Σάββατο 19 Δεκεμβρίου 2009

AROMATASE INHIBITORS TOP TAMOXIFEN- A NEW METAANALYSIS

NEW YORK (Reuters Health) Dec 11 - Breast cancer recurrence rates are lower with aromatase inhibitors than with tamoxifen, according to meta-analyses published online by the Journal of Clinical Oncology.

Furthermore, recurrence is reduced whether the aromatase inhibitors are given initially or after several years of tamoxifen therapy, the researchers report.

Dr. Mitch Dowsett, from Royal Marsden Hospital in London, UK, and members of the Early Breast Cancer Trialists' Collaborative Group analyzed data from six trials involving nearly 19,000 women, all of whom had estrogen-receptor positive tumors.

The trials were grouped into two cohorts. Cohort 1 included 9,856 enrollees in two 5-year trials that compared aromatase inhibitors with tamoxifen, with each drug started immediately after surgery.

Cohort 2 comprised 9,015 participants in four 5-year trials in which all women started on tamoxifen after surgery. After two to three years, some were switched to aromatase inhibitors for the remainder of the study, and the rest continued with tamoxifen.

In the first cohort, aromatase inhibitor therapy led to an absolute decrease in recurrence of 2.9% (9.6% for aromatase inhibitors vs 12.6% for tamoxifen; 2p <>

In the second cohort, at 3 years from treatment divergence (approximately 5 years after starting hormonal therapy), aromatase inhibitors were associated with an absolute 3.1% decrease in recurrence (5.0% vs 8.1%, 2p < 2p =" 0.02).

"When the switch to an aromatase inhibitor is made after 2 to 3 years of tamoxifen, there seems to be a particularly marked reduction in risk of recurrence (by 40%) during the following 3 years," the authors comment. They also note that aromatase inhibitors were not associated with any increase in non-breast cancer deaths relative to tamoxifen.

On the other hand, the adverse effect profile differs between the two classes of drugs. Aromatase inhibitors are associated with fewer endometrial cancers and thromboembolic events than the selective estrogen receptor modulator, but with more arthralgia and fractures.

"The decision on whether to initiate treatment with an aromatase inhibitor or tamoxifen or whether to switch to an aromatase inhibitor after 2 to 3 years of tamoxifen rather than continuing with tamoxifen for 5 years depends on a careful evaluation of these factors in individual patients," Dr. Dowsett and his associates maintain.

They conclude: "This overview has provided greater confidence in the efficacy aspects of this evaluation."

J Clin Oncol 2009.

CHEMOTHERAPY FOR ER+ POSTMENOPAUSAL WOMEN?

December 18, 2009 (San Antonio, Texas) — Postmenopausal women with hormone-receptor-positive and node-positive breast cancer who are at especially high risk for recurrence might be the main beneficiaries of the addition of chemotherapy to tamoxifen to prevent recurrence. This suggestion comes from 10-year results of a landmark clinical trial published online December 10 in the Lancet.

Furthermore, a multigene assay might help rule out women who do not benefit from the added chemotherapy, according to a related study.

This second study, which uses a group of patients from the same landmark trial, was presented as a poster here at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS).

The landmark trial, known as Southwest Oncology Group (SWOG)-8814, randomized 1477 patients. The new results from a 10-year follow-up show that chemotherapy added to tamoxifen (in both a concurrent and sequential fashion) provides statistically significantly better disease-free survival than tamoxifen alone (57% vs 48%; P = .002).

For the secondary end point of overall survival, chemotherapy added to tamoxifen is superior to tamoxifen alone, but not statistically significantly so (65% vs 60%; P = .043).

The chemotherapy regimen used was anthracycline-based CAF (cyclophosphamide, doxorubicin [Adriamycin], and fluorouracil), which was one of the "most commonly used regimens when this trial was designed," write SWOG investigators. Tamoxifen was taken daily for 5 years.

Despite the 5% improvement in overall survival from adjuvant chemotherapy, the majority of the patients (95%) who received the chemotherapy did not derive any additional benefit, notes an editorial that accompanies the study.

"There is a price to pay" for the incremental improvement that is seen, write editorialists Michael Gnant, MD, and Guenther Steger, MD, both from the Medical University of Vienna in Austria. The price includes toxic effects in many of those who do not have a survival benefit, including early deaths, congestive heart failure, and secondary neoplasms, they write.

Because of all the toxicity of chemotherapy, identifying "subgroups of patients who have an above-average outcome" and predicting response are important, say the editorialists.

"Avoidance of ineffective treatment should be one of the main goals in adjuvant breast oncology today," declare Dr. Gnant and Dr. Steger.

High-Risk Women Seem to Benefit

To see if there was "variation in the efficacy of chemotherapy," the SWOG investigators performed an unplanned subgroup analysis.

"Patients with 4 or more positive nodes derived more benefit than did those with 1 to 3 positive nodes" observe the investigators, led by Kathy Albain, MD, from Loyola University Stritch School of Medicine in Maywood, Illinois. Also, "patients less than 65 years might have had a greater degree of benefit than older patients," they note.

In short, in this postmenopausal, hormone-receptor-positive, node-positive breast cancer population, the patients at "high risk of relapse" (large tumors, age younger than 65 years, and more than 4 affected nodes) mainly show a benefit of adjuvant chemotherapy, summarize the editorialists.

Although this unplanned analysis from SWOG-8814 lacks statistical power, the editorialists note that this finding is in keeping with findings from other adjuvant trials. Namely, "overall benefit is mainly accounted for by the high-risk subgroup of patients," they write

This is where the second study, which was presented as a poster here at SABCS by Dr. Albain and published online December 10 in the Lancet Oncology, comes in.

"It might be possible to identify some subgroups that do not benefit from anthracycline-based chemotherapy despite positive nodes," write the SWOG investigators.

Among the patients in SWOG-8814, there were 367 specimens with sufficient RNA for analysis with a 21-gene recurrence-score assay (Oncotype DX, Genomic Health).

The 21-gene recurrence-score assay was developed to predict which patients with estrogen-positive breast cancer can avoid adjuvant chemotherapy, explain Fabrice Andre, MD, and Suzette Delaloge, MD, from Institut Gustave Roussy in Villejuif, France, in an editorial in Lancet Oncology.

Sixteen of the genes in the test are cancer-related, including those related to estrogen receptor and HER2.

"The test is all about the biology of the tumor," Julie Gralow, MD, told Medscape Oncology. Dr. Gralow is a member of the Fred Hutchison Cancer Research Center in Seattle, Washington, and a coinvestigator of the recurrence-score study.

The 21-gene recurrence-score assay is prognostic for women with node-negative, estrogen-receptor-positive breast cancer treated with tamoxifen, note Dr. Albain, Dr. Gralow, and their colleagues. A low recurrence score predicts little benefit from chemotherapy.

The SWOG team therefore investigated whether the assay would be prognostic in node-positive women.

Assay is Prognostic in This Setting Too

Specifically, Dr. Albain and colleagues looked at node-positive SWOG-8814 patients treated with both tamoxifen alone and with chemotherapy plus tamoxifen.

Although reported as a continuous variable, the recurrence score is usually split into 3 categories — low risk (score <18),>

The study authors conclude that the recurrence score predicts "significant benefit of CAF" in patients with tumors with a high recurrence score.

A low recurrence score identifies women who "might not benefit from anthracycline-based chemotherapy, despite positive nodes," they also conclude.

Editorialists Dr. Andre and Dr. Delaloge say that the 21-gene recurrence-score assay is clearly a prognostic tool, but that more studies are needed to better define its indications.

Dr. Albain agreed. "Prospective studies with larger sample sizes are needed to determine who will optimally benefit from chemotherapy," she said in a press statement.

Dr. Gralow currently uses the assay in her clinic. "I send it in when I need to decide about chemotherapy," she said. "But it is not 100% of the decision," she added.

Avoiding chemotherapy in patients who will not benefit is a very worthwhile thing, explained Dr. Gralow. "Chemotherapy is awful," she said, referring to adverse effects and quality of life for patients.

Dr. Albain and coauthors report being speakers bureau members, lecturers, or advisory board members for Genomic Health, the maker of the Oncotype DX assay. Dr. Andre reports receiving honorarium from Genomic Health. Dr. Gralow reports receiving honoraria from Genentech, Novartis, and Roche, and research funding from Amgen, Bayer, Bristol-Myers Squibb, Genentech, Novartis, Roche, and Sanofi-Aventis.

Lancet. 2009;374:2029-2030, 2055-2063. Abstract, Abstract

Lancet Oncol. Published online December 10, 2009. Abstract, Abstract

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract 112. Presented December 10, 2009.

USE CT SCAN ONLY WHEN IT IS APPROPRIATE

December 17, 2009 — Computed tomography (CT) scans are widely used and are an invaluable tool for medical imaging. However, the possible overuse of CT scans and the variability in radiation doses might subsequently lead to thousands of cases of cancer, according to findings from 2 new studies published in the December 14/28 issue of the Archives of Internal Medicine.

In the first study, researchers found that radiation doses from common CT procedures are higher and more variable than what is typically cited. For example, the authors note that the median effective dose of an abdomen and pelvis CT scan is often cited as 8 to 10 mSv, but they found that the median dose of this type of scan was actually 66% higher, and the median dose of a multiphase CT scan of the abdomen and pelvis was nearly 4 times higher.

