BE CAREFUL WITH CONCOMINANT USE OF ANTIDEPRESSANTS AND TAMOXIFEN

February 9, 2010 — Paroxetine and fluoxetine should not be prescribed for depression or hot flashes in women who have had breast cancer and are now taking tamoxifen to prevent a recurrence. Citalopram or venlafaxine should be considered instead.

This message comes from a new study showing that paroxetine, by interfering with the metabolism of tamoxifen, reduces or abolishes its protective effect against breast cancer recurrence, and that women taking both drugs have an increased risk for death from breast cancer. Paroxetine is a strong inhibitor of the CYP2D6 enzyme that converts tamoxifen to its active metabolite, reducing the amount of active drug that is released.

"We found that women with breast cancer who received paroxetine in combination with tamoxifen were at increased risk of death from breast cancer and death from any cause," say the researchers, led by Catherine Kelly, MD, medical oncology fellow at the Sunnybrook Health Sciences Center in Toronto, Ontario. The increase in risk was directly related to the extent of coprescribing, they note.

"These results highlight a drug interaction that is extremely common, widely underappreciated, potentially life-threatening, yet uniformly avoidable," they add.

The study, published online February 8 in the British Medical Journal, provides the "first evidence of a clinical effect of long-term CYP2D2 inhibition during tamoxifen treatment," according to an accompanying editorial.

There have been suggestions of this, but the data were inconclusive. Two studies presented at last year's annual meeting of the American Society of Clinical Oncology reported contradictory results; nevertheless, the message to clinicians was to avoid coprescribing the selective serotonin reuptake inhibitors (SSRIs) paroxetine and fluoxetine in patients taking tamoxifen.

This is also the message in the BMJ editorial, authored by Frank Andersohn, MD, and Stefan Willich, MD, from the Institute for Social Medicine, Epidemiology and Health Economics at Charité University Medical Center, in Berlin, Germany.

In light of these findings, clinicians treating depression or hot flashes in women who are taking tamoxifen should avoid prescribing strong CYP2D6-inhibiting SSRIs, such as paroxetine and fluoxetine, and consider instead drugs with low potential to inhibit CYP2D6, such as citalopram or venlafaxine, they write.

In patients on tamoxifen who are already taking paroxetine or fluoxetine, a switch to another antidepressant with no or low inhibition of CYP2D6 should be considered, they add. But there is no justification for "abrupt discontinuation" of paroxetine or fluoxetine, they report. "The potential longer-term benefits of discontinuing their use do not yet clearly outweigh the potential adverse effects of immediate withdrawal of effective SSRI treatment (such as recurrence of severe depression)," they note.

The study showed an effect on the risk for breast cancer death only with paroxetine, not with fluoxetine, although it, too, is a strong inhibitor of CYP2D6. The authors speculate that this is due to the low number of women taking fluoxetine in this study. The editorialists note that the further study is needed but, in the meantime, "for safety reasons, the coprescription of fluoxetine and tamoxifen in women with breast cancer should be avoided until additional evidence becomes available."

Study Shows Increase in Deaths From Breast Cancer

The study reported by the Canadian researchers was retrospective and population based, and initially analyzed data from 24,430 women over a 13-year period (1993 to 2005). These women were 66 years or older, living in Ontario, and were taking tamoxifen after a diagnosis of breast cancer. Of these women, 7489 (30.6%) received at least 1 antidepressant during the time they were taking tamoxifen. Because some women were excluded from the study — for reasons such as poor adherence to tamoxifen and death from unknown causes — there were 2430 women in the primary analysis.

Most of these women started taking tamoxifen within a year of their breast cancer diagnosis, and the median duration of tamoxifen treatment was 4 years.

The most commonly prescribed antidepressant was paroxetine (in 25.9% of women), followed by sertraline (22.3%), citalopram (19.2%), venlafaxine (15%), fluoxetine (10.4%), and fluvoxamine (7.2%). Older cyclic antidepressants were prescribed in 18.3% of women.

By the end of follow-up (mean, 2.38 years), a total of 1074 women (44.2%) had died; breast cancer was recorded as the cause of death in 374 women (15.4%).

"In the primary analysis, we found an increased risk of death from breast cancer among women who received paroxetine, an irreversible CYP2D6 inhibitor, in combination with tamoxifen," the authors write.

By contrast, no such risk was seen with the other antidepressants, they note.

"The choice of antidepressant can significantly affect survival in women receiving tamoxifen for breast cancer," Dr. Kelly and colleagues note.

We estimate that the use of paroxetine in 41% of those receiving tamoxifen treatment (the median overlap in our sample) would result in 1 additional breast cancer death within 5 years of the discontinuation of tamoxifen for every 19.7 patients so treated," they explain.

"The risk with more extensive overlap would be greater," they add.

Absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine were associated with an increase of 25%, 54%, and 91%, respectively, in the risk for death from breast cancer, the researchers report. Each comparison was statistically significant (P < .05).

"The increased risk was directly related to the extent of coprescribing and is consistent with the hypothesis that irreversible CYP2D6 inhibition by paroxetine can reduce or abolish the survival advantage conferred by long-term tamoxifen therapy in patients with breast cancer," the researchers write.

"Our findings are consistent with an emerging body of literature indicating the critical role of CYP2D6 in metabolic activation and clinical effectiveness of tamoxifen," they add. Among the papers cited are several by Mathew Goetz, MD, and colleagues from the Mayo Clinic in Rochester, Minnesota, who have been vocal about how testing for CYP2D6 can identify women who are poor metabolizers of tamoxifen and who are therefore likely to respond less well to the drug. However, a recent editorial in the Journal of Clinical Oncology suggested that the data to date are not clear enough for routine use of such testing; it did agree, however, that the use of drugs that are known to inhibit CYP2D6 are be avoided in women taking tamoxifen.

The editorialists and all of the authors except for 1 have disclosed no relevant financial relationships. Kathleen Pritchard, MD, from Sunnybrook Health Sciences Center, reports acting as a consultant and receiving research funding from several pharmaceutical companies, as detailed in the paper.

BMJ. Published online February 9, 2010.

TESTING FOR CYP2D6 POLYMORPHISMS BEFORE TAMOXIFEN USE REMAINS CONTROVERSIAL

February 9, 2009 — In clinical practice, there is a "hesitation" about testing for CYP2D6 before prescribing tamoxifen to reduce the risk for breast cancer recurrence, observes an editorial published online February 1 in the Journal of Clinical Oncology.

Tamoxifen is widely used to prevent breast cancer recurrence in women with hormone-positive disease. However, it is not the drug itself that exerts this beneficial effect, but an active metabolite, and there is a genetically determined variation in the ability to metabolize tamoxifen. This variation occurs on the CYP2D6 gene, and testing for an inherited deficiency in this gene identifies women who are poor metabolizers of tamoxifen and who appear to derive less benefit from the protection that the drug offers against breast cancer recurrence.

