to determine the true net benefit or harm of the test. The task force concluded that there is not yet enough information to permit an assessment of the benefits and harms of CTC, so it did not mention the procedure at all when updating its recommendations for colorectal cancer screening.

The updated findings show that "we're not ready for CT colonography yet," even though patients are requesting it, said Wayne Dysinger, MD, chair of the Department of Preventive Medicine at Loma Linda University, in California. "This makes it clear that I can tell patients we don't have the science yet to pursue CT colonography." Dr. Dysinger, who was not involved in developing the recommendations, said he was a little surprised that the task force concluded it could not recommend CTC.

BREAST RADIOTHERAPY FOR METASTATIC DISEASE

Radiotherapy Helpful When Breast Cancer Is Advanced at Diagnosis

NEW YORK (Reuters Health) Feb 17 - Locoregional radiotherapy (LRR) is an effective approach in breast cancer patients with synchronous metastases at the time of diagnosis, according to French researchers.

"Our results," lead investigator Dr. Romuald Le Scodan told Reuters Health, "confirm the survival advantage conferred by surgery or radiation therapy of the primary tumor in breast cancer patients with synchronous metastases."

"Exclusive LRR may be an effective alternative to surgery," he continued, "with the added advantage of being a conservative treatment."

In the February 9th on-line issue of the Journal of Clinical Oncology, Dr. Le Scodan and colleagues at Centre Rene Huguenin in Saint Cloud report on 581 patients with synchronous metastases at diagnosis of their breast cancer. Locoregional therapy was employed in 320 patients (exclusive LRR in 249, resection of the primary tumor plus adjuvant LRR in 41, and surgery alone in 30). In the remaining 261 patients, no locoregional therapy was used.

"Locoregional therapy, consisting mainly of exclusive LRR, was associated with improved survival," the authors found. In patients who received any locoregional treatment, the median survival was 32 months and the 3-year overall survival rate was 43.4%. In those with no locoregional treatment, median survival was 21 months and the 3-year overall survival rate was 26.7% (p=0.00002).

"Our results," added Dr. Le Scodan, "suggest that patients with extensive metastatic disease at diagnosis also benefit from LRR of the primary tumor."

"Well designed prospective studies, including LRR as the only locoregional treatment, are needed to re-evaluate treatment of the primary breast tumor in patients with metastases at diagnosis, and to identify those patients who are most likely to benefit," he concluded.

DO NOT USE TIBOLONE FOR BREAST CANCER PATIENTS

Tibolone for Vasomotor Symptoms and Bone Loss Increases Risk for Breast Cancer Recurrence

February 19, 2009 — Tibolone (Livial, Schering-Plough) — a synthetic steroid used to treat vasomotor symptoms and prevent bone loss — should not be prescribed to any woman with current, past, or suspected breast cancer. Tibolone is approved for use in European and many other countries, but is not approved the United States.

This advisement accompanies the results of the LIBERATE (Livial Intervention Following Breast Cancer: Efficacy, Recurrence, and Tolerability Endpoints) trial, which showed that tibolone significantly increases the risk for recurrence in breast cancer patients.

The results are published in the February issue of the Lancet Oncology.

"Currently, many patients with breast cancer use tibolone to reduce climacteric symptoms," write the study authors, led by Peter Kenemans, MD, PhD, from the Department of Obstetrics and Gynecology at the VU University Medical Center, in Amsterdam, the Netherlands. This is off-label use because a history of breast cancer is a contraindication for tibolone. However, tibolone has been used to provide women with breast cancer with relief from climacteric symptoms because, as the authors point out, "no reliable evidence of harm is available."

The latest results state that they should not do so.

In the LIBERATE trial, postmenopausal women with a history of breast cancer were treated with tibolone for vasomotor symptoms. The drug significantly improved vasomotor symptoms and bone-mineral density, compared with placebo.

However, an interim analysis found a 40% increase in the risk for breast cancer recurrence with tibolone, and led to the trial being stopped 6 months early. An intent-to-treat analysis found that 237 (15.2%) of the 1516 women taking 2.5 mg of tibolone daily had a recurrence of their cancer, compared with 165 (10.7%) of the 1542 women receiving placebo. The median follow-up was 3.1 years.