The authors also found a considerable range in doses within and across the institutions included in their study, with a mean 13-fold variation between the highest and lowest dose for each CT type studied.

In the second study, researchers estimated future cancer risks from current CT scan use in the United States, and projected that 29,000 future cancers will be directly attributable to CT scans that were performed in 2007. It is expected that the majority of these projected cancers will be caused by scans of the abdomen and pelvis (n = 14,000), chest (n = 4100), and head (n = 4000), and by CT coronary angiography (n = 2700).

More than 19,500 CT scans are performed every day in the United States; these expose each patient to the equivalent of 30 to 442 chest radiographs per scan, notes Rita F. Redberg, MD, MSc, professor of medicine at the University of California, San Francisco School of Medicine and editor of the Archives of Internal Medicine, in an accompanying editorial.

However, there is a question of benefit — whether these scans will lead to "demonstrable benefits through improvements in longevity or quality of life are hotly debated," she writes. "What is becoming clear, however, is that the large doses of radiation from such scans will translate, statistically, into additional cancers."

"We need to do something now, not wait 10 or 20 years to see the effects. It's not like radiation exposure can be undone after we find out that it does cause cancer," Dr. Redberg told Medscape Oncology.

Estimates Too High?

In response to this news about the cancer risk from CT scans, which has been widely reported in the lay media, the American College of Radiology (ACR) has questioned the methodology used in the 2 studies.

In a statement, the ACR acknowledges that the widespread use of imaging exams has resulted in increased radiation exposure, and advises that no imaging exam be performed unless there is a clear medical benefit that outweighs any associated risk. They support the concept of "as low as reasonably achievable," which urges providers to use the minimum level of radiation needed in imaging exams to achieve the necessary results.

However, in their statement, the ACR notes that "no published studies show that radiation from imaging exams causes cancer." They also question how the risk was measured, pointing out that the "conclusions of the authors of the Archives' studies rely largely on data that equate radiation exposure and effects experienced by atomic-bomb survivors in Japan to present-day patients who receive CT scans."

Most CT scans are conducted in controlled settings, which results in limited radiation exposure to a small portion of the body, whereas atomic-bomb survivors experienced instantaneous exposure to their entire body, they write. CT exams also only expose patients to x-rays, whereas survivors of the atomic bomb were exposed not only to x-rays, but also to particulate radiations, neutrons, and other radioactive materials.

Thus, the known biologic effects are very different for these 2 scenarios, they note, and "cancer assumptions based on this paradigm should be considered, but not accepted as medical fact."

The ACR also noted that, after excluding patients with cancer or within 5 years of the end of life, the studies assume that the patients undergoing CT scanning have the same life expectancy as the general population. "This is not accurate, so the estimates are undoubtedly high," they write.

In direct contrast to some of these comments, Dr. Redberg said, in an interview, that "the evidence is very strong as far as the link between radiation exposure and cancer." She supports the evidence presented in these papers, and believes that it makes it clear that more attention needs to paid to radiation exposure from medical CT scanning. "Both studies underwent rigorous peer review and I have confidence in their findings and scientific methods."

All scans are not life-saving, and it would be hard to argue against there being variation in the radiation doses, or that all scans are necessary, Dr. Redberg said.

"Whenever people first question the safety of a standard practice — whether it's driving without seatbelts or x-raying children's feet to assess their correct shoe size — there will be others who say things are just fine as they are," she said. "We felt these data were accurate and significant enough to raise concern in the medical community."

Doses Higher and More Variability

In the first of the 2 studies, Rebecca Smith-Bindman, MD, a professor in residence of radiology, University of California, San Francisco, and colleagues conducted a retrospective cross-sectional study with the goal of estimating future cancer risks from current CT scan use. They assessed the radiation dose associated with the 11 most common types of diagnostic CT studies that were conducted on 1119 consecutive adult patients at 4 facilities in California between January 1 and May 30, 2008. These data were then used estimate the lifetime attributable risk for cancer associated with these imaging scans.

"It is important to understand how much radiation medical imaging delivers, so this potential for harm can be balanced against the potential for benefit," the authors write. "This is particularly important because the threshold for using CT has declined, and CT is increasingly being used among healthy individuals, in whom the risk of potential carcinogenesis from CT could outweigh its diagnostic value."

The 11 types of CT scans evaluated in the study comprised approximately 80% of all CT scans performed. The mean patient age was 59 years, and nearly half (48%) were female.

They found that the doses of radiation varied significantly among the different types of CT scans, with the overall median effective doses ranging from 2 mSv for a routine head CT scan to 31 mSv for a multiphase abdomen and pelvis CT scan. The comparison of organ-specific doses showed that CT coronary angiogram delivers a dose to the breast that is equivalent to approximately 15 mammography screenings. It also delivers a radiation dose to the lung that is equivalent to 711 chest x-rays, the authors note.

Effective doses also varied significantly within and across institutions for each type of CT scan. Effective doses tended to be higher and more variable in CT scans of the abdomen and pelvis, and the largest dose range was seen in multiphase abdomen and pelvis CT scanning (range, 6 to 90 mSv).

Women Face Greater Risk

The authors estimated lifetime attributable risks for cancer by scan type from these measured doses and, as they expected, the number of CT scans that would result in a cancer varied considerably by sex, age, and type. It would take far fewer CT scans to result in a cancer in women than in men, for example, reflecting a higher cancer risk from radiation.

They estimated that 1 in 270 women who underwent a CT coronary angiogram at the age of 40 years will eventually develop cancer, compared with 1 in 600 men. For a routine head CT, the estimated risk was 1 in 8100 for a 40-year-old woman and 1 in 11,080 for a man of the same age. For 20-year-old patients, these risks were approximately double; for 60-year-old patients, they were approximately 50% lower.

Based on the highest effective dose that was observed, a 20-year-old women who received a CT scan for suspected pulmonary embolism, a CT coronary angiography, or a multiphase abdomen and pelvis CT scan could have an associated increased risk of developing cancer of as high as 1 in 80, note the authors. "The risks declined substantially with age and were lower for men, so radiation-associated cancer risks are of particular concern for the younger, female patient," they write.

Thousands of Future Cancers?

In the second study, Amy Berrington de González, DPhil, from the National Cancer Institute, in Bethesda, Maryland, and colleagues conducted a study to determine the estimated risk for future cancer from current CT scan use in the United States according to age, sex, and scan type.

They used risk models based on the National Research Council's "Biological Effects of Ionizing Radiation" report, and organ-specific radiation doses derived from a national survey.

An estimated 72 million CT scans were performed in the United States in 2007. For their calculations, the researchers excluded scans obtained in the last 5 years of life and those with a diagnostic code related to cancer, lowering the number to 57 million.

The number of CT scans performed increased with age at exposure until the age of 45 years, the authors note; it is estimated that 30% of scans are performed in adults 35 to 54 years. In addition, it is estimated that about 60% of the scans were performed in women.

The projected number of incident cancers per 10,000 scans generally decreased with increasing age at exposure, and although the risk varied according to the type of scan, there were consistently high risks for chest or abdomen CT angiography and whole-body CT, they noted.

When age- and sex-specific annual frequencies were combined with the estimated risk per 10,000 scans, the authors estimated that approximately 29,000 (95% uncertainty limits [UL], 15,000 - 45,000) future cancers could be related to the number of CT scans performed in 2007.

When broken down by cancer site, lung cancer was estimated to be the most common projected radiation-related cancer (n = 6200; 95% UL, 2300 -13,000). This was followed by colon cancer (n = 3500; 95% UL, 1000 - 6800) and leukemia (n = 2800; 95% UL, 800 - 4800).

"Changes made to practice now could help to avoid the possibility of reaching the level of attributable risk suggested above," the authors write. "Our detailed estimates highlight several areas of use in which the public health impact may be largest, specifically abdomen and pelvis and chest CT scans in adults aged 35 to 54 years."

The study by Dr. Smith-Bindman and colleagues was funded by the National Institutes of Health (NIH), a National Institute of Biomedical Imaging and BioEngineering training grant, NIH National Cancer Institute grants, and the University of California, San Francisco School of Medicine Bridge Funding Program. The authors have disclosed no relevant financial relationships.

The study by Dr. Berrington de González and colleagues received no outside funding. Study coauthor Mahadevappa Mahesh, MS, PhD, from Johns Hopkins University School of Medicine, in Baltimore, Maryland, reports receiving funding from Siemens Medical Systems. None of the other authors have disclosed any relevant financial relationships.

Arch Intern Med. 2009;169:2049-2050, 2071-2077, 2078-2086.

ADJUVANT CHEMOTHERAPY FOR LUNG CANCER

NEW YORK (Reuters Health) Dec 15 - Treatment of early-stage non-small-cell lung cancer (NSCLC) with cisplatin and vinorelbine after complete tumor resection significantly improves 5-year survival, a recent study has found.

The results reflect what the authors say is the longest follow-up of any recent trial of adjuvant therapy in NSCLC. The report, by Dr. Charles A. Butts of the Cross Cancer Institute, Edmonton, Alberta and colleagues, was published online November 23 by the Journal of Clinical Oncology.

After complete resection, 482 NSCLC patients with stage IB or II cancers were randomized to adjuvant therapy or observation only. They were followed for a median of 9.3 years (range, 3.2 to 13.4). Thirty-three patients were lost to follow-up and 271 died - 143 in the observation group and 128 in the chemotherapy group.