Commercial tests for CYP2D6 genotyping are available, and some experts have argued that they should be used in clinical practice, particularly in the case of postmenopausal women, where there is an alternative therapy to tamoxifen that can be offered (i.e., aromatase inhibitors).

But the editorial states that "routine use should await more reliable evidence from well-designed studies."

Currently, there remains an "uncertaincy" about such testing because it is based on "incomplete biological evidence and inconsistent epidemiologic evidence," write editorialists Timothy Lash, MD, PhD, and Carol Rosenberg, MD, from Boston University School of Health in Massachusetts. They also point out that there is no current consensus guideline that recommends CYP2D6 genotyping in patients prescribed tamoxifen.

One Exception — Other Drugs That Affect Metabolism

Among all of this uncertainly, however, there is one situation in which a practice recommendation can be made, the editorialists explain. They urge physicians to "to be cautious about prescribing comedication that might interact with tamoxifen via CYP2D6 inhibition." Where there are therapeutically similar drugs available, it is "prudent to prescribe medications that inhibit CYP2D6 very little," they add.

One example of this is the drugs that are often coprescribed in this patient population for depression and/or vasomotor symptoms — paroxetine and fluoxetine have been reported to interfere with CYP2D6, whereas citalopram and venlafaxine have not.

New data on the interaction between paroxetine and tamoxifen have just been published online in the British Medical Journal, and make this case more forcefully. This interaction was shown to reduce the ability of tamoxifen to protect against breast cancer recurrence to the extent that it increased the risk for death from breast cancer. As a result, clinicians have now been warned against coprescribing the 2 drugs.

Highly Variable Practice Patterns

Apart from that exception, however, the editorial emphasizes the "uncertainty" over the data that are available so far on CYP2D6.

"At present, we do not routinely perform CYP2D6 genotyping for any patient," Dr. Rosenberg told Medscape Oncology. "There are a few individualized exceptions, but they are rare and the situations can't be generalized," she added.

This is in contrast to the practice that others have reported, in particular at the Mayo Clinic in Rochester, Minnesota, where Matthew Goetz, MD, said his team has been testing for CYP2D6 for 3 years now. Dr. Goetz and colleagues were among the first to report the effect of CYP2D6 on tamoxifen efficacy, and last year published additional data on 1325 women.

"In the postmenopausal setting, where there is an alternative therapy, the role of genotyping is very compelling, and I think it's very reasonable in that situation to discuss this test," Dr. Goetz told Medscape Oncology.

The situation is different in premenopausal women, where the data are sparse and there is no proven alternative therapy, but even here, "what data there are suggest that genotyping is also important in this patient population," Dr. Goetz explained.

"The data do not suggest that the poor metabolizers do not benefit from tamoxifen, but the data suggest that they do not do nearly as well as the extensive metabolizers," he added. "I strongly believe that pharmacogenetics does play a role here."

These 2 opposing opinions are reflected in what the editorialists describe as "highly variable practice patterns for CYP2D6 genotyping." They report carrying out an informal survey among medical oncologists, and also report discovering many different views.

"Some never assay the genotype, some decide on a case-by-case basis, and a few assay frequently," the editorialists report. "Some wonder whether it is ethical to prescribe a drug that may be ineffective if an alternative exists. Most agree that interpreting the assay's results can be problematic, given the lack of definitive data."

They add that even clinicians who do carry out the test "seem to cross their fingers that the patient turns out to be a 'normal metabolizer,' so they can prescribe tamoxifen without concern."

New Study With "Dramatic" Results

The editorial was prompted by a study also published online February 1 in the Journal of Clinical Oncology, which reported that CYP2D6 testing identifies women who have a poor response to tamoxifen. The researchers, led by Kazuma Kiyotani, from the RIKEN Center for Genomic Medicine, Yokohama, Japan, reported data from a series of 282 patients, 67 of whom they had reported on previously.

These women had invasive hormone-receptor-positive breast cancer, had undergone surgery, and were prescribed tamoxifen for 5 years to reduce the risk for breast cancer recurrence.

Women who were identified by CYP2D6 testing as poor metabolizers of tamoxifen had a 9.5-fold higher rate of recurrence than those who were identified as good metabolizers, the researchers report. Those who were identified as "intermediate metabolizers" (with only 1 fully functional allele) had a 4.5-fold higher rate of recurrence.

"These results are dramatic," say the editorialists, but they add that this study shares "important limitations with earlier reports." These include selection of study participants, limited consideration of other prognostic markers, and perhaps most important, immortal person-time bias. This arises in observational studies when follow-up time is included in person-time at risk for the study outcome, even though that time precedes the last event required for entry into the study population, they explain.

In contrast, Dr. Goetz said that "this study provides additional evidence in regard to the role of CYP2D6 metabolism and clinical outcome."

"What needs to happen in our community is that we have to come up with some guidelines as to when it is and when it is not appropriate to carry out this testing," he added.

The editorialists and the researchers have disclosed no relevant financial relationships. Dr. Goetz reports that he is named, along with colleagues and the Mayo Clinic, as an inventor on nonprovisional patent applications for tamoxifen and CYP2D6; the technology is not licensed and no royalties have accrued yet. Dr. Goetz also reports having acted as a consultant for Roche and having received honoraria from Pfizer, Roche, and DNA Direct.

J Clin Oncol. Published online February 1, 2010. Abstract, Abstract

A GRREK STUDY FOR GASTRIC CANCER

Cancer Chemother Pharmacol. 2010 Feb 4. [Epub ahead of print]

A randomized phase III study of adjuvant platinum/docetaxel chemotherapy with or without radiation therapy in patients with gastric cancer.

Bamias A, Karina M, Papakostas P, Kostopoulos I, Bobos M, Vourli G, Samantas E, Christodoulou C, Pentheroudakis G, Pectasides D, Dimopoulos MA, Fountzilas G.

Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece, abamias@med.uoa.gr.

The optimal adjuvant treatment for gastric cancer remains controversial. We compared the efficacy of a docetaxel and platinum adjuvant chemotherapy regimen, in patients with high-risk gastric cancer, with that of the same chemotherapy plus radiation therapy (RT). In addition, we evaluated the prognostic and/or predictive value of a panel of molecular markers. Patients with histologically proven, radically resected gastric cancer, stage >/=T3 and/or N+ were randomized to 6 cycles of docetaxel with cisplatin, both at 75 mg/m(2) every 3 weeks (arm A) or the same treatment with RT (arm B; 45 Gy). Due to excessive nausea and vomiting, cisplatin was substituted by carboplatin at AUC (area under the curve) of 5 after the first 45 patients (22 group A, 23 group B). The prognostic value of EGFR, ERCC1, HER2, MET/HGFR, MAP-Tau, and PTEN expression was also studied in a subset of 67 patients using immunohistochemistry on tissue microarrays (TMAs). A total of 147 patients were randomized. After a median follow-up of 53.7 months, no differences in overall (OS) and disease-free survival (DFS) were found between the two arms. The most common grade 3/4 toxicities for arms A and B (excluding alopecia) were non-febrile neutropenia (11 and 17%, respectively), febrile neutropenia (9 and 7%) and diarrhea (7 and 4%, respectively). Patients with ERCC1 positive tumors had significantly longer median DFS (33.1 vs. 11.8 months, Wald P = 0.016) and OS (63.2 vs. 18.8 months, Wald P = 0.046). Our results indicate that the addition of RT to platinum/docetaxel adjuvant chemotherapy does not appear to improve survival in high-risk, radically resected gastric cancer. However, the possibility that a benefit by the addition of RT was not detected due to decreased power of the study should not be excluded.