The only other randomized placebo-controlled trial with tibolone that assessed breast cancer risk was in osteoporotic women without breast cancer at entry (N Engl J Med. 2008;359:697-708). The LIFT (Long-Term Intervention on Fractures with Tibolone) trial showed that breast-cancer incidence was significantly reduced after 3 years of tibolone use, compared with placebo. It also showed that tibolone more than doubled the risk for stroke, as reported by Medscape Medical News.

Can Women Not on Adjuvant Therapy Use Tibolone?

Women treated with surgery for early-stage breast cancer often have severe flushes, resulting from adjuvant treatment with tamoxifen, aromatase inhibitors, gonadotropin-releasing hormone analogues, or chemotherapy, Dr. Kenemans and colleagues explain.

At entry into the LIBERATE trial, 2068 of the 3098 (67%) women used tamoxifen and 202 (6·5%) used aromatase inhibitors to reduce the likelihood of breast cancer recurrence. "Tibolone is likely to interfere with the protective action of these agents," write the authors, explaining a possible way in which the steroid is associated with recurrence.

So, the question arises: Is tibolone safe to use in women not on adjuvant therapy? The authors say that the study was not powered to assess any differences that may exist between subgroups in the study. "There are insufficient data to establish the safety of tibolone in women who have had breast cancer and do not require or have finished adjuvant therapy," they write.

However, the study authors admit that the generalizability of the study results to future populations of breast cancer survivors is questionable because adjuvant treatment options are "moving rapidly" and because of developments in risk assessment. Symptomatic breast cancer survivor populations are likely to be different in the future, they say.

What About the Protective Effect Seen in the LIFT Trial?

In the LIFT trial, 1.25 mg of tibolone daily (the dose for treatment of osteoporosis) decreased the risk for invasive breast cancer, compared with placebo (hazard ratio, 0.32; 95% confidence interval, 0.13–0.80).

The discrepancy between the results of the 2 major trials of tibolone to date that assessed breast cancer risk, LIBERATE and LIFT, can be explained in 2 outstanding ways, according to the authors.

First, the populations are not comparable, they said. The LIFT population was osteoporotic, older (mean age, 68 years), weighed less (mean body mass index (BMI), 25.7 kg/m²), and had no tamoxifen exposure. The LIBERATE population comprised breast cancer survivors with a mean age of 52.7 years and a mean BMI of 27.0 kg/m², and more than two thirds of the women had tamoxifen exposure.

Second, the effect of tibolone on healthy breast tissue "most probably" differs from its effect on cancer cells because of differences in the 2 kinds of cells, write the authors.

ATRA/ATO COMBINATION FOR APML

Retinoic Acid/Arsenic Therapy for Leukemia Seen Safe, Effective Over Long Term

NEW YORK (Reuters Health) Feb 16 - A new report confirms the long-term safety and efficacy of all-trans retinoic acid (ATRA)/arsenic trioxide (ATO) combination therapy in patients with newly diagnosed acute promyelocytic leukemia.

The safety and efficacy of ATRA/ATO had been shown in short-term studies, Dr. Zhu Chen and colleagues explain in the February 16th Early Edition of the Proceedings of the National Academy of Sciences, but long-term data were lacking.

In the current report, Dr. Chen, from the Shanghai Institute of Hematology, China, and colleagues discuss the outcomes of 85 patients who were followed for a median of 70 months.

Complete remission was achieved in 94.1% of patients, the report indicates.

Overall and event-free survival at 5 years were 91.7% and 89.2%, respectively. Among complete responders, the 5-year relapse-free and overall survival rates were 94.8% and 97.4%, respectively.

Initial white blood cell count, distinct PML-RAR-alpha types, or FLT3 mutations had no bearing on prognosis in the study group.

In general, ATRA/ATO therapy was well tolerated and side effects were mild and reversible. No secondary malignancies were seen, and 2 years after the final dose of therapy, urine arsenic levels were well below toxic levels.