The 5-year survival rate for was 67% with adjuvant chemotherapy and 56% in the control group. Median survival times were 3.6 years with observation versus 6.8 years with treatment.

Whereas stage II patients had had significantly improved survival with chemotherapy (hazard ratio, 0.68), treatment afforded no overall survival benefit in stage IB disease.

A "clinically meaningful benefit" of adjuvant treatment for stage IB patients did become evident when subgroups were analyzed, however. For instance, stage IB patients with tumors 4 cm or larger had 5-year survival rates of 79% with chemotherapy, versus 59% with observation. Patients with tumors smaller than 4 cm had no clinical benefit from the treatment, however.

Adjuvant chemotherapy was not associated with an increase in death from other causes, and there was no evidence of unexpected late toxicity or of any increase in second malignancies, the researchers said.

The study is an updated survival analysis of the JBR.10 trial, a phase III randomized trial in which no postoperative radiation was permitted.

Both this report and an accompanying editorial note that the finding of a long-term benefit from the adjuvant regimen is at odds with most other recent studies of adjuvant chemotherapy in NSCLC.

This cisplatin-plus-vinorelbine combination "has been the only regimen that has shown a consistent result in terms of improvement in survival in the adjuvant setting," Dr. Butts told Reuters Health by e-mail.

In the editorial, Dr. Jean-Yves Douillard of the Centre Rene Gauducheau, St. Herblain, France, suggests that based on this and other recent studies, the choice of both the platinum-based agent and the drug to combine with it could be crucial.

In light of current evidence, Dr. Douillard writes, "cisplatin and vinorelbine should be the recommended regimen for a durable and reproducible benefit" in the types of NSCLC covered in the present study.

J Clin Oncol 2009.

INDIVIDUALIZED TREATMENT FOR ALL

December 16, 2009 (New Orleans, Louisiana) — Two conclusions from the 5-year results of a trial in childhood acute lymphoblastic leukemia (ALL), which were presented at the American Society of Hematology (ASH) 51st Annual Meeting, are potentially practice-changing, according to program cochair Richard Van Etten, MD, PhD, chief of hematology/oncology and director of the Cancer Center at Tufts Medical Center, in Boston, Massachusetts.

In an interview with Medscape Oncology, he said the results show that individualizing the dose of asparaginase on the basis of pharmacokinetic measurements produced superior results to those seen with a fixed-dose regimen, and "everybody should now start doing this."

In addition, the trial showed superior results with dexamethasone, compared with prednisone, when added to asparaginase, he noted.

The findings come from the Dana-Farber Cancer Institute Protocol 00-01, and 5-year results were presented at the meeting by Lynda M. Vrooman, MD, from the Dana-Farber Cancer Institute in Boston. The protocol was designed with the overall goal of improving the efficacy of therapy and minimizing treatment-related toxicity.

To that end, explained Dr. Vrooman, the researchers evaluated an alternative dosing method for asparaginase, which is associated with toxicities such as allergy, thrombosis, and pancreatitis. They also studied the use of dexamethasone in postinduction therapy, because both preclinical and clinical data have suggested that, compared with prednisone, dexamethasone has a higher antileukemia effect, although a greater degree of toxicity has been noted.

The cohort consisted of 492 children from 10 institutions, between the ages of 1 and 18 years, and who were recruited between 2000 and 2004. All patients were newly diagnosed with ALL, and 282 were classified as standard risk and 210 were classified as high risk. Postinduction treatment for all study participants included 30 weeks of intramuscular Escherichia coli asparaginase (beginning at week 7) and vincristine/corticosteroid pulses every 3 weeks for 24 months.

Of this group, 473 achieved complete remission and were then eligible for a randomized comparison.

Asparaginase Results

In the asparaginase section of the trial, 384 (of 473) patients (81%) were assigned to 1 of 2 treatments for 30 weeks: 195 received a fixed dose of asparaginase (25,000 IU/m2); and 189 received an individualized dose, with a starting dose of 12,500 IU/m2. The nadir serum asparaginase activity (NSAA) was evaluated every 3 weeks, and doses in patients receiving individualized therapy were adjusted to maintain NSAA between 0.10 and 0.14 IU/mL.

Patients randomized to individualized dosing demonstrated better 5-year event-free survival than fixed dosing (± standard error, 90 ± 2% vs 82 ± 3%; P = .04); this was observed across all subgroups.

Event-Free Survival at 5 Years: Individualized vs Fixed-Dose Asparaginase

ALL Population Individualized Dose
(± Standard Error)
Fixed Dose
(± Standard Error)
Overall 90 ± 2% 82 ± 3%
Standard-risk group 89 ± 3% 86 ± 4%
High-risk group 93 ± 3% 78 ± 5%
1–10 year age group 90 ± 3% 85 ± 3%
10–18 year age group 90 ± 5% 72 ± 7%

The frequency of asparaginase-related allergy, pancreatitis, and thrombosis were similar between the 2 groups and on multivariable analysis, explained Dr. Vrooman, and both dexamethasone and individual-dose asparaginase were independent predictors of a favorable outcome (hazard ratio [HR] for dexamethasone, 0.49 [P = .02]; HR for individual-dose asparaginase, 0.52 [P = .04]), with no indication of interaction.

"We found that individualizing dosing with asparaginase was feasible in a multi-institution study," said Dr. Vrooman.

Although individualized dosing was associated with a superior outcome, she pointed out that this was not because of a reduction in toxicity or improved tolerability. "We are currently analyzing the association of asparaginase levels and asparaginase antibody formation with outcome in greater detail," she said.

Dexamethasone Superior to Prednisone

The steroid part of the trial was conducted in a cohort of 408 (of 473) children (86%) who were randomized to receive either dexamethasone (n = 201) or prednisone (n = 207) as 5-day pulses every 3 weeks.

Using dexamethasone in the postinduction phase resulted in one third fewer relapses than prednisone, Dr. Vrooman reported. In addition, the 5-year event-free survival (± standard error) for patients who received dexamethasone (n = 201) was 90 ± 2%, and for patients who received prednisone (n = 207) was 81 ± 3%.

Event-Free Survival at 5 Years: Dexamethasone vs Prednisone

ALL Population Dexamethasone
(± Standard Error)
Prednisone
(± Standard Error)
Overall 90 ± 2% 81 ± 3%
Standard-risk group 89 ± 3% 84 ± 4%
High-risk group 91 ± 4% 78 ± 5%
1–10 year age group 91 ± 3% 82 ± 3%
10–18 year age group 88 ± 5% 77 ± 6%

Another trial, presented at ASH 2008, showed that dexamethasone is more effective in childhood ALL. In that study, dexamethasone decreased the risk for relapse by one third when given early in the treatment cycle, compared with prednisone. However, there were no differences in long-term survival in that trial.

Increase in Toxicity

In the latest study, Dr. Vrooman reported that dexamethasone was associated with more bone and infectious toxicities than prednisone, especially in older children and adolescents.

Although there was a significant increase in the rate of osteonecrosis in older patients receiving dexamethasone, the researchers did not observe a difference in the 5-year cumulative index of osteonecrosis in younger patients (aged 1 to 10 years); for dexamethasone it was 2.6% and for prednisone it was 4.3% (P = .43).

Fractures were more common among patients 10 to 18 years old who received dexamethasone than among those who received prednisone (P = .06), but this increased incidence was not observed in the younger group (P = .25). There was also a higher rate of infection in the dexamethasone group (n = 38; 18.8%) than in the prednisone group (n = 22; 10.6%).

No difference in the rate of death in remission was observed between the groups; it was 0% for dexamethasone and 2% for prednisone (P = .5).

"There was a very high rate of osteonecrosis in the older patients," said Nicola Gökbuget, MD, from the Goethe University Hospital, in Frankfurt, Germany. "If we use this regimen in adults, then we need to follow patients closely and monitor them for this complication."

It isn't certain that these findings would extrapolate to adults, explained Dr. Gökbuget, who was not involved in the study but was approached by Medscape Oncology for independent comment. "But we saw that this complication was higher in older children, so it could be even higher in adults," she said. "It could also be that this population is the most vulnerable."

Dr. Gökbuget also noted that, at the current time, little is known about prophylaxis for osteonecrosis. "We need to think about preventing it from occurring in the first place, as this can significantly affect the patient's quality of life," she said. "We also need to think about treating it. There are new approaches being investigated, but there is a lot of work left to do in this field."

Of the 92 patients who were randomized to both dexamethasone and individual-dose asparaginase, only 5 (5%) experienced an event.

Dr. Vrooman concluded that although dexamethasone is associated with superior event-free survival, the toxicity was higher. "Future studies should focus on minimizing dexamethasone toxicity in older pediatric patients without compromising efficacy," she said.

Dr. Vrooman has disclosed no relevant financial relationships. Study coauthors Jeffrey G. Supko, PhD, from Massachusetts General Hospital in Boston, and Stephen E. Sallan, MD, from the Dana-Farber Cancer Institute in Boston, report receiving research funding from Enzon, Inc.

American Society of Hematology (ASH) 51st Annual Meeting: Abstract 321. Presented December 7, 2009.

ANTIESTROGENS PROTECT AGAINST LUNG CANCER

December 17, 2009 (San Antonio, Texas) — In a large Swiss observational study, women who were taking antiestrogens, mainly tamoxifen, for the prevention of breast cancer recurrence had a lower risk of dying from lung cancer than similar women not taking these drugs.