AN INTERESTING REGIMEN FOR MELANOMA

Cancer. 2010 Jan 29. [Epub ahead of print]

A phase 2 pilot trial of low-dose, continuous infusion, or "metronomic" paclitaxel and oral celecoxib in patients with metastatic melanoma.

Bhatt RS, Merchan J, Parker R, Wu HK, Zhang L, Seery V, Heymach JV, Atkins MB, McDermott D, Sukhatme VP.

Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

BACKGROUND:: Tumor angiogenesis has been associated with a poor prognosis in patients with metastatic melanoma (MM). Microtubule stabilizers and cyclooxygenase 2 (COX-2) inhibitors, alone and in combination, have produced inhibitory effects on endothelial cells and tumor angiogenesis. Angiogenesis, which is the growth of new blood vessels, is necessary for tumor growth and progression. Thus, the authors tested the safety and efficacy of a low dose of paclitaxel and celecoxib in patients with MM. METHODS:: Patients received paclitaxel 10 mg/m(2) for 96 hours weekly as a continuous intravenous infusion and oral celecoxib 400 mg twice daily. Systemic tumor response was assessed at 6-week intervals. Tumor measurements at the end of Cycle 1 were used as the baseline for assessment of tumor progression. Patients with unacceptable toxicity or disease progression after Cycle 2 relative to the end of Cycle 1 were taken off study. RESULTS:: Twenty patients were enrolled. Twelve of 20 patients (60%) had received >/=2 previous systemic therapies. Three patients did not receive treatment because of rapid disease progression. Treatment-related grade 3/4 toxicities were limited to catheter-related complications. One patient achieved a partial response, and 3 of 20 patients (15%) had stable disease for >6 months. The median time to progression was 57 days (95% confidence interval, 43-151 days), and the median overall survival was 212 days (95% confidence interval, 147-811 days). CONCLUSIONS:: Low-dose, continuous intravenous infusion paclitaxel and oral celecoxib produced disease stabilization in a significant proportion of heavily pretreated patients with MM. These findings support a role for metronomic therapy in patients with this disease. Cancer 2010. (c) 2010 American Cancer Society.

PET FOR HEAD AND NECK CANCER STAGING

NEW YORK (Reuters Health) Feb 10 - Squamous cell carcinoma of the head and neck can be staged more accurately with whole-body positron emission tomography using (18F)fluorodeoxyglucose (PET-FDG), according to European researchers.

In the February 1 online issue of the Journal of Clinical Oncology, the investigators report that in their study, adding PET-FDG to staging in newly diagnosed patients improved accuracy in 20% of cases and altered management in 13.7%.

According to lead author Dr. Max Lonneux of the Cliniques Universitaires Saint-Luc, Brussels, this prospective study, with 233 patients, is the largest so far on PET-FDG for initial staging of such cancers.

"PET is cost-effective in many oncological situations," he noted in email to Reuters Health. "By increasing the accuracy of pretherapeutic staging, PET allows for a better selection of the appropriate therapeutic regimen for a particular patient."

Dr. Lonneux pointed out that PET-FDG is already "a standard of care for the management of non-small cell lung cancer, lymphoma, recurrent colorectal cancer and melanoma."

The average age of patients in the study was 60 years; 78% were men. All had conventional screening tests, including fibroscopic and direct endoscopic examinations with biopsy, CT or MRI of the head/neck region, and CT of the thorax. Each patient was staged based on this information. Then, after whole-body PET-FDG scan, they were staged again.

In 100 patients, the two staging assignments were discordant. In 40 of these cases, the discrepancies were not investigated because the treating physician did not expect that treatment would change based on new information.

Among the remaining 60 patients with discordant findings, PET-FDG was accurate in 47 cases, leading 30 to be upstaged and 17 to be downstaged. Therapeutic plans for 32 patients (13.7% of 233) were altered on the basis of PET-FDG results.

According to the researchers, the factor with the greatest effect on patient management was confirmation or exclusion of metastatic or additional disease. In six patients, this finding shifted the approach from curative to palliative. In nine others, PET-FDG ruled out metastatic disease, qualifying those patients for curative-intent therapies.

The researchers conclude, "Our results support the implementation of PET-FDG imaging in the routine imaging work-up of head and neck squamous cell carcinoma."

J Clin Oncol 2010.

CHEMOTHERAPY IN SARCOMAS

Expert Rev Anticancer Ther. 2010 Feb;10(2):249-60.

Role of chemotherapy in the management of soft tissue sarcomas.

Krikelis D, Judson I.

University Hospital of Ioannina, Stavros Niarchos Avenue, 45500, Ioannina, Greece. krikelis@yahoo.com.

Soft tissue sarcomas are a diverse group of rare tumors that comprise 1% of all cancers. Few randomized trials of chemotherapy have been performed but there is a clear role for agents such as doxorubicin and ifosfamide in the palliation of advanced disease. There is uncertainty as to whether sequential single-agent treatment is equivalent to combination chemotherapy. For the majority of histological subtypes adjuvant chemotherapy is not of proven value, although there may be situations where it is advantageous. However, there are other subtypes, such as the Ewing's sarcoma family tumors, for which chemotherapy is an essential part of primary management and has definitely improved survival. Apart from Ewing's sarcoma family tumor and rhabdomyosarcoma, there is increasing specialization of chemotherapy according to histological subtype, such as the use of taxanes for angiosarcoma, gemcitabine and docetaxel for leiomyosarcoma, and trabectedin for leiomyosarcoma and liposarcoma, especially the myxoid/round cell variant. Nevertheless, there are serious limitations to existing treatment and novel therapies need to be developed.

A NEW STANDARD FOR BREAST RT

February 10, 2010 — A hypofractionated 3-week schedule of whole-breast radiation is as effective as a conventional 5-week schedule in preventing local breast cancer recurrence at 10 years. Furthermore, the different approaches had similar rates of "good or excellent" cosmetic outcome.

These results, from a 1234-patient randomized controlled trial of the different radiation treatment schedules, are reported in the February 11 issue of the New England Journal of Medicine.