"The ATRA/ATO-based treatment regimen incorporating chemotherapy for both remission induction and postremission therapy for newly diagnosed acute promyelocytic leukemia yields an encouraging long-term survival rate greater than 90% with alleviated side effects, and thus reinforces its potential use as a frontline therapy for de novo acute promyelocytic leukemia," the authors conclude.

PEMOX FOR GASTRIC CANCER

Ann Oncol. 2009 Feb 13. [Epub ahead of print]

Related Articles, LinkOut

Pemetrexed in combination with oxaliplatin as a first-line therapy for advanced gastric cancer: a multi-institutional phase II study.

Celio L, Sternberg CN, Labianca R, La Torre I, Amoroso V, Barone C, Pinotti G, Cascinu S, Di Costanzo F, Cetto GL, Bajetta E.

Medical Oncology Unit 2, Foundation IRCCS National Tumour Institute, Milan.

BACKGROUND: This clinical trial assessed the efficacy of pemetrexed combined with oxaliplatin (PEMOX) in patients with advanced gastric cancer (AGC). PATIENTS AND METHODS: Forty-four patients with untreated AGC were enrolled to evaluate response rate (RR). Patients received pemetrexed (500 mg/m(2)) with vitamin supplementation and oxaliplatin (120 mg/m(2)) every 21 days for six cycles or until disease progression occurred. RESULTS: Median age was 62 years (range 26-76). The majority of patients (93%) had metastatic disease. Sixteen of the 44 patients achieved confirmed response [RR 36%; 95% confidence interval (CI) 22% to 52%]; four complete responses and 12 partial responses (complete and partial responses according to the RECIST guidelines are the confirmed-responses observed in the study population). Median time to tumor progression (TTP) was 6.2 months (95% CI 4.3-7.5) and median survival was 10.8 months (95% CI 7.7-17.2). A total of 220 cycles were administered, with a median of six cycles. Most common grade 3/4 toxic effects were neutropenia in 41% of patients (19% of cycles) and thrombocytopenia in 11% of patients (4% of cycles). Treatment delays or dose reductions for toxicity occurred in 10% and 5% of cycles, respectively. CONCLUSIONS: PEMOX is active and well tolerated in AGC. RR, TTP, and survival were comparable to those achieved in studies using different 5-fluorouracil (5-FU)-oxaliplatin combinations, without the inconvenience of prolonged 5-FU schedules

COFFE AND OROPHARYNGEAL CANCER

An inverse association between coffee consumption and the risk of oral, pharyngeal, and esophageal cancers has been suggested in case-control studies, but few results from prospective studies are available. Data from the Miyagi Cohort Study in Japan were used to clarify the association between coffee consumption and the risk of these cancers. Information about coffee consumption was obtained from self-administered food frequency questionnaires in 1990. Among 38,679 subjects aged 40-64 years with no previous history of cancer, 157 cases of oral, pharyngeal, and esophageal cancers were identified during 13.6 years of follow-up. Hazard ratios were estimated by the Cox proportional hazards regression model. The risk of oral, pharyngeal, and esophageal cancers was inversely associated with coffee consumption. The multivariate-adjusted hazard ratio of these cancers for ≥1 cups of coffee per day compared with no consumption was 0.51 (95% confidence interval: 0.33, 0.77). This inverse association was consistent regardless of sex and cancer site and was observed both for subjects who did not drink or smoke and for those who currently drank or smoked at baseline. In conclusion, coffee consumption was associated with a lower risk of oral, pharyngeal, and esophageal cancers, even in the group at high risk of these cancers.

LOCOREGIONAL TREATMENT FOR METASTATIC BREAST CANCER

Question
How would you treat a postmenopausal patient with a T2 N1 M1 (bone) estrogen receptor- and progesterone receptor-positive carcinoma in the left breast? As per National Comprehensive Cancer Network guidelines,^[1] she would receive only hormonal therapy. But would she also benefit from either a simple mastectomy or lumpectomy, or induction chemotherapy and lumpectomy?