This finding, presented here at the 32nd Annual San Antonio Breast Cancer Symposium, supports the hypothesis that estrogens play a role in lung cancer, said lead researcher Elisabetta Rapiti, MD, MPH, from the Geneva Cancer Registry at the University of Geneva in Switzerland.

Dr. Rapiti explained that the idea for the study was sparked by the report earlier this year of a link between lung cancer and hormone replacement therapy, based on an analysis of data from the Women's Health Initiative. These data suggested that hormone replacement therapy increases the risk of dying from lung cancer, especially nonsmall-cell lung cancer, although there was no increase in the incidence of lung cancer. This finding was reported in May 2008 by Rowan Chlebowski, MD, PhD, from the Harbor-UCLA Medical Center in Los Angeles, California, at the annual meeting of the American Society of Clinical Oncology, and subsequently published in The Lancet (2009;374:1243-1251).

"If hormones are associated with an increase in mortality from lung cancer, then maybe antiestrogens would be associated with a lower risk," Dr. Rapiti said.

To investigate this possibility, her team analyzed data from the Geneva Cancer Registry and identified 6715 patients with breast cancer between 1980 and 2003. Nearly half of these women (46%, n = 3066) received antiestrogen therapy, mostly tamoxifen.

In this patient cohort, there were 40 cases of lung cancer (diagnosed at least 6 months after the breast cancer). Of these, 12 cases (and 2 deaths) were found in women taking antiestrogens and 28 cases (and 16 deaths) were found in the remaining women.

Next, the team calculated standardized incidence ratios and standardized mortality ratios to compare the study population with the general female population in Geneva.

The incidence of lung cancer in both groups of women with breast cancer was similar to that of the general population, Dr. Rapiti said. Compared with the general population, the risk of developing lung cancer was 0.63 among women taking antiestrogens and 1.12 among those not taking these drugs.

Commenting on this finding, chair of the session, Patricia Ganz, MD, from the University of California in Los Angeles School of Medicine, told Medscape Oncology that the difference was not statistically significant, but that the rate was lower among women taking antiestrogens, and the "trend was clear." However, she added that there was likely to be an ascertainment bias here, in that these women with breast cancer would be followed and monitored more closely than women in the general population, and thus would be more likely to have lung cancer diagnosed if it did occur.

In addition, Dr. Rapiti made the point during the question period that women with breast cancer were likely to have received radiotherapy to the chest area, which increases the risk for lung cancer.

Significant Reduction in Risk for Death

When the researchers calculated mortality rates from lung cancer, they found a significant decrease in the risk for death from lung cancer in women taking antiestrogens. The rate in the general population was 31.44 per 100,1000; for women taking antiestrogens, it was 9.23 per 100,000, and for women not taking antiestrogens, it was 44.97 per 100,000. The standardized mortality ratio for lung cancer was significantly lower in women taking antiestrogens than in women not taking these drugs (0.13 vs 0.76; P < .001).

Women taking antiestrogens for the prevention of breast cancer had a significantly reduced risk of dying from lung cancer, Dr. Rapiti concluded. "This result further supports the role of estrogens in lung cancer prognosis and suggests that exposure to antiestrogens may offer some protection against tumor mortality."

She noted that there are phase 2 clinical trials currently underway that are evaluating the use of antihormone therapy as an adjunct to traditional chemotherapy for lung cancer. "If prospective studies confirm our results and find that antiestrogen agents improve lung cancer outcomes, this could have substantial implications for clinical practice," she said.

However, Dr. Rapiti emphasized, this is an observational study, and so "we cannot exclude residual confounding factors."

Approached for comment, Dr. Ganz said this finding is hypothesis-generating, and supports a role for estrogens and hormones in the control of lung cancer in women. She said this is an area of great interest at the moment, because other results are also pointing in this direction.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract 35. Presented December 11, 2009.

GENETIC MAP FOR MELANOMA AND LUNG CANCER

December 17, 2009 — The first genetic maps of lung cancer and melanoma reveal the pivotal role of smoking and sunlight in triggering these two deadly forms of cancer.

In two new studies, researchers have sequenced the genome and mapped the entire series of thousands of genetic mutations that are not inherited but accumulate in the cells to cause small-cell lung cancer and melanoma.

The results show most of the 23,000 gene mutations associated with small-cell lung cancer are caused by the cocktail of chemicals found in cigarettes.

"On the basis of average estimates, we can say that one mutation is fixed in the genome for every 15 cigarettes smoked,” says researcher Peter Campbell, of the Cancer Genome Project at the Wellcome Trust Sanger Institute in Cambridge, England, in a news release.

More than 33,000 gene mutations were associated with melanoma, a rare but deadly form of skin cancer responsible for most skin cancer deaths.

Researchers say ultraviolet (UV)-light-induced gene mutations caused by exposure to sunlight were responsible for the vast majority of these mutations.

"Indeed because of the clarity of the genome data, we can distinguish some of the early, UV-induced mutations from the later mutations that do not have this signature, presumably occurring after the cancer cells spread from the skin to deeper tissues,” says Campbell.

"These are the two main cancers in the developed world for which we know the primary exposure," says researcher Mike Stratton, also of the Wellcome Trust Sanger Institute, in the release.

"For lung cancer, it is cigarette smoke and for malignant melanoma it is exposure to sunlight. With these genome sequences, we have been able to explore deep into the past of each tumour, uncovering with remarkable clarity the imprints of these environmental mutagens on DNA, which occurred years before the tumour became apparent,” says Stratton.

"We can also see the desperate attempts of our genome to defend itself against the damage wreaked by the chemicals in cigarette smoke or the damage from ultraviolet radiation," Stratton says."Our cells fight back furiously to repair the damage, but frequently lose that fight."

In the studies, published in Nature, researchers used new DNA sequencing technology to decode the genome of cancerous tissue samples taken from one adult with small-cell lung cancer and another with melanoma and compared it with the genome of normal healthy tissue.

Researchers say the results represent a complete catalog of the genetic changes and mutations that occur on the road to lung cancer and melanoma.

The next step will be to identify which of those gene mutations drive the cells to become cancerous. Then, researchers would be able to develop new drugs to target the specific gene mutations and create individualized treatments based on each patient's cancer genome.

SORAFENIB FOR BREAST CANCER

December 14, 2009 (San Antonio, Texas) — The targeted agent sorafenib (Nexavar, Onyx/Bayer), currently approved for use in kidney and liver cancer, has shown activity in breast cancer in phase 2 clinical trials, and a large registration phase 3 trial is planned for next year.

The results from the latest studies of sorafenib were presented here at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS).

Two of these studies investigated the use of the drug in combination with chemotherapy, either capcitebine or paclitaxel, in women with locally advanced or metastatic HER2-negative breast cancer. But perhaps the most intriguing results come from a third study, which suggests that sorafenib can overcome resistance to aromatase inhibitors (AI) in postmenopausal estrogen-receptor-positive breast cancer.

Overcoming Resistance to AI?

The study of overcoming resistance was presented at the meeting by Claudine Isaacs, MD, clinical director of the breast cancer program at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. Resistance to AIs appears to involve the Ras–Raf–MAPK pathway, and sorafenib was investigated because it is an inhibitor of multi(Raf)-kinase, she explained.

The trial involved 35 postmenopausal women with hormone-receptor-positive metastatic breast cancer who had received more than 2 previous chemotherapy regimens, and who had disease recurrence or progression on the AI anastrozole (Arimidex, AstraZeneca). They continued taking anastrozole, but also received sorafenib, either 200 mg or 400 mg twice daily.

Dr. Isaacs reported that 20% of women showed a clinical benefit — complete or partial response — or stable disease for at least 6 months. She said this result was "encouraging" and worthy of further study.

It appears that sorafenib is acting to reverse resistance to AIs, because this type of response would not be expected with either drug used alone, Dr. Isaacs said. Sorafenib has shown "negligible activity" as a single agent in metastatic breast cancer, she added, although it has shown activity in combination with chemotherapy.

"We believe that sorafenib might disrupt the machinery created by the tumor to grow without the estrogen," she said in a statement. "After the machinery is destroyed, the aromatase inhibitor can do its work again."

"To manage breast cancer long-term, it's apparent that we may need to continually switch drugs to keep up with how a cancer evolves and evades each approach," she added.

Adverse effects were common, and included hand and foot syndrome, skin rash, fatigue, nausea/vomiting, diarrhea, and hypertension. However, most were mild or were managed by reducing the dose, Dr. Isaacs said.

In Combination With Chemotherapy

The other phase 2 trials with sorafenib reported at the meeting each involved more than 200 women with locally advanced or metastatic HER2-negative breast cancer. Both were funded by the manufacturer and are part of the Trials to Investigate the Effects of Sorafenib in Breast Cancer (TIES) program.

One trial looked at first-line treatment in women who had not received any previous chemotherapy in this setting. They were randomized to receive 1 of 2 treatment regimens: sorafenib 400 mg twice daily plus paclitaxel 90 mg/m2 weekly for 3 weeks, followed by a week of rest; or paclitaxel plus a placebo.

This trial results were presented at the meeting by William Gradishar, MD, from the Feinberg School of Medicine, Northwestern University, in Chicago, Illinois. He said the results "demonstrated a trend in favor of the combination arm."

The primary end point of progression-free survival was not significantly different in the 2 treatment groups (6.9 months in the combination group vs 5.6 months in the paclitaxel group; P = .0875). However, one of the secondary end points, time-to-progression, did reach significance (8.1 vs 5.6 months; P = .017).