The 10-year cosmetic results of the study are especially important, say the authors, because "there was concern that late toxic effects of radiation associated with the hypofractionated regimen could develop."

Indeed, there was a worsening of cosmetic outcome over time, but the patients treated with hypofractionated radiation had cosmetic outcomes similar to those treated with the standard regimen, report the Canadian authors, led by Timothy Whelan, BM, BCh, from McMaster University and the Juravinski Cancer Center in Hamilton, Ontario.

Dr. Whelan and colleagues emphasized that the results are only applicable to the women in the study population: those with node-negative invasive breast cancer with clear margins after lumpectomy.

For those women, "an abbreviated course of radiation therapy should be more convenient and less costly than standard treatment," write Dr. Whelan and his coauthors.

The authors hope that the results will lead to an increase in the number of women who receive radiation after surgery. Currently, "up to 30% of women in North America" who have breast-conserving surgery do not receive any radiation, they say.

Another recent study, published online February 5 in The Lancet Oncology, extends the definition of outcomes in this treatment population. This study found that hypofractionated radiation for breast cancer produces "no detriment to body image."

The investigators, who are from the Standardization of Breast Radiotherapy (START) trials in the United Kingdom, assessed quality-of-life issues related to skin-tissue effects, which are not often evaluated in breast cancer, notes an accompanying editorial.

"These researchers show a consideration of the patient's point of view that is too often absent," writes editorialist Julie Schnur, PhD, from Mount Sinai School of Medicine in New York City, about the British study.

Cosmetics Are the Same

In the Canadian study, women with node-negative invasive breast cancer were randomized to either standard whole-breast irradiation (50 Gy given in 25 fractions over a period of 35 days) or accelerated hypofractionated irradiation (42.5 Gy given in 16 fractions over a period of 22 days).

The risk for local recurrence at 10 years was 6.7% among the 612 women in the standard-treatment group and 6.2% among the 622 women in the hypofractionated-treatment group (absolute difference, 0.5 percentage points; 95% confidence interval [CI], –2.5 to 3.5).

There were 126 deaths in the standard-treatment group and 122 in the hypofractionated-treatment group. "The probability of survival over time was similar in the 2 groups (P = .79)" write the authors.

At 10 years, 71.3% of the women in the standard-treatment group and 69.8% in the hypofractionated-treatment group had good or excellent cosmetic outcomes (absolute difference, 1.5 percentage points; 95% CI, –6.9 to 9.8).

With regard to toxic effects and cosmetic outcome, the "global cosmetic outcome worsened over time," but there were no significant differences between the 2 treatment groups at any time, the authors write.

In the long term, radiation therapy can cause telangiectasia and fibrosis of subcutaneous tissue, note the authors. These lead to "loss of volume and retraction of the breast," which adversely affect cosmetics.

The authors note that women with large breasts were not included in the study, and that "few women" received adjuvant chemotherapy as part of their treatment.

Overall, the 10-year efficacy and toxicity results of this Canadian trial are "consistent" with 5-year results from a pair of British trials, START A and START B, say Dr. Whelan and his colleagues.

Better Quality of Life

Conducted in the United Kingdom, START A compared 2 different hypofractionation schedules (39 Gy and 41.6 Gy) given over 5 weeks with standard radiation (Lancet Oncol. 2008;9:331-341); START B compared a single schedule (40 Gy) given over 3 weeks with standard radiation (Lancet. 2008;371:1098-1107). Standard radiation was 50 Gy given in 25 fractions.

Since publishing their efficacy and toxicity data, the START researchers went on to analyze patient-reported quality-of-life issues from both the A and B trials, and these are the findings now reported in the Lancet Oncology.

Specifically, they compared the different radiotherapy regimens with respect to changes in breast, arm, shoulder symptoms, and in function and body image.

Over the 5 years of the studies, the most frequently reported adverse effects were breast hardness (41%) and change in breast appearance (39%), report the START investigators, led by Penelope Hopwood, MD, from the Institute of Cancer Research in Sutton, United Kingdom.

For most of the adverse effects, hypofractionated schedules had rates that were lower than or similar to standard radiation.

Adverse change in skin appearance after radiotherapy was the only symptom to differ significantly between the radiotherapy schedules — and the patients treated with hypofractionated radiation had better outcomes.

Specifically, adverse change in skin appearance was significantly lower for patients who received 39 Gy than for those who received the standard 50 Gy (hazard ratio [HR], 0.63; 95% CI, 0.47 to 0.84), and for those who received 40 Gy than for those who received the standard 50 Gy (HR, 0.76; 95% CI, 0.60 to 0.97).

No significant difference was observed between patients who received 41.6 Gy and those who received the standard 50 Gy (HR, 0.83; 95% CI, 0.63 to 1.08).

More research examining quality of life and radiotherapy outcomes is needed, writes Dr. Schnur in her editorial accompanying the study.

"The study of quality of life as it relates to normal tissue effects in patients with breast cancer is woefully understudied," she notes.

The Canadian study was supported by grants from the Canadian Breast Cancer Research Alliance and the Canadian Cancer Society. The START study had support from Cancer Research UK, the UK Medical Research Council, and the UK Department of Health. For both studies, the researchers have disclosed no relevant financial relationships.

N Engl J Med. 2010;362:513-520.
Lancet Oncol. 2010. Published onlineFebruary 5, 2010. Abstract, Abstract

NERATINIB AND DIARRHEA

J Clin Oncol. 2010 Feb 8. [Epub ahead of print]

Neratinib, an Irreversible ErbB Receptor Tyrosine Kinase Inhibitor, in Patients With Advanced ErbB2-Positive Breast Cancer.

Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, Awada A, Ranade A, Jiao S, Schwartz G, Abbas R, Powell C, Turnbull K, Vermette J, Zacharchuk C, Badwe R.

Dana-Farber Cancer Institute, Boston, MA; Oncology Center AZ St Augustinus, Antwerp; UZ Gasthuisberg, Leuven; and Institut Jules Bordet, Brussels, Belgium; Cancer Hospital, Chinese Academy of Medical Sciences; Chinese People's Liberation Army General Hospital; and The Hospital Affiliated Academy of Military Medical Science, Beijing, China; Cancer Institute of New Jersey, New Brunswick, NJ; Deenanath Mangeshkar Hospital, Pune; and Tata Memorial Hospital, Mumbai, India; Dartmouth-Hitchcock Medical Center, Lebanon, NH; and Wyeth Research, Collegeville, PA and Cambridge, MA.