Response from Thomas A. Buchholz, MD Professor of Radiation Oncology; Chair, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas

How to incorporate local-regional treatments into therapy for patients with metastatic breast cancer is a controversial topic. When considering such interventions, the associated morbidities of local-regional treatments must be weighed against the potential benefits. For most patients with metastatic disease, there are no clear benefits to be gained from local therapies. However, there are 2 situations in which local-regional therapies may be indicated:

When they have the potential to improve a patient's quality of life by palliating symptoms associated with uncontrolled growth of primary or regional disease; and In situations where aggressive interventions may prolong the life of a patient.

A number of studies have explored whether mastectomy improves survival compared with systemic treatments alone for patients with metastatic disease. These studies were nicely reviewed in a recent article published in Oncology by Seema Kahn, MD, of the Department of Surgery at Northwestern School of Medicine.^[2] Many retrospective studies comparing the outcomes of patients treated with surgery plus systemic treatments vs those treated with systemic treatments alone have reported a better progression-free or overall survival for those patients treated with surgery. However, selection biases have a significant influence on such studies, in that clinicians tend to offer surgery to those patients who are doing very well and not offer surgery to those patients with rapid progression of their disease.

In my own opinion, surgery and adjuvant radiation treatments of the primary and regional lymph nodes may be appropriately considered for highly selected patients who are first treated with systemic therapy and demonstrate a complete response at the sites of the metastatic disease. At MD Anderson Cancer Center, we also consider aggressive approaches for patients with few sites of visceral disease (oligometastases) that are amenable to local interventions in addition to the treatment of the primary and regional disease. The goal of treatments for such patients is to prolong life; accordingly, such patients should receive the optimal combination of surgery and radiation. We have adopted this strategy for highly selected patients at MD Anderson and have achieved a 5-year progression-free survival rate of 42% in the patients treated with surgery and radiation when they have first achieved an excellent response to systemic treatment.^[3]

For the patient presented, I would favor initial treatment with hormonal therapy, and I would monitor her response. Local-regional treatments should be considered only if an excellent and prolonged response is achieved.

MONITOR IMATINIB LEVELS?

Eur J Clin Pharmacol. 2009 Feb 12. [Epub ahead of print]

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Drug monitoring of imatinib levels in patients undergoing therapy for chronic myeloid leukaemia: comparing plasma levels of responders and non-responders.

Singh N, Kumar L, Meena R, Velpandian T.

Department of Medical Oncology, Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India.

PURPOSE: Imatinib mesylate is used as first line therapy in the treatment of chronic myeloid leukaemia. This study was designed to study the correlation of plasma levels of imatinib with response to the therapy. METHODS: A total of 40 chronic myeloid leukaemia patients in the chronic phase of the disease were recruited and placed into two groups of 20 patients: imatinib responders and imatinib non-responders, respectively. Each blood sample was taken 24 h after and immediately prior to taking a 400 mg oral dose of imatinib. Drug levels were detected by high-performance liquid chromatography. RESULTS: The mean plasma imatinib levels in the imatinib non-responders were significantly lower than those in the imatinib responders (0.70 vs. 2.34 microM, respectively; p = 0.002). CONCLUSIONS: Plasma levels of imatinib were correlated with response to the therapy, so routine monitoring of the therapeutic levels of the drug should be carried out specifically in treatment-resistant cases for determining dose escalation.

WHY NOT TO TRY KERAMIDA?

World J Urol. 2009 Feb 13. [Epub ahead of print]

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The novel use of intravesical docetaxel for the treatment of non-muscle invasive bladder cancer refractory to BCG therapy: a single institution experience.

Barlow LJ, McKiernan JM, Benson MC.

Department of Urology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, Herbert Irving Pavilion - 11th Floor, 161 Fort Washington Ave., New York, NY, 10032, USA, ljb2119@columbia.edu.