The other trial investigated a similar patient population, but some of the women had received 1 previous chemotherapy in this setting. This trial compared the combination of sorafenib plus capecitabine 100 mg/m2 with capecitabine plus placebo.

Known as SOLTI-0701, this trial was presented at the meeting by José Baselga, MD, from the Vall d'Hebron University Hospital in Barcelona, Spain

In this case, the primary end point of progression-free survival did reach statistical significance (median, 6.4 months in the combination group vs 4.1 months in the capecitabine group; P = .0006).

A post hoc subgroup analysis split the participants into those who had not previously been treated with a previous chemotherapy (i.e., first-line therapy) and those who had received a previous chemotherapy (i.e., second-line therapy). The improvements in progression-free survival were statistically significant in both groups.

These findings for sorafenib plus paclitaxel "are the basis for a registrational phase 3 program that is expected to begin next year," according to the manufacturer.

In the meantime, 2 other phase 2 trials with sorafenib in breast cancer are ongoing, although they were not discussed at the meeting. One is exploring sorafenib plus gemcitabine or capecitabine in a second-line setting following progression on bevacizumab, and the other is evaluating sorafenib plus docetaxel and/or letrozole in the first-line setting.

The 400 mg twice-daily dose of sorafenib used in these trials was associated with frequent adverse effects, including hand and foot syndrome and hypertension. Dr. Isaacs said that "there is activity, but at this dose, there is a fair amount of toxicity." But she noted that in her own study, the adverse effects were manageable when the dose was reduced. "There is a lot of interest in sorafenib because it is an oral drug and it appears to increase the response to chemotherapy. There would be a benefit to taking it if it improved progression-free survival and the quality of life was good," she added.

In the SABCS Medscape Oncology blog, Lida Mina, MD, from the Indiana University School of Medicine, in Indianapolis, noted that the SOLTI-0701 trial of sorafenib plus capecitabine was "very promising, with a near 40% increase in progression-free survival, but unfortunately the toxicity was humungous, with a 45% grade 3 hand and foot syndrome." Commenting more generally on trials with sorafenib, as well as on other new targeted therapies, all with some antiangiogenic properties, she said these trials "do send a signal of efficacy," but it appears to be "somewhat diluted."

The study of overcoming resistance was funded by the Avon Patients for Progress Award, and partly funded by Bayer. Both of the chemotherapy combination studies were funded by the manufacturer of sorafenib, Onyx/Bayer. Dr. Isaacs reports serving on a speaker's bureau for Pfizer, Abraxis Oncology, Genentech, GlaxoSmithKline, and Novartis. Dr. Gradishar reports acting as a consultant for Bayer. Dr. Baselga reports acting as a consultant for Merck, Novartis, Roche, and Exelixis, and receiving grant support from GlaxoSmithKline.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstracts 44, 45, 3090. Presented December 11, 2009.

Τετάρτη 16 Δεκεμβρίου 2009

T-DM1: A BETTER HERCEPTIN?

SAN ANTONIO -- A novel form of trastuzumab (Herceptin) with a chemotherapy-like conjugate attached appears to substantially improve outcomes in heavily-pretreated metastatic breast cancer, researchers said.

Median progression-free survival was 7.3 months (range 0.0 to 11.7) with single agent trastuzumab-DM1 (T-DM1) in a Phase II study reported here at the San Antonio Breast Cancer Symposium.

The objective response rate was 32.7% in women whose tumors had progressed after treatment with an anthracycline, taxane, capecitabine (Xeloda), trastuzumab, and lapatinib (Tykerb), including two HER2-targeted agents in the metastatic setting.

Moreover, the investigational agent was well tolerated, with no dose-limiting cardiotoxicity, according to Ian Krop, MD, PhD, of the Dana-Farber Cancer Center in Boston, and colleagues.

A response this good didn't even seem possible in a setting where women had received an average of seven prior agents, José Baselga, MD, of the Vall d'Hebron University Hospital in Barcelona, Spain, commented at the poster discussion session he moderated.

The new molecule consists of the trastuzumab monoclonal antibody, chemically fused to a cytotoxin: a potent microtubule inhibitor called maytansine that's derived from a sea sponge.

"It is supposed to pack the antibody, which targets the pathway, and the chemotherapy, which targets the cancer cell, hopefully as a smart missile that will target the cancer cell with minimal toxicity," explained Mothaffar Rimawi, MD, of Baylor College of Medicine in Houston, who wasn't involved in the study.

The agent is being developed by Genentech in partnership with ImmunoGen as a possible "replacement" for Genentech's trastuzumab, which comes off patent in 2015.

"Many people feel the data is worth bringing to the FDA, even though it is only Phase II, because these patients have no other options," Knop said standing at his poster.

The companies have given no specifics on filing but hinted in an investigator conference call that "clearly there is potential for filing and approval over the next 12 months for T-DM1." The drug is going into Phase III study for first-line treatment around May 2010.

Regardless, the early results presented here at SABCS generated a buzz at the meeting.

"It is just remarkable in Phase II activity against HER2-positive breast cancer that's resistant to trastuzumab and lapatinib," commented targeted therapy pioneer Mark Pegram, MD, of the University of Miami.

The study included 110 women assigned to open-label treatment with single agent trastuzumab-DM1 (3.6 mg/kg intravenously every three weeks).

Objective response rate as judged by an independent review board -- the primary endpoint -- was 32.7%, all partial responses. The duration ranged from 1.2 to 8.4 months.

Clinical benefit rate -- stable disease or complete or partial response maintained for at least 28 days -- was 44.5% as judged by the same outside experts.

For the 83.5% of patients confirmed to have HER2-positive disease, the objective response rate was even better (39.5%), as was the clinical benefit rate (52.6%).

The researchers reported no new safety signals with the drug, with observed toxicities called "acceptable and manageable."

Overall, 22.7% of patients had a serious adverse event -- most

METANALYSIS OF AROMATASE INHIBITORS

NEW YORK (Reuters Health) Dec 11 - Breast cancer recurrence rates are lower with aromatase inhibitors than with tamoxifen, according to meta-analyses published online by the Journal of Clinical Oncology.

Furthermore, recurrence is reduced whether the aromatase inhibitors are given initially or after several years of tamoxifen therapy, the researchers report.

Dr. Mitch Dowsett, from Royal Marsden Hospital in London, UK, and members of the Early Breast Cancer Trialists' Collaborative Group analyzed data from six trials involving nearly 19,000 women, all of whom had estrogen-receptor positive tumors.

The trials were grouped into two cohorts. Cohort 1 included 9,856 enrollees in two 5-year trials that compared aromatase inhibitors with tamoxifen, with each drug started immediately after surgery.

Cohort 2 comprised 9,015 participants in four 5-year trials in which all women started on tamoxifen after surgery. After two to three years, some were switched to aromatase inhibitors for the remainder of the study, and the rest continued with tamoxifen.

In the first cohort, aromatase inhibitor therapy led to an absolute decrease in recurrence of 2.9% (9.6% for aromatase inhibitors vs 12.6% for tamoxifen; 2p <>

In the second cohort, at 3 years from treatment divergence (approximately 5 years after starting hormonal therapy), aromatase inhibitors were associated with an absolute 3.1% decrease in recurrence (5.0% vs 8.1%, 2p < 2p =" 0.02).

"When the switch to an aromatase inhibitor is made after 2 to 3 years of tamoxifen, there seems to be a particularly marked reduction in risk of recurrence (by 40%) during the following 3 years," the authors comment. They also note that aromatase inhibitors were not associated with any increase in non-breast cancer deaths relative to tamoxifen.

On the other hand, the adverse effect profile differs between the two classes of drugs. Aromatase inhibitors are associated with fewer endometrial cancers and thromboembolic events than the selective estrogen receptor modulator, but with more arthralgia and fractures.

"The decision on whether to initiate treatment with an aromatase inhibitor or tamoxifen or whether to switch to an aromatase inhibitor after 2 to 3 years of tamoxifen rather than continuing with tamoxifen for 5 years depends on a careful evaluation of these factors in individual patients," Dr. Dowsett and his associates maintain.

They conclude: "This overview has provided greater confidence in the efficacy aspects of this evaluation."

J Clin Oncol 2009.

USE TRASTUZUMAB WITH CHEMOTHERAPY

December 15, 2009 (San Antonio, Texas) — Giving trastuzumab (Herceptin, Genentech-Roche) concurrently — as opposed to sequentially — with adjuvant chemotherapy should be the standard of care, suggested the lead investigator of the only trial designed to compare the 2 approaches.

The recommendation comes from a portion of the trial that involved 1903 women with HER2-positive early breast cancer.

Updated results, now with a median follow-up of 5.3 years, show a rate of disease-free survival of 84.2% for concurrent therapy and 79.8% for the sequential therapy, said Edith Perez, MD, here at the 32nd Annual San Antonio Breast Cancer Symposium. She is chair of the North Central Cancer Treatment Group Breast Committee, which ran the study (N9831), and is from the Mayo Clinic in Jacksonville, Florida.

The difference is not statistically significant, but the 25% reduction in the risk for recurrence or death with concurrent therapy, compared with sequential therapy, shows a "strong trend," said Dr. Perez.

She explained that the result was not statistically significant because there were not as many patient events as the investigators initially projected. "We did not think the drug would be this effective at study design," she added.