PURPOSE: Neratinib is an oral, irreversible pan-ErbB receptor tyrosine kinase inhibitor. The efficacy and safety of neratinib were evaluated in two cohorts of patients with advanced ErbB2-positive breast cancer-those with and those without prior trastuzumab treatment-in an open-label, multicenter, phase II trial. PATIENTS AND METHODS: Patients in the two cohorts (prior trastuzumab, n = 66; no prior trastuzumab, n = 70) received oral neratinib 240 mg once daily. The primary end point was the 16-week progression-free survival (PFS) rate for the evaluable population (prior trastuzumab, n = 63; no prior trastuzumab, n = 64), as assessed by independent review. RESULTS: The 16-week PFS rates were 59% for patients with prior trastuzumab treatment and 78% for patients with no prior trastuzumab treatment. Median PFS was 22.3 and 39.6 weeks, respectively. Objective response rates were 24% among patients with prior trastuzumab treatment and 56% in the trastuzumab-naïve cohort. The most common adverse events were diarrhea, nausea, vomiting, and fatigue. Diarrhea was the most frequent grades 3 to 4 adverse event, occurring in 30% of patients with prior trastuzumab treatment and in 13% of patients with no prior trastuzumab treatment, which prompted dose reductions in 29% and 4% of patients, respectively, but treatment discontinuation in only one patient. No neratinib-related, grades 3 or 4 cardiotoxicity was reported. CONCLUSION: Oral neratinib showed substantial clinical activity and was reasonably well tolerated among both heavily pretreated and trastuzumab-naïve patients who had advanced, ErbB2-positive breast cancer. Diarrhea was the most common adverse effect but was manageable with antidiarrheal agents and dose modification.

SECOND LINE CHEMOTHERAPY FOR PANCREATIC CANCER

Am J Clin Oncol. 2010 Feb 5. [Epub ahead of print]

Irinotecan Plus Bolus/Infusional 5-Fluorouracil and Leucovorin in Patients With Pretreated Advanced Pancreatic Carcinoma: A Multicenter Experience of the Gruppo Oncologico Italia Meridionale.

Gebbia V, Maiello E, Giuliani F, Borsellino N, Arcara C, Colucci G.

From the *La Maddalena Clinic for Cancer, Department of Experimental Oncology and Clinical Applications, University of Palermo, Palermo, Italy; daggerIRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; double daggerIstituto Oncologico, Bari, Italy; section signOspedale Buccheri La Ferla, Palermo, Italy.

BACKGROUND:: Patients with advanced pancreatic cancer failing gemcitabine-based first-line chemotherapy are still in relatively good clinical conditions and may still require second-line chemotherapy, which is frequently administered in daily clinical practice given to without solid scientific support. PATIENTS AND METHODS:: A retrospective survey was carried out including 40 patients with stage III or IV gemcitabine-refractory pancreatic carcinoma. Patients received standard FOLFIRI regimen biweekly until progression or unacceptable toxicity. Response evaluation criteria in solid tumors and National Cancer Institute common toxicity criteria were employed respectively for response and toxicity assessment. RESULTS:: Six partial responses (15%) and 14 stabilizations of disease (35%) were recorded for a tumor growth control rate of 50%. The median time to progression was 3.7 (range, 1-6.5 months), and median overall survival was 6 months (range, 2-8.2 months). A stabilization of performance status and a subjective improvement of cancer-related symptoms were recorded in 21 patients (52.5%). No correlation has been found between length of time to progression during first-line chemotherapy and length of that reported in the second-line setting or objective response. Grade 3-4 diarrhea and mucositis was observed in 15% and 10% of cases, respectively. CONCLUSIONS:: Data presented in this article demonstrate that the second-line FOLFIRI regimen are able to induce an objective response in a relatively small fraction of patients with gemcitabine-refractory adenocarcinoma of the pancreas. The use of second-line chemotherapy should be carefully proposed to patients with good performance status or those who had a good response to first-line therapy.

DENOSUMAB FOR GIANT CELL TUMORS

February 11, 2010 — The novel biologic agent denosumab (Amgen) could offer a breakthrough in the treatment of the rare giant cell tumor of bone, suggests an editorial published online February 10 in The Lancet Oncology. It accompanies the publication of a small open study, which reports that the drug produced a tumor response in 30 of 35 patients (86%).

"To our knowledge, this is the first report that clearly shows a promising systemic treatment option for this rare type of tumor," write the editorialists, Maurice Balke, MD, and Jendrik Hardes, MD, from the Department of Trauma and Orthopedic Surgery at the University of Witten-Herdecke in Cologne, Germany. There have been reports of beneficial effects with bisphosphonates, but no successive prospective trials, they add.

The current treatment for giant cell tumor of bone is surgery, the editorialists point out. "If done thoroughly, the patient may be cured in up to 90% of cases."

But there are some cases of atypical giant cell tumor of bone with multiple local recurrences, multicentricity, pulmonary metastases, or lesions that are impossible to remove surgically without causing substantial morbidity, they continue.

"Surgery that causes major functional deficits is hardly justifiable for a lesion that is typically benign," but until now, promising alternatives have been lacking. "Hopefully, this will change," they write. "This excellent study . . . might change clinical practice in the treatment of complicated giant cell tumor of bone."

Denosumab is not currently marketed, although a launch is expected this year. It is awaiting approval for use in the treatment and prevention of postmenopausal osteoporosis, and for the prevention of bone loss in breast cancer patients receiving aromatase inhibitors and in prostate cancer patients receiving androgen-deprivation therapy. Another indication in late development is the treatment of bone metastases in patients with breast and prostate cancer. For most of these indications, the drug would be competing against bisphosphonates, but denosumab is a "first in its class" product — a monoclonal antibody directed against RANKL, a key mediator in bone turnover.

Majority of Patients Responded

The study was conducted by David Thomas, FRACP, PhD, from the Peter MacCallum Cancer Center in East Melbourne, Victoria, Australia, and colleagues in the United States and France, as well as researchers from Amgen, which funded the trial.

A total of 37 patients at 8 centers were enrolled, but 2 patients had insufficient histology or radiology data for efficacy assessment. All patients had recurrent or unresectable giant cell tumor of bone, and the most common sites for lesions were the pelvis, lungs, and lower extremities.

All patients were treated with denosumab 120 mg subcutaneously once a month (after loading doses on days 8 and 15 of the first month).

The primary end point was tumor response, defined as the elimination of at least 90% of giant cells or no radiologic progression of the target lesions up to week 25. This was seen in 30 of the 35 evaluable patients (86%), the researchers report.

Histology results were available for 20 patients, and all of these showed a complete or near complete elimination of giant cells. Radiologic results were available for 15 patients, and 10 of these showed a lack of progression or stable disease; in some cases, objective partial responses were observed. These observations correlate with reports of clinical benefit by the investigators, such as reductions in pain requiring less analgesia and improvements in function, mobility, and bone repair, Dr. Thomas and colleagues note.

Adverse events were reported by most patients (33 of 37), most frequently pain in an extremity (n = 7) or the back (n = 4) and headache (n = 4).

The results suggest that denosumab has "activity as a therapeutic agent" for giant cell tumor of bone, the researchers conclude.

Limitations of the current study are the fact that the sample size was small, the duration was short, and it was a single-group design, they note.