OBJECTIVES: Since the success of our Phase I trial of intravesical docetaxel for treatment-refractory non-muscle invasive bladder cancer (NMIBC), we have found this agent to be a favorable alternative for BCG-refractory patients unable or unwilling to undergo cystectomy. This study analyzes the safety and efficacy of intravesical docetaxel in a larger patient population with extended follow-up. METHODS: A retrospective analysis of all patients who received salvage intravesical docetaxel at our institution was conducted, including 18 patients treated during the Phase I trial and 15 patients treated after the trial's completion. Toxicity, efficacy and recurrence-free survival were analyzed. RESULTS: Thirty-three patients with refractory NMIBC received salvage intravesical docetaxel therapy between 2003 and 2008 at a single institution. Twenty of thirty-three (61%) patients had a complete response (CR) after six weekly induction treatments. Ten patients with CRs were given maintenance docetaxel therapy, and one patient received maintenance BCG and interferon. With a median follow-up of 29 months, 1 and 2-year recurrence-free survival rates were and 45 and 32%, respectively. Twelve of thirty-three patients (36%) had Grade 1 or 2 local toxicities. No patients experienced Grade 3 or 4 toxicities. CONCLUSIONS: Docetaxel is a promising intravesical agent with minimal toxicity and significant efficacy and durability for the management of BCG-refractory NMIBC.

ENDOCRINE THERAPY AND ZOMETA

N Engl J Med. 2009 Feb 12;360(7):679-91.

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Endocrine therapy plus zoledronic acid in premenopausal breast cancer.

Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C, Jakesz R, Seifert M, Hubalek M, Bjelic-Radisic V, Samonigg H, Tausch C, Eidtmann H, Steger G, Kwasny W, Dubsky P, Fridrik M, Fitzal F, Stierer M, Rücklinger E, Greil R; ABCSG-12 Trial Investigators, Marth C.

Medical University of Vienna, Austria. michael.gnant@meduniwien.ac.at

BACKGROUND: Ovarian suppression plus tamoxifen is a standard adjuvant treatment in premenopausal women with endocrine-responsive breast cancer. Aromatase inhibitors are superior to tamoxifen in postmenopausal patients, and preclinical data suggest that zoledronic acid has antitumor properties. METHODS: We examined the effect of adding zoledronic acid to a combination of either goserelin and tamoxifen or goserelin and anastrozole in premenopausal women with endocrine-responsive early breast cancer. We randomly assigned 1803 patients to receive goserelin (3.6 mg given subcutaneously every 28 days) plus tamoxifen (20 mg per day given orally) or anastrozole (1 mg per day given orally) with or without zoledronic acid (4 mg given intravenously every 6 months) for 3 years. The primary end point was disease-free survival; recurrence-free survival and overall survival were secondary end points. RESULTS: After a median follow-up of 47.8 months, 137 events had occurred, with disease-free survival rates of 92.8% in the tamoxifen group, 92.0% in the anastrozole group, 90.8% in the group that received endocrine therapy alone, and 94.0% in the group that received endocrine therapy with zoledronic acid. There was no significant difference in disease-free survival between the anastrozole and tamoxifen groups (hazard ratio for disease progression in the anastrozole group, 1.10; 95% confidence interval [CI], 0.78 to 1.53; P=0.59). The addition of zoledronic acid to endocrine therapy, as compared with endocrine therapy without zoledronic acid, resulted in an absolute reduction of 3.2 percentage points and a relative reduction of 36% in the risk of disease progression (hazard ratio, 0.64; 95% CI, 0.46 to 0.91; P=0.01); the addition of zoledronic acid did not significantly reduce the risk of death (hazard ratio, 0.60; 95% CI, 0.32 to 1.11; P=0.11). Adverse events were consistent with known drug-safety profiles. CONCLUSIONS: The addition of zoledronic acid to adjuvant endocrine therapy improves disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. (ClinicalTrials.gov number, NCT00295646.) 2009 Massachusetts Medical Society

CTCs AND SURVIVAL IN METASTATIC PROSTATE CANCER

February 13, 2009 — Circulating tumor cell (CTC) count is a more powerful early predictor of survival than prostate-specific antigen (PSA), according to a retrospective study of metastatic prostate cancer patients undergoing chemotherapy.

Among 164 men with progressive castration-resistant metastatic disease, changes in CTC number 4, 8, and 12 weeks after chemotherapy were "strongly associated" with mortality risk, whereas changes in PSA were "weakly or not associated," note the authors, led by Howard Scher, MD, chief of the Genitourinary Oncology Service and D. Wayne Calloway Chair in urologic oncology at Memorial Sloan–Kettering Cancer Center, in New York City.