The "implication for practice" from the study is that "adjuvant trastuzumab be incorporated in a concurrent fashion with taxane chemotherapy," said Dr. Perez.

"The results of this trial have been awaited all over the world," said Claudine Isaacs, MD, who moderated a meeting press conference highlighting the study. Dr. Isaacs is from the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC.

Trastuzumab is approved for both concurrent and sequential therapy by the US Food and Drug Administration, but concurrent is used by most clinicians in the United States, said Dr. Isaacs. However, in other parts of the world, only sequential therapy is practiced, she continued.

"This could mean that up to 10,000 women around the world each year may have a better outcome if [trastuzumab] is used along with chemotherapy. Given that, I believe this study will lead to a global re-evaluation of the way [trastuzumab] is used," Dr. Perez said in a press statement.

Dr. Perez credited a "positive interaction between chemotherapy and [trastuzumab]" for the additional benefit seen with the concurrent administration.

The chemotherapy in the trial was anthracycline-based, which was a feature of another phase 3 clinical trastuzumab trial presented here — the Breast Cancer International Research Group 006 trial.

Unlike that trial, however, there seemed to be no controversy surrounding Dr. Perez's results.

Dr. Perez highlighted one of the concerns with anthracyclines — cardiac safety — in her presentation, telling reporters during a press conference that it "generates a tremendous amount of interest." The 3-year cumulative incidence of grade 3/4 congestive heart failure or sudden cardiac death was 3.3% for concurrent therapy and 2.8% for sequential therapy. No one in the audience commented on the data, which were previously published (J Clin Oncol. 2004;22:322-329).

"I feel very confident that anthracycline-based therapy is appropriate," said Dr. Perez.

Other experts were also positive about the trial. "It's a very important finding," said Dr. Isaacs.

"An exciting report," is how the director of the meeting, C. Kent Osborne, MD, described the results.

Sequential Therapy Is Effective Too

"Scientifically, this is an important result because it clarifies a previously muddy picture," Eric Winer, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, told Medscape Oncology.

Dr. Winer was referring to an early result from the trial that suggested there was no benefit from sequential therapy with trastuzumab, compared with the chemotherapy alone.

The trial consisted of 2 comparisons, one of which was the abovementioned sequential versus concurrent therapy. The other comparison involved 2448 patients randomly assigned to chemotherapy alone or chemotherapy sequentially followed by trastuzumab.

The chemotherapy in both comparisons was doxorubicin (Adriamycin, Bedford Laboratories) and cyclophosphamide, then paclitaxel (Abraxane, Abraxis Bioscience).

After a median follow-up of 5.5 years, the investigators found that the rate of disease-free survival was 80.1% for chemotherapy with sequential trastuzumab and 71.9% for chemotherapy alone. This difference is statistically significant (P = .019).

The outcome was adjusted for possible confounding variables such as tumor size, number of positive nodes, and estrogen-receptor status, report the investigators.

"Now it's been shown that sequential therapy is beneficial too," said Dr. Winer.

"You get benefit if you give trastuzumab after chemotherapy and you get even more if you give it at the same time," summarized Dr. Winer.

The study was supported by the National Institutes of Health, the Breast Cancer Research Foundation, and Genentech. Dr. Perez reports serving on steering committees for Bayer HealthCare and Genentech and on an independent monitoring committee for Novartis. Dr. Isaacs reports being a member of the speakers bureau for GlaxoSmithKline, Genentech, Novartis, and AstraZeneca. Dr. Osborne reports being on the advisory board of Onyx Pharmaceuticals. Dr. Winer has disclosed no relevant financial relationships.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract 80. Presented December 12, 2009.

OBESITY AND BREAST CANCER PROGNOSIS

December 14, 2009 (San Antonio, Texas) — In women who have early breast cancer, being overweight or obese at diagnosis is associated with a higher risk for distant recurrences and disease-specific death later on, according to a new long-term study presented here at the 32nd Annual San Antonio Breast Cancer Symposium.

Being overweight or obese was also associated with being diagnosed at a more advanced stage of disease.

In the study, overweight (body mass index [BMI], 25 to 30 kg/m2) and obese (BMI ≥ 30 kg/m2) women were compared with normal-weight women (BMI <>2).

With nearly 19,000 women, the study has more cases than any other study examining this issue, said Michelle D. Holmes, MD, DrPH, from Harvard University in Boston, Massachusetts.

"Most studies in women with breast cancer have found increased mortality with increased BMI," said Dr. Holmes, who acted as a discussant of the study, which was presented by Marianne Ewertz, MD, from Odense University Hospital in Denmark.

"These Danish data confirm other results and add detail," said Dr. Holmes.

Among the new details is evidence that adjuvant treatment seems to be less effective in obese women, said Dr. Holmes.

"Previous research has shown that obese women have not gotten correct weight-based doses," Dr. Holmes explained.

In addition to having an unprecedented number of cases, the new study followed patients for 30 years (1977 to 2006). "That's a very long time," said Dr. Holmes.

In Time, the Extra Weight Is Costly

Using the Danish Breast Cancer Cooperative Group database, Dr. Ewertz and colleagues examined the influence of obesity at diagnosis on the risk for breast cancer recurrence and mortality in relation to adjuvant treatment.

Information from almost 54,000 women with early breast cancer was evaluated, including age and menopausal status at diagnosis, tumor size, number of lymph nodes removed, number of positive lymph nodes, histological type, grade of malignancy, estrogen-receptor status, and treatment protocol.

The investigators were able to calculate BMI for 35% (n = 18,967) of the women for whom height and weight information was available.

The researchers grouped the distant recurrence data into 2 periods: 0 to 5 years and 5+ years.

A multivariate analysis of the effect of obesity on the risk for distant metastases showed a "clear relationship," between the 2, said Dr. Ewertz. However, the increased risk did not show up immediately.

In years 0 to 5, there was no increased risk for distant metastases for overweight women (BMI, 25 to 30 kg/m2). However, after 5 years, for these women, there was an adjusted hazard ratio of 1.42 (95% confidence interval [CI], 1.17 - 1.73; P = .0005). The women with a BMI under 25 kg/m2 served as the reference group for the calculations.

For the obese women (BMI ≥ 30 kg/m2), the same pattern held true. There was no increased risk for distant metastases for the first 5 years; thereafter, the hazard ratio was similar to that for the overweight women.

The researchers grouped the mortality data into 2 periods: 0 to 10 years and 10+ years. For both overweight and obese women, the first 10 years after diagnosis carried no increased risk for disease-specific death.

At 10+ years, there was an adjusted hazard ratio of 1.26 (95% CI, 1.09,1.46; P = .002) for the overweight women and of 1.38 (95 CI, 1.11 - 1.71; P = .003) for the obese women.

However, although the risk for distant metastases increased with BMI, being overweight did not influence loco-regional recurrence, the investigators reported.

Adjuvant Therapy Less Effective?

Adjuvant treatment seemed to lose its effect more rapidly in obese patients, according to Dr. Ewertz.

The adjuvant therapy included the chemotherapy regimens of cyclophosfamide, metotrexate, and fluorouracil up to 1999 and of cyclophosfamide, epirubicin, and fluorouracil from 1999 onward. In addition, endocrine therapy, of which tamoxifen was most common, consisted of durations of 1 to 5 years. Only 294 patients were recorded as having received trastuzumab (Herceptin, Genentech).

The researchers created 3 groups for the purposes of analysis: chemotherapy, endocrine therapy, and the combination of chemotherapy and endocrine therapy.

For the first 10 years, among the overweight women, there was no impact on survival by treatment. But at 10+ years, there was increased risk for death among those treated with chemotherapy and combination therapy but not those treated with endocrine therapy alone

The obese women had an increased risk for death both in the first 10 years (combination therapy) and at 10+ years (all treatment groups).

"More research is needed into the mechanisms behind the poorer response to adjuvant treatment among obese women with breast cancer," said Dr. Ewertz.

The study was conducted without support from pharmaceutical companies. Dr. Ewertz's participation at the meeting was sponsored by GlaxoSmithKline and she reports receiving a research grant from Novartis. Dr. Holmes has disclosed no relevant financial relationships.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract 18. Presented December 10, 2009.

KEEP TRASTUZUMAB AND ADD LAPATINIB

December 14, 2009 (San Antonio, Texas) — For the first time, an improvement in overall survival has been seen in women with metastatic breast cancer who responded to but then progressed on trastuzumab (Herceptin, Genentech/Roche). Continuing with trastuzumab and adding on lapatinib (Tykerb, GlaxoSmithKline) produced a significant survival advantage of 4.5 months, compared with treatment with lapatinib alone, and resulted in a median overall survival of 14 months, which is "astonishing," according to one breast cancer expert.

These results come from the EGF104900 phase 3 clinical trial of dual HER2 blockade, and were presented here at the 32nd Annual San Antonio Breast Cancer Symposium (SABCS) by Kimberly Blackwell, MD, from Duke University Medical Centre in Durham, North Carolina.

"This is a very impressive improvement in overall survival," Dr. Blackwell said. It compares with what has been seen in first-line therapy in metastatic breast cancer when trastuzumab is added to chemotherapy, but the patients in this trial were heavily pretreated, so this is second-, third-, even fourth-line use, and this result was achieved without using chemotherapy, she pointed out.