The small sample size and the heterogeneity of these patients "does not downgrade the results," according to the editorialists, "because the study population accurately represents patients with complications who are in need of additional systemic therapy."

But several issues remain to be addressed, including the mechanism of action involved and the duration of therapy needed, they explain. In 1 patient enrolled in the trial, tumor progression recurred after the drug was discontinued. "This raises the question of whether the inhibitory effect is only temporary and how long treatment must continue until a long-term or definitive effect is achieved," they write.

Prospective randomized trials with a high enrolment and a follow-up of at least 2 years will be necessary, they conclude.

The study was sponsored by Amgen, the manufacturer of denosumab. Dr. Thomas reports receiving consulting fees from Amgen and research grants from Novartis and Pfizer. Two of his coauthors report relationships with a variety of pharmaceutical companies, and 6 of his coauthors are employees of Amgen, as detailed in the paper. The editorialists have disclosed no relevant financial relationships.

Lancet Oncol. Published online February 10, 2010.

AN INTERESTING CASE

Clin Breast Cancer. 2010 Feb 1;10(1):E3-5.

Metastatic prostatic adenocarcinoma mimicking inflammatory breast carcinoma: a case report.

Njiaju UO, Truica CI.

Johns Hopkins University and Sinai Hospital Program in Internal Medicine.

Prostate adenocarcinoma can manifest as a fairly indolent tumor or as a very aggressive cancer with significant invasive and metastatic potential. Common metastatic sites include bone, liver, lymph nodes, and adrenal glands. Dermatologic manifestations are rare. We present a case of a man who presented with breast skin changes that mimicked inflammatory breast carcinoma with specialized testing ultimately giving a diagnosis of metastatic prostatic adenocarcinoma. A 78-year-old man presented with left breast redness and swelling. Examination revealed an erythematous rash with subcutaneous edema over the left hemithoracic area. A breast ultrasound showed no focal mass, and a breast core biopsy had no evidence of tumor. A skin biopsy showed metastatic carcinoma in dermal lymphatics, and the tumor was found to have no estrogen or progesterone receptors or HER2 expression. Computed tomography scans, positron emission tomography, and a nuclear bone scan revealed widespread skeletal metastases. The patient received a 3-month course of capecitabine and cyclophosphamide with no improvement in his skin lesions. Subsequent immunohistochemical staining on the tumor specimen was positive for prostate-specific antigen (PSA) and alpha-methyl-CoA-racemase, confirming a diagnosis of metastatic prostatic adenocarcinoma. He received leuprolide and bicalutamide and demonstrated significant improvement with near-complete resolution of his skin lesions and a decrease in his PSA level. Prostatic adenocarcinoma presenting initially as a breast malignancy is a rarely recognizable clinical event. Undoubtedly, increased awareness and recognition of the rare entity described herein will allow for the prompt initiation of specific therapies, which might be of benefit to many patients.

LAPATINIB AND TRASTUZUMAB COMBINATION

J Clin Oncol. 2010 Feb 1. [Epub ahead of print]

Randomized Study of Lapatinib Alone or in Combination With Trastuzumab in Women With ErbB2-Positive, Trastuzumab-Refractory Metastatic Breast Cancer.

Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J.

Duke University Medical Center, Durham, NC; Dana-Farber Cancer Institute, Boston, MA; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN; University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; Medicine Development Center Oncology, GlaxoSmithKline, Collegeville, PA; Texas Oncology, PA, US Oncology, Tyler; Baylor Sammons Cancer Center, Texas Oncology, PA, US Oncology, Dallas, TX; Otto von Guericke Univeristäte, Madgeburg, Germany; and Vall d'Hebron University Hospital, Barcelona, Spain.

PURPOSE: Preclinical studies in ErbB2-positive cell lines demonstrated a synergistic interaction between lapatinib and trastuzumab, suggesting that dual blockade is more effective than a single agent alone. EGF104900 compared the activity of lapatinib alone or in combination with trastuzumab in patients with ErbB2-positive, trastuzumab-refractory metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients with ErbB2-positive MBC who experienced progression on prior trastuzumab-containing regimens were randomly assigned to receive either lapatinib alone or in combination with trastuzumab. The primary end point was progression-free survival (PFS). Secondary efficacy end points included overall response rate (ORR), clinical benefit rate (CBR; complete response, partial response, and stable disease for >/= 24 weeks), and overall survival (OS). RESULTS: In the intent-to-treat population (N = 296) who received a median of three prior trastuzumab-containing regimens, the combination of lapatinib with trastuzumab was superior to lapatinib alone for PFS (hazard ratio [HR] = 0.73; 95% CI, 0.57 to 0.93; P = .008) and CBR (24.7% in the combination arm v 12.4% in the monotherapy arm; P = .01). A trend for improved OS in the combination arm was observed (HR = 0.75; 95% CI, 0.53 to 1.07; P = .106). There was no difference in ORR (10.3% in the combination arm v 6.9% in the monotherapy arm; P = .46). The most frequent adverse events were diarrhea, rash, nausea, and fatigue; diarrhea was higher in the combination arm (P = .03). The incidence of symptomatic and asymptomatic cardiac events was low (combination therapy = 2% and 3.4%; monotherapy = 0.7% and 1.4%, respectively). CONCLUSION: Despite disease progression on prior trastuzumab-based therapy, lapatinib in combination with trastuzumab significantly improved PFS and CBR versus lapatinib alone, thus offering a chemotherapy-free option with an acceptable safety profile to patients with ErbB2-positive MBC.

BORTEZOMIB FOR FOLLICULAR LYMPHOMA

NEW YORK (Reuters Health) Feb 02 - The proteasome inhibitor bortezomib (Velcade) is effective in patients with follicular lymphoma and other indolent non-Hodgkin's lymphomas, according to a report in the January 12th issue of Clinical Cancer Research.

Approved for managing mantle cell lymphoma, bortezomib has shown an inconsistent pattern of activity across many subtypes of lymphoma, the authors explain, and its activity in follicular lymphoma has been a subject of controversy.

Dr. Owen A. O'Connor from the College of Physicians and Surgeons, Columbia University, New York, and colleagues investigated the activity of bortezomib monotherapy in 77 patients (69 assessable for response) with mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), marginal zone lymphoma, or Waldenstrom's macroglobulinemia.

The overall response rate was 45% (40% on an intention-to-treat basis).

Nine of 18 patients with follicular lymphoma achieved a major response, including 4 with complete remission. Three of 8 patients with marginal zone lymphoma attained a partial remission; 1 of 9 patients with Waldenstrom's macroglobulinemia had stable disease; and 1 of 6 patients with SLL/CLL responded to treatment.

The median time to response was 11 to 12 weeks for patients with follicular lymphoma, compared with 4 weeks for patients with mantle cell lymphoma and all other subtypes of non-Hodgkin's lymphoma.