The new study, published online February 11 in Lancet Oncology, is a reanalysis of the IMMC38 clinical trial, which showed that 5 tumor cells or more per 7.5 mL of blood at baseline and after treatment predicted a worse overall survival.

"It's a very compelling result," said Joel B. Nelson, MD, who was not involved with the trial and is professor and chair of the Department of Urology at the University of Pittsburgh School of Medicine, in Pennsylvania. "Going forward, clinical trials will have to decide whether or not they will include CTCs as a measure of disease progression," he said in an interview with Medscape Oncology.

"We desperately need more tools to measure disease progression," he added.

However, Dr. Nelson also believes that the new study is not practice-changing and that "CTC still needs to be well-established as to when and how you use it."

To date, Dr. Nelson and his colleagues at the University of Pittsburgh have not used CTC counts clinically.

"We have not been clear about how beneficial it is. This [IMMC38 trial] is the first large multicenter study in which it has been shown to be helpful," he said, stressing that other studies have been small.

CTCs "still need to be validated as a biomarker" in prostate cancer in prospective clinical trials, said Dr. Nelson.

Dr. Scher agreed. "If CTCs were a drug, they would be in phase 2 of the clinical trial process. That means CTCs have given a strong signal [as a surrogate marker of survival], but it now needs confirmation," he said in an interview with Medscape Oncology.

Nevertheless, Dr. Scher said the new study accomplished the goal of showing that CTCs are prognostic of survival.

CTC Count: Cutoff vs Continuous

The original IMMC38 analysis evaluated survival with first-line docetaxel-based chemotherapy treatment in 2 groups of patients — those above and those below a CTC cutoff point (classified as favorable or unfavorable, respectively).

The reanalysis evaluated survival based on lab values at baseline and at 4, 8, and 12 weeks, with no regard to cutoff values.

In effect, the reanalysis emphasizes the importance of using CTCs as a continuous measure for monitoring patients instead of as a cutoff point. Treatment "should be continued as long as CTC counts are stable or decreasing and there are no other signs of worsening disease," suggest the authors.

As part of the original study, PSA and CTC numbers were measured at baseline and before each chemotherapy cycle until disease progression was noted. Other clinical variables, including lactate dehydrogenase (LDH), were also measured, but only at baseline. CTC counts were done with the CellSearch and CellTracks systems (Veridex LLC).

Of the 164 patients in the study, 103 had died by the time of this survival analysis. The median follow-up for the 61 patients still living was 21.6 months.

In the new analysis, the change in CTC count relative to baseline at 4, 8, and 12 weeks after treatment was a strong indicator of the risk for death, but the association between change in PSA titer and survival was weak, note the authors. For instance, at 12 weeks, the hazard ratio (HR) was 1.49 for CTC change (P < .0001) and 1.21 for PSA change (P = .0424).

The investigators also analyzed the association between individual biomarkers at baseline and the risk for death.

Variables associated with risk for death were high LDH concentration (HR, 6.44; 95% confidence interval [CI], 4.24–9.79), high CTC count (HR, 1.58; 95% CI, 1.41–1.77), and high PSA titer (HR, 1.26; 95% CI, 1.10–1.45), low albumin (HR, 0.10; 95% CI, 0.03–0.39), and low hemoglobin (HR, 0.72; 95% CI, 0.64–0.81) at baseline.

Although a high CTC count at baseline is associated with mortality risk, Dr. Scher and his colleagues note that "low CTC counts at baseline do not ensure favorable prognosis" for individual patients. "There is a large range of survival times for patients with low counts at baseline," said Dr. Scher.

When discussing the increased risk for death associated with high LDH at baseline, Dr. Scher said that the next study of CTCs measured with the Veridex technologies will include continuous measurement of LDH. Thus, the prognostic value of CTCs will be compared with that of LDH and PSA.

Practical Advice for Clinicians About CTCs

The study authors offered clinicians some advice about using CTCs with metastatic patients undergoing chemotherapy.

"CTC counts tend to drop very fast if chemotherapy is working," said Dr. Scher.