Trastuzumab and lapatinib might be "acting together to form a sort of 'dual blockade' to obstruct the HER2 pathways necessary for the tumor to thrive," Dr. Blackwell suggested. Both agents are specific for HER2, but lapatinib works inside the cell and trastuzumab works on the outside of the cell, and this combination might "provide a more complete antitumor attack," she said in a statement.

"This is a refreshing study for all of us," Dr. Blackwell told Medscape Oncology. "The last time there was such an impact [was] the original trastuzumab study."

The improvement in overall survival in this patient population "is astonishing," said Claudine Isaacs, MD, director of the Clinical Breast Cancer Program at the Lombardi Comprehensive Cancer Center in Washington, DC, in an interview with Medscape Oncology.

Edith Perez, MD, director of the Breast Cancer Program at the Mayo Clinic in Jacksonville, Florida, who moderated the press briefing at which these results were discussed, said the breast cancer community has been "eagerly awaiting these results."

In an interview with Medscape Oncology, Dr. Perez said she agrees that this is an "impressive" improvement in overall survival, and pointed out that this is the first time a survival advantage has been demonstrated in metastatic breast cancer that has progressed after trastuzumab. The trial that resulted in the approval of lapatinib for this indication, in combination with capcitebine, showed an effect on progression-free survival but not on overall survival, she pointed out.

Dr. Perez said that she would now recommend use of the combination of lapatinib and continuing with trastuzumab in women who have already progressed on trastuzumab, noting that this combination was less toxic than lapatinib and capcitebine.

Dr. Blackwell also said that, in her clinical practice, she would now consider using this combination in women who had "previously done well on HER2-based therapy."

Benefit From Continuation of Trastuzumab?

There was some discussion over how much of the benefit seen in this trial came from continuing trastuzumab after progression, and how much from the addition of lapatinib.

Dr. Perez told reporters that this study validates the idea of continuing on trastuzumab therapy, even after progression on the drug. "This is important, because there are many physicians who stop trastuzumab once the patient progresses," she said.

Eric Winer, MD, chief of the Division of Women's Cancers at the Dana-Farber Cancer Institute in Boston, Massachusetts, who was approached for comment, said he was surprised by the overall survival result. He agreed that this is the first improvement in survival that has been seen in this patient population, but pointed out that "it hasn't been looked for that often."

His take was that this study shows that continuing trastuzumab after a patient has progressed is beneficial; this has also been shown in several other studies. "This is another study that shows that trastuzumab is a remarkable drug, and is a better drug than we ever thought when it was first approved," he said. The product has changed the natural history of the disease, he added.

However, Dr. Winer added, there does appear to be an interaction between trastuzumab and lapatinib, and said the combination should be studied further.

This combination is being studied further. The ALLTO trial is looking at lapatinib and trastuzumab in combination and in sequential use, and comparing both with chemotherapy, but is in a different patient population — women with early breast cancer. Another trial, the Neo-ALLTO study, will look at the same treatments but they will be administered prior to surgery, Dr. Blackwell told Medscape Oncology.

Unethical Not to Offer Lapatinib

The point about trastuzumab continuation was also raised after Dr. Blackwell's presentation. During the question period that followed, Kathy Pritchard, MD, from the Toronto-Sunnybrook Regional Cancer Center, in Ontario, said: "What you have shown is that continuing trastuzumab in this setting is useful." She suggested that the trial should have had a group in which the treatment was continuation of trastuzumab without the addition of lapatinib.

Dr. Blackwell countered that when the trial was being designed, such a treatment group had been considered but was discounted because it was thought to be unethical to offer women who had already progressed on trastuzumab only continuation of treatment with trastuzumab when there was another HER2-specific drug that was available. Hence, the trial offered these women treatment with lapatinib or lapatinib plus a continuation of trastuzumab, she explained.

The trial involved 296 women with HER2-positive metastatic breast cancer who had progressed on trastuzumab-containing regimens (the median number of previous regimens was 3). All women were treated with lapatinib, either alone (at a dose of 1500 mg once daily) or together with trastuzumab (in this group the dose of lapatinib was 1000 mg once daily, and trastuzumab was given at 2 mg/kg after a loading dose of 4 mg/kg).

Women in the lapatinib group who progressed were allowed to cross over to the combination group, and about half did so (77 of 148 patients; 52%).

The results that Dr. Blackwell presented come from an updated survival analysis conducted after 218 deaths (77%) had occurred.

They show a significant survival advantage for the combination group, in which the median overall survival was 14 months, compared with 9.5 months in the lapatinib group (hazard ratio [HR], 0.74; 95% confidence interval 0.57 - 0.97; P = .026).

This represents a 26% reduction in the risk of dying, Dr. Kimberley said. "After 1 year, there were 15 more women out of 100 who were still alive in the combination arm, compared with the lapatinib alone arm," she said.

"The actual survival benefit of the combination may be underestimated because of the high frequency of the crossover," Dr. Blackwell explained. If you take away the patients who crossed over, the reduction in the risk of dying on the combination rises to 36% (HR, 0.64), she told Medscape Oncology.

The combination had an acceptable tolerability profile and there was no increase in the cardiac signal. "As a practicing clinician, I found it remarkable that there was no safety issue," Dr. Blackwell said.

Dr. Blackwell reports receiving honoraria from GlaxoSmithKline and Genentech to conduct the study. Dr. Perez receives no direct funding from pharmaceutical companies, but has served on independent monitoring committees for Genentech and Novartis.

32nd Annual San Antonio Breast Cancer Symposium (SABCS): Abstract 61. Presented December 12, 2009.

10% Ki67 DISCRIMINATES BETWEEN LUMINAL-A AND LUMINAL-B

Ki67 and response to hormonal therapy

16.12.09
Category: Scientific News

Highlights from the 32nd San Antonio Breast Cancer Symposium, 9-13 December 2009, Texas, USA


In postmenopausal patients with T2/3 tumors who wish to preserve their breasts, neoadjuvant endocrine treatment may be recommended. Treatment can shrink the tumor, frequently making the patient a good candidate for breast conservation therapy, and can also allow assessment of response to the therapeutic agent. A problem arises, however, when the tumor does not respond to the drug during the ~4 months of neoadjuvant treatment, resulting in a delay in switching to chemotherapy, which may adversely affect the chance of achieving breast conservation therapy and the overall outcome.

The Preoperative Endocrine Prognostic Index (PEPI) is based on the independent prognostic effects of tumor size, nodal status, estrogen receptor status, and Ki67 level, and is used to predict long-term outcomes after the completion of neoadjuvant endocrine treatment.

Because these markers are measured in the surgical sample after the completion of the neoadjuvant therapy, the prognostic information becomes available only after 4 months of treatment. An alternative approach, based on measuring the Ki67 level in a tumor biopsy sample taken only 2 to 4 weeks after beginning neoadjuvant therapy, was described by Matthew Ellis, MD, PhD, from Washington University.

A Ki67 cut-off of 10% was determined by comparing Ki67 data with the PAM50 intrinsic subtype profile, essentially making Ki67 values ≤10 or >10 surrogates for the LumA and LumB molecular subtypes of breast cancer. This cut-off was applied to the baseline and early on-treatment Ki-67 data in 2 trials, comparing that data with Ki67 values from the surgical samples. In the preoperative letrozole phase 2 trial, in which the patients received 4 to 6 months of neoadjuvant letrozole therapy, these cut-off points measured on 4-week biopsy samples predicted low- and high-risk groups of patients that were significantly correlated with recurrence-free survival at 60 months. Only 1/20 patients with a PEPI score of 0 (very low risk) had a Ki67 value >10, whereas 10/36 patients in this PEPI category had a Ki67 value ≤10. Similar results were seen with 2-week biopsies taken from patients in the IMPACT trial. In the ACOSOG Z1031 trial, where patients are being randomized to receive exemestane, letrozole, or anastrozole as neoadjuvant therapy, an amendment has been activated whereby all patients will be biopsied at 2 to 4 weeks after the initiation of treatment for measurement of Ki67 levels. Those designated as high risk will be switched to either chemotherapy or surgery. Those classified as low risk will continue with aromatase inhibitor therapy until surgery, after which a decision about adjuvant chemotherapy will be made based on PEPI score and pathologic stage. A remaining problem in implementing Ki67 assessment in early biopsies is standardizing measurement; this problem is currently being addressed by BIG/NABCG.

RIBBON-2: NO EFFECT ON SURVIVAL YET

RIBBON-2 is the first positive phase III study of bevacizumab in second-line metastatic breast cancer

15.12.09
Category: Scientific News

Highlights from the 32nd Annual CTRC-AACR San Antonio Breast Cancer Symposium, 9-13 December 2009, Texas, USA


Sarah Hurvitz, MD, from the University of California, Los Angeles, presented on 12 December 2009, results from the RIBBON-2 trial, a randomized, double blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of HER2-negative metastatic breast cancer. She reported final progression-free survival (PFS) and overall response rate (ORR) analyses, as well as the interim overall survival (OS) analysis (consisting of 315 events and accounting for ~57% of information). In this study, 684 previously treated patients with metastatic breast cancer were randomized to receive investigator-chosen chemotherapy plus placebo or investigator-chosen chemotherapy plus bevacizumab as second-line therapy. Patients were required to have no prior therapy with bevacizumab or any VEGF pathway–targeting therapy. The primary endpoint was PFS; secondary endpoints were OS, PFS within individual chemotherapy cohorts, ORR, duration of objective response, 1-year survival rate, and safety. For the primary efficacy analysis, PFS was 7.2 months in the bevacizumab treatment arm compared to 5.1 in the placebo arm (P=0.0072). Similar results were seen in the individual chemotherapy cohorts. ORR was 39.5% in the bevacizumab arm versus 29.6% in the placebo arm (P=0.0193). OS rates for the bevacizumab arm and the placebo arm (18.0 months and 16.4 months, respectively) were not significantly different, but these data are immature. As expected, patients receiving bevacizumab plus chemotherapy showed an increased incidence of neutropenia, hypertension, sensory neuropathy, and proteinuria. With the reporting of these results, RIBBON-2 became the first positive phase III study of bevacizumab in second-line metastatic breast cancer.