The overall progression-free survival was 4.75 months, the researchers note, compared with 9.8 months for the line of prior chemotherapy just before entry into this study.

Patients entering the study with refractory disease did worse than patients with relapsed disease, but the difference was of only borderline significance (p = 0.06).

There were no major hematologic toxicities besides lymphopenia and thrombocytopenia, and there were no opportunistic infections, but electrolyte abnormalities were common.

"These data suggest bortezomib has significant single-agent activity in patients with follicular lymphoma, and that longer durations of treatment may improve overall response," the authors say.

They add that theirs is the first report to suggest "that the time to treatment response may be one of the most important determinants of activity" for bortezomib in these patients.

The delayed response may be due to "the immunomodulatory effects of bortezomib on the lymphoma node microenvironment," they speculate.

"Future directions focused on understanding the merits of bortezomib in the indolent lymphomas will continue to explore how best to combine the agent with other known drugs used for these diseases," the investigators add.

Millennium Pharmaceutical, which manufactures bortezomib, provided commercial research grant support and an honorarium to Dr. O'Connor.

Clin Cancer Res 2010;16:719-726.

PERTUZUMAB REVERSES TRASTUZUMAB RESISTANCE?

NEW YORK (Reuters Health) Feb 01 - When given with trastuzumab, pertuzumab, a HER2-targeted monoclonal antibody, can be an effective treatment for HER2-positive breast cancer that progressed during prior trastuzumab therapy, new research suggests.

By contrast, pertuzumab (rhuMAb 2C4) is probably not useful for HER2-negative disease, according to a separate study conducted by many of the same researchers.

Both papers appear in the February 1 Journal of Clinical Oncology.

The first study -- an open-label phase II trial led by Dr. Jose Baselga, from Vall d'Hebron University Hospital in Barcelona - involved 66 patients who received pertuzumab plus trastuzumab after disease progression with trastuzumab-based therapy. Along with trastuzumab, patients received pertuzumab in an 840-mg loading dose, followed by 420 mg every 3 weeks until disease progression or excessive toxicity.

Roughly 24% of patients had an objective response, defined as confirmed complete or partial responses. Fifty percent of patients had a clinical benefit, defined as the total number of objective responses plus stable disease >6 months. Complete response, partial response, and stable disease rates were roughly 8%, 17%, and 26%, respectively.

The median progression-free survival period was 5.5 months, the researchers note.

The drug combination was generally well tolerated, and side effects were mild to moderate. Cardiac toxicity was minimal and no patients discontinued therapy for cardiac-related reasons.

The authors note that single-agent pertuzumab is now being evaluated in the same patient population.

The second study, headed by Dr. Luca Gianni from Istituto Nazionale Tumori in Milan, assessed stable disease rates in 78 patients with HER2-negative metastatic breast cancer, all of whom received an 840-mg loading dose of pertuzumab. The patients were then randomized to continue with either 420 mg or 1050 mg given every 3 weeks.

Eighteen patients (44%) given 420 mg of pertuzumab and 14 (38%) given 1050 mg had stable disease lasting 12 weeks or longer. However, only 6 patients had a treatment response or stable disease lasting 6 months or more.

As in the first study, pertuzumab was generally well tolerated with minimal side effects. Eight patients had a potentially clinically relevant drop in cardiac function, including one with congestive heart failure.

"The limited efficacy observed in this study" and the "generally stable disease of relatively short duration" suggests there is little point to further studies of monotherapy with pertuzumab in unselected patients with HER2-negative breast cancer, the authors conclude.

Both studies were supported by F. Hoffmann-La Roche, which manufactures pertuzumab.

J Clin Oncol 2010.

SIMPLE OVARIAN CYSTS IN POSTMENOPAUSAL WOMEN

NEW YORK (Reuters Health) Feb 02 - In women over 55, simple ovarian cysts are common, usually resolving or persisting without progression, according to data from the prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO).

The presence of simple cysts, often found incidentally during transvaginal ultrasound (TVU) exams, did not affect the risk of ovarian cancer, according to lead author Dr. Robert T. Greenlee and colleagues -- bolstering recent recommendations that unilocular simple cysts in postmenopausal women be followed without intervention.

Dr. Greenlee, from the Marshfield Clinic Research Foundation, Wisconsin, and associates followed 15,735 postmenopausal women through 4 years of annual TVU screening. All were between 55 and 74 years old at enrollment, and all had CA-125 measurements and TVU studies at baseline. Both tests were repeated annually. In addition, for a woman to be included in the study, both ovaries had to be visualized at least once by TVU.

Simple cysts were defined as having a volume <>

In a paper published online January 25 in the American Journal of Obstetrics and Gynecology, the investigators report that the prevalence of at least 1 simple cyst detected during the first fully visualized TVU screening was 14.1%. Potential correlates of prevalent simple cysts were younger age (55 to 59), education past high school, and early menopause. The odds were also higher in women with a history of benign ovarian cysts, menopause before age 40, and a first pregnancy at or beyond age 30.

Among women without a cyst of any kind on their first fully visualized TVU screening, the incidence of simple cysts was approximately 8% per year, remained fairly constant, and did not vary by age.

One-third of ovaries with simple cysts were cyst-free the following year. Even when 2 or more cysts were present, all resolved a quarter of the time. Only 6% progressed in complexity from 1 year to the next.

Women with and without simple cysts were at similar risk of invasive ovarian cancer after nearly 8 years of follow-up evaluation, the authors write. Furthermore, traditional ovarian cancer risk factors, such as increasing age, family history of breast or ovarian cancer, nulliparity, and infertility, were not associated with simple cysts. Finally, changes in average CA-125 were not correlated with increases in the number or progression of simple cysts.

Thus, Dr. Greenlee and his group conclude, "Simple cysts are not likely cancer precursors or markers of increased risk and can be followed conservatively."

Am J Obstet Gynecol 2010.

ASCO FOR GENETIC TESTING

February 4, 2010 — The American Society of Clinical Oncology (ASCO) has issued an updated policy statement on genetic and genomic testing for cancer susceptibility. The new document, an update of a statement issued in 2003, was published online January 11 in the Journal of Clinical Oncology.

The update was prompted by an increase in the number of such tests, and it raises 2 main concerns — the fact that some tests are of unproven clinical benefit, and the fact that some are now being marketed directly to consumers.

More than 900 genetic tests are now available, although only 5% to 10% of all cancers are considered to be hereditary, according to ASCO.

"The awareness of individual genetic differences within the population has sparked a number of significant developments and an unprecedented level of raw information being made available, not only to health professionals, but also to the public in the form of direct-to-consumer [DTC] tests," said senior author Kenneth Offit, MD, MPH, chief of the Clinical Genetics Service at Memorial Sloan-Kettering Cancer Center in New York City, and a member of ASCO's Ethics Committee.

These updated recommendations "attempt to get back to the basics — patient safety and clinical utility — for the individuals considering genetic testing and the doctors who offer testing or may be asked by patients to interpret direct-to-consumer test results," Dr. Offit said in a statement.