The authors also note that, when using CTCs, the measuring of PSA titers did not provide "additional predictive power." This finding "argues against the making of treatment decisions on changes in PSA titers alone when CTC counts are being monitored."

Finally, when monitoring CTCs, think of them as providing a continuous evaluation of clinical status and not as a tool that provides a cutoff point, suggest the authors. "Cut points have been overemphasized," said Dr. Scher.

Use of discrete cutoff values in clinical practice could lead to some inappropriate decisions, they say. Cutoff values suggest that "therapy should be discontinued in the patient with a posttreatment value that remains in the unfavorable range [5 cells or more per 7.5 mL blood], independent of whether or not the value has declined from the pretreatment baseline," write the authors.

Study data were provided by the study sponsor, Immunicon Corporation, for this analysis. Funding was provided by the Prostate Cancer Foundation (Santa Monica, California). The researchers have disclosed no relevant financial relationships.

Lancet Oncol. Published online before print February 11, 2009.

BIPHOSPHONATES ANTIAGIOGENIC DRUGS AND OSTEONECROSIS OF THE JAW

Oncology. 2009 Feb 12;76(3):209-211. [Epub ahead of print]

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Combination of Bisphosphonates and Antiangiogenic Factors Induces Osteonecrosis of the Jaw More Frequently than Bisphosphonates Alone.

Christodoulou C, Pervena A, Klouvas G, Galani E, Falagas ME, Tsakalos G, Visvikis A, Nikolakopoulou A, Acholos V, Karapanagiotidis G, Batziou E, Skarlos DV.

Second Oncology Department, Metropolitan Hospital, Athens, Greece.

Background: The use of bisphosphonates is associated with osteonecrosis of the jaw (ONJ). Antiangiogenic agents are used with increasing frequency and may induce the risk of ONJ, especially when administered concurrently with bisphosphonates. Patients and Methods: We retrospectively reviewed data of 116 patients receiving bisphosphonates, 78 zoledronic acid and 38 ibandronic acid, with or without antiangiogenic agents for osseous metastases from various tumors in our department from June 2007 to June 2008. Results: ONJ developed in: 2 patients with breast cancer and 1 with colon cancer receiving concurrently bisphosphonates and bevacizumab, 1 patient with renal cell carcinoma receiving sunitinib and zoledronic acid concurrently, and 1 patient with prostate cancer receiving zoledronic acid without antiangiogenic agents. The incidences of ONJ among patients receiving bisphosphonates with or without antiangiogenic agents were 16 and 1.1%, respectively. The difference was statistically significant (p = 0.008). The treatment duration of bisphosphonates did not differ significantly between the 2 groups. Conclusions: The combination of bisphosphonates and antiangiogenic factors induces ONJ more frequently than bisphosphonates alone. These preliminary observations should be evaluated in large cohorts of patients and in prospective studies. Copyright © 2009 S. Karger AG, Basel.

A SAFE CETP INHIBITOR?

Am Heart J. 2009 Feb;157(2):352-360.e2. Epub 2008 Dec 20.

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Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients.

Bloomfield D, Carlson GL, Sapre A, Tribble D, McKenney JM, Littlejohn TW 3rd, Sisk CM, Mitchel Y, Pasternak RC.

Merck Research Laboratories, Rahway, NJ 07065-0900, USA. daniel_bloomfield@merck.com