Τρίτη 15 Δεκεμβρίου 2009

PARP INHIBITORS ARE THE WINNERS

PARP inhibitor with chemotherapy may improve breast cancer survival by almost 60 percent.

MedPage Today (12/11, Bankhead) reported, "Treatment with a drug that inhibits DNA repair in cancer cells improved breast cancer patients' survival by almost 60 percent when added to conventional chemotherapy," according to results presented at the San Antonio Breast Cancer Symposium. Researchers found that "patients who received the investigational drug BSI-201 in addition to chemotherapy had a median survival of 12.2 months, compared with 7.7 months for chemotherapy alone." The drug works by inhibiting "the nuclear enzyme PARP1, which is involved in multiple cellular processes." The results "confirm and extend" findings "reported at the American Society of Clinical Oncology meeting, when survival was more than nine months with BSI-201 plus chemotherapy, versus less than six months with chemotherapy alone."

G-SECRETASE INHIBITOR FOR BREAST CANCER

Experimental drug may stop stem cell growth in patients with breast cancer.

The Houston Chronicle (12/12, Finley) reported that, according to research reported at the San Antonio Breast Cancer Symposium, researchers "have an experimental drug that seems to stop" stem cells "in breast cancers." For the study, the researchers "first identified a vulnerable target on the breast stem cells called the Notch receptor and used an experimental drug, gamma-secretase inhibitor, along with a common anticancer drug, docetaxel -- first on mice grafted with human tumors, and later in a few women with advanced breast cancer."

MedPage Today (12/12, Phend) reported that "compared with baseline biopsies, those taken at the end of treatment had significantly fewer cancer stem cells measured by CD44/CD24 expression." But, "tumor regression wasn't seen immediately with Notch inhibition," which the researchers said "likely reflects daughter cells dying off from chemotherapy with progressively fewer stem cells to repopulate them."

BETTER TO USE HERCEPTIN WITH CHEMOTHERAPY

Herceptin during chemotherapy may boost survival in some patients with breast cancer.

HealthDay (12/12, Dotinga) reported, "New research suggests that certain breast cancer patients who take the drug Herceptin [trastuzumab] during chemotherapy, instead of taking it afterward, fare better." In a study presented at the San Antonio Breast Cancer Symposium, researchers examined "outcomes for hundreds of women who underwent different treatment regimens" for "HER2-positive breast cancer."

MedPage Today (12/13, Phend) reported that patients "had 25 percent better disease-free survival rates at five years when trastuzumab was started concurrently with chemotherapy, rather than sequentially." But, "the trial was complicated by temporary closure of the concurrent trastuzumab arm early in the study for analysis of potentially adverse cardiac events."

But, because the study showed that "the five-year survival rate increased to 84 percent among women taking the drugs concurrently versus 80 percent among those taking the drugs sequentially," the researchers concluded that "concurrent use is the best way" to "decrease the risk of cancer recurrence," the Los Angeles Times (12/12, Roan) "Booster Shots" blog reported.

Anthracyclines with Herceptin may be linked to heart damage in HER2-positive breast cancer patients. The Wall Street Journal (12/14, A5, Wang, subscription required) reports that, according to findings reported at the San Antonio Breast Cancer Symposium, anthracyclines, a class of chemotherapy drugs, may be linked to heart damage when used in combination with Roche Holding AG's Herceptin [trastuzumab] in women with HER2-positive breast cancer.

Bloomberg News (12/13, Waters) reported that although the study showed that "women who got anthracyclines and Herceptin were less likely to have recurrences of their cancer and to die," researchers also found that two percent of patients receiving the combination treatment "developed heart failure, 0.7 percent died of leukemia, and 19 percent had changes in their heart function that might lead to heart failure in the future." Meanwhile, "among those who got Herceptin without anthracyclines, 0.4 percent developed heart failure and nine percent had worsened heart function."

The researchers concluded that "eliminating the anthracycline from chemotherapy when using trastuzumab (Herceptin) may be just as effective long term," MedPage Today (12/12, Phend). They noted that "a nonanthracycline based regimen with trastuzumab was not associated with significantly more breast cancer recurrences or deaths." Furthermore, no "group of HER2-positive patients, high risk or otherwise...benefitted more from the anthracycline-based regimen."

Herceptin plus Tykerb may improve survival in patients with HER2-positive breast cancer. The AP (12/12) reported that "a combination of two drugs that more precisely target tumors significantly extended the lives of women who had stopped responding to other treatments," according to research presented at the San Antonio Breast Cancer Symposium. The study of 300 patients showed that women receiving Herceptin [trastuzumab] and Tykerb [lapatinib] "lived 20 weeks longer than those given Tykerb alone."

Researchers found that "Tykerb inhibits HER2 and the receptor, while Herceptin binds to the HER2 protein," resulting in "significant improvement in overall survival," HealthDay (12/11, Doheny) reported. In fact, "there was a 26 percent reduction in the risk of death if both agents were used."

On average, participants receiving the combination treatment lived "about 14 months vs. 9.5 months for those who got Tykerb alone," WebMD (12/11, Laino) reported. Furthermore, "adding Tykerb to Herceptin did not worsen the side effects."

Combined Herceptin, DM1 treatment may shrink tumors in some breast cancer patients. The UK's Telegraph (12/13, Donnelly) reported, "A new breast cancer drug has been shown to shrink tumors in women for whom all other treatments have failed." According to research presented at the San Antonio Breast Cancer Symposium, the drug, "a combination of Herceptin with a type of chemotherapy called DM1," reduced tumors in "forty percent of women with an aggressive and advanced form of breast cancer." The study included 110 women with HER2-positive breast cancer who "had already undergone seven types of different drug treatments."

Bloomberg News (12/13, Waters) reported, "The therapy combines Roche's Herceptin with a potent cancer-killing drug developed by Immunogen. Herceptin acts as a guidance system, using its ability to home in on cancer cells to deliver the cancer treatment directly to its target."

A NEW GENE FOR OVARIAN CANCER

Overexpressed gene may be linked to ovarian cancer.

WebMD (12/11, Warner) reported, "Researchers found a gene called MAGP2, which has not previously been associated with any type of cancer, was overexpressed in the most fatal types of ovarian cancer," according to a study published in the journal Cancer Cell. In "samples from 53 advanced papillary serous ovarian cancer tumors," researchers found that "the MAGP2 gene was overexpressed in...women who died most quickly from their cancer. Further testing showed MAGP2 levels were also higher than normal in another group of ovarian cancer tumors, but not in normal ovarian tissue." Meanwhile, "levels of MAGP2 were lower in women whose tumors responded well to chemotherapy."

PREDICTIVE FACTORS FOR METRONOMIC CHEMOTHERAPY AND BEVACIZUMAB

. Clin Cancer Res. 2009 Dec 8. [Epub ahead of print]

Predictive Potential of Angiogenic Growth Factors and Circulating Endothelial Cells in Breast Cancer Patients Receiving Metronomic Chemotherapy Plus Bevacizumab.

Calleri A, Bono A, Bagnardi V, Quarna J, Mancuso P, Rabascio C, Dellapasqua S, Campagnoli E, Shaked Y, Goldhirsch A, Colleoni M, Bertolini F.
PURPOSE: The association of chemotherapy and antiangiogenic drugs has shown efficacy in clinical oncology. However, there is a need for biomarkers that allow selection of patients who are likely to benefit from such treatment and are useful for indicating best drug combination and schedule. EXPERIMENTAL DESIGN: We investigated the predictive potential of six angiogenic molecules/transcripts and nine subpopulations of circulating endothelial cells (CEC) and progenitors (CEP) in 46 patients with advanced breast cancer treated with metronomic cyclophosphamide and capecitabine plus bevacizumab. RESULTS: Median time to progression was 281 days. Baseline CECs higher than the first quartile were associated with an increased time to progression (P = 0.021). At progression, CECs were markedly reduced (P = 0.0002). In the cohort of 15 long-term responders, who progressed later than 1 year after beginning of therapy, circulating vascular endothelial growth factor (VEGF)-A levels measured after 2 months of therapy were significantly reduced, and there were significant trends toward lower levels of PDGF-BB, CEPs, and CECs. At the time of progression, angiogenic growth factors VEGF-A and basic fibroblast growth factor were significantly increased. CONCLUSIONS: Baseline CECs (likely reflecting an active vascular turnover) predicted a prolonged clinical benefit. At the time of relapse, a pattern of decreased CECs and increased angiogenic growth factors suggested a switch toward a different type of cancer vascularization. VEGF-A and basic fibroblast growth factor levels after 2 months of therapy were also useful to identify patients whose disease was likely to progress. These biomarkers are likely to be useful for treatment selection and might be incorporated in design of future studies. (Clin Cancer Res 2009;15(24):7652-7).