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) levels are inversely associated with cardiovascular risk. Cholesteryl ester transfer protein inhibition is one strategy for increasing HDL-C. This study evaluated the lipid-altering efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy or coadministered with atorvastatin in patients with dyslipidemia. METHODS: A total of 589 patients with primary hypercholesterolemia or mixed hyperlipidemia (53.8% of the study population had low HDL-C) were randomized equally to one of 10 groups: 5 groups received background statin therapy of atorvastatin 20 mg and 5 did not, and each of these was randomized to placebo, anacetrapib 10, 40, 150, and 300 mg once daily for 8 weeks. An equal proportion of patients had triglycerides >150 mg/dL in each group. RESULTS: For placebo and anacetrapib monotherapy (10, 40, 150, and 300 mg), least squares mean percent changes from baseline to week 8 for low-density lipoprotein cholesterol (LDL-C) were 2%, -16%, -27%, -40%, and -39%, respectively, and for HDL-C were 4%, 44%, 86%, 139%, and 133%, respectively (P < .001 vs placebo for all doses). Coadministration of anacetrapib with atorvastatin produced significant incremental LDL-C reductions and similar HDL-C increases versus atorvastatin monotherapy. For both anacetrapib monotherapy and coadministration with atorvastatin, the LDL-C reductions were similar in patients with baseline triglyceride levels greater than and less than or equal to the median. Anacetrapib was well tolerated, and the incidence of adverse events was similar for placebo and all active treatment groups. There were no increases in systolic or diastolic blood pressure in any treatment arm. CONCLUSIONS: Anacetrapib, as monotherapy or coadministered with atorvastatin, produced significant reductions in LDL-C and increases in HDL-C; the net result of treatment with anacetrapib + atorvastatin was approximately 70% lowering of LDL-C and more than doubling of HDL-C. Anacetrapib was generally well tolerated with no discernable effect on blood pressure.

NO BENEFIT OF DOCETAXEL FOR LUMINAL A NODE POSITIVE PATIENTS

J Clin Oncol. 2009 Feb 9. [Epub ahead of print]

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Breast Cancer Subtypes and Response to Docetaxel in Node-Positive Breast Cancer: Use of an Immunohistochemical Definition in the BCIRG 001 Trial.

Hugh J, Hanson J, Cheang MC, Nielsen TO, Perou CM, Dumontet C, Reed J, Krajewska M, Treilleux I, Rupin M, Magherini E, Mackey J, Martin M, Vogel C.

University of Alberta; Cross Cancer Institute, Edmonton, Alberta; Genetic Pathology Evaluation Centre, Vancouver Coastal Health Research Institute, British Columbia Cancer Agency, and University of British Columbia, Vancouver, British Columbia, Canada; Lineberger Comprehensive Cancer Center and Departments of Genetics and Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC; L'Institut National de la Santé et de la Recherche Médicale, U590; Hospices Civils de Lyon; Université Lyon; Centre Léon Bérard, Lyon; Cancer International Research Group; Sanofi-aventis, Paris, France; Burnham Institute for Medical Research, La Jolla, CA; Hospital Universitario San Carlos, Madrid, Spain; and Lynn Cancer Center, Boca Raton, FL.

PURPOSE: To investigate the prognostic and predictive significance of subtyping node-positive early breast cancer by immunohistochemistry in a clinical trial of a docetaxel-containing regimen. METHODS: Pathologic data from a central laboratory were available for 1,350 patients (91%) from the BCIRG 001 trial of docetaxel, doxorubicin, and cyclophosphamide (TAC) versus fluorouracil, doxorubicin, and cyclophosphamide (FAC) for operable node-positive breast cancer. Patients were classified by tumor characteristics as (1) triple negative (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, HER2/neu [HER2]-negative), (2) HER2 (HER2-positive, ER-negative, PR-negative), (3) luminal B (ER-positive and/or PR-positive and either HER2-positive and/or Ki67(high)), and (4) luminal A (ER-positive and/or PR-positive and not HER2-positive or Ki67(high)), and assessed for prognostic significance and response to adjuvant chemotherapy. RESULTS: Patients were subdivided into triple negative (14.5%), HER2 (8.5%), luminal B (61.1%), and luminal A (15.9%). Three-year disease-free survival (DFS) rates (P values with luminal B as referent) were 67% (P < .0001), 68% (P = .0008), 82% (referent luminal B), and 91% (P = .0027), respectively, with hazard ratios of 2.22, 2.12, and 0.46. Improved 3-year DFS with TAC was found in the luminal B group (P = .025) and a combined ER-positive/HER2-negative group treated with tamoxifen (P = .041), with a marginal trend in the triple negatives (P = .051) and HER2 (P = .068) subtypes. No DFS advantage was seen in the luminal A population. CONCLUSION: A simple immunopanel can divide breast cancers into biologic subtypes with strong prognostic effects. TAC significantly complements endocrine therapy in patients with luminal B subtype and, in the absence of targeted therapy, is effective in the triple-negative population.