Oncologists and other healthcare providers who offer genetic tests should continue to be guided by a recommendation made in 2003, which states that testing should be offered only when the following criteria are met:

• the individual being tested has a personal or family history suggestive of genetic cancer susceptibility
• the genetic test can be adequately interpreted
• the test results have accepted clinical utility.

The updated statement acknowledges that emerging technologies, like genomic profiling for low-penetrance genetic variants (markers of very low disease risk), might be appropriate for patients who do not have a personal or family history suggestive of cancer risk, provided that clinical utility is established and results can be easily interpreted. However, it also points out that the genomic tests for low-penetrance variants currently do not have proven clinical utility.

"None of us in this field is trying to block or delay the transmissions of useful genetic information to the broadest possible constituency," Dr. Offit emphasized in an interview with Medscape Oncology. "But we want to do this in a responsible way," he added, and there is concern that "the premature dissemination of some of these technologies can lead to problems of false reassurances and false alarms."

There are 2 separate issues, Dr. Offit explained.

There is a clear demarcation between genetic tests for high-prevalence mutations, which have proven clinical utility, and genomic tests for low-prevalence variants, which currently have no proven clinical utility, he said.

He explained that there is also a big difference between using these tests in a traditional medical model, where the test is ordered by and discussed with a healthcare provider who is responsible for the patient's health, and the new situation, where these tests are marketed by commercial companies over the internet and where results are issued in a computer printout without any human interaction.

Tests With Accepted Clinical Utility

Examples of genetic tests for which clinical utility is accepted are testing for high-penetration mutations, such as BRCA1/2 for breast cancer and MLH1/MSH2 for colorectal cancer. These tests inform clinical decision-making and facilitate the prevention or amelioration of adverse health outcomes, the authors explain.

For example, women found to carry the BRCA1 mutation, which increases the relative risk of developing breast cancer 32-fold by the age of 40 to 49 years, can be offered increased screening with mammography or magnetic resonance imaging, or risk-reducing surgery. Individuals found to carry the MSH2 mutation, which increases the risk for colon cancer 13.1-fold by the age of 30 years and 9.3-fold by the age of 50 years, can be offered earlier and more frequent endoscopy and a prophylactic colectomy after a diagnosis of malignancy.

Similar interventions can be offered to individuals found to carry another high-penetrance mutation, APC, which increases the risk for colorectal cancer 19-fold over a lifetime. Another high-penetrance mutation is RET, which increases the risk for medullary thyroid cancer 125-fold over a lifetime; people found to carry this mutation are offered prophylactic thyroidectomy.

However, although these high-penetrance mutations are clinically relevant, they are uncommon, the authors point out.

Most inherited cancer susceptibility arises from a number of DNA sequence variants, each of which, in isolation, confers a limited increase in risk. Genetic tests for intermediate-penetrance mutations and low-penetrance variants (single-nucleotide polymorphisms [SNPs]) are of uncertain clinical utility because the cancer risk associated with the mutation or SNP is too small to form an appropriate basis for clinical decision-making. For all of these intermediate- and low-penetrance variants, there is no proven intervention.

ASCO recommends that genetic tests with uncertain clinical utility, including genomic risk assessment, be administered in the context of clinical trials. However, some of these tests are being directly marketed to the public.

One example of a low-penetrance variant (SNP) is rs10505477 at 8q24, which increases the relative risk for colon cancer 1.27-fold and the relative risk for prostate cancer 1.43-fold.

There are also 2 low-penetrance variants, rs13281615 at 8q24 and rs1219648 at FGFR2, which increase the relative risk for breast cancer 1.21-fold and 1.23-fold, respectively. The authors note that this increase in the relative risk of developing breast cancer is equivalent to that of delaying childbearing from age 30 to age 35. "This level of risk does not warrant changes in recommendations for screening or prevention," they add.

Considerable Concern Over DTC Genetic Testing

Genetic testing for cancer susceptibility has become an accepted part of oncologic care, Dr. Offit and colleagues write. To date, most of this testing is professionally mediated and is of accepted clinical utility, they explain.

However, there is "considerable concern within the medical community about various aspects of direct-to-consumer genetic testing," the authors note. With marketing over the internet, there are concerns about informed consent and inadequate counseling, both before and after testing.

"Not all DTC testing companies offer counseling, and they may only offer counseling to consumers who pay additional fees," the team points out. "Where counseling is provided, there is some concern that the advice offered by testing companies may be biased in favor of testing."

It makes for a tricky situation when individuals who obtain DTC tests then turn to a healthcare professional for help interpreting test results. Such requests can "pose significant challenges," the authors write.

"While most of us look forward to a time when all doctors will offer genome scans to guide preventive care of their patients," Dr. Offit said, he is not as sure that the DTC delivery of these services by for-profit companies is the model to aim for.

Some of these points were raised recently by researchers from the University of Michigan Comprehensive Cancer Center in Ann Arbor.

"While the test is a very easy thing to do — it's a simple blood test — the interpretation of the results can sometimes be very complicated," said Mark Pearlman, MD, professor of obstetrics and gynecology at the University of Michigan Medical School.

"It's important to understand that getting the genetic test result is only a piece of the puzzle," he continued. "It really takes a professional who understands genetics to work with individual women and men to allow them to understand exactly what the piece of information means to them in terms of their risk, their loved ones' risks, and what can then be done to lower that risk."

These comments appear in a press statement issued by the university in response to a new advertising campaign in the United States that encourages women to be tested for gene mutations related to breast and ovarian cancer (BRCA1/2).

Only 2% of the population should be tested for these mutations, Dr. Pearlman and colleagues point out.

"It's very important that the right women seek out genetic testing for breast and ovarian cancer," said Sofia Merajver, MD, PhD, director of the Breast and Ovarian Risk Evaluation Program at the University of Michigan. "Cancer risk is more complex than a simple yes or no, and the test for genetic mutations is only part of the picture."

Most cases of breast and ovarian cancer are random and are not linked to BRCA gene mutations, the doctors point out. Less than 10% of all women with breast cancer and less than 15% of all women with ovarian cancer carry a BRCA gene mutation.

Only 1 of the 5 authors of the ASCO policy statement update reports a relevant financial relationship: Mark Robson, MD, from Memorial Sloan-Kettering Cancer Center, reports receiving research funding from AstraZeneca and Kudos Pharmaceuticals.

J Clin Oncol. Published online January 11, 2010. Abstract

ATYPICAL ENDOMETRIAL HYPERPLASIA AND CANCER

NEW YORK (Reuters Health) Feb 02 - The cumulative 20-year risk of endometrial carcinoma for women with atypical endometrial hyperplasia is 28%, compared with a combined rate of less than 5% for women with simple or complex hyperplasia, according to a new report.

"Before our study there were major questions about how likely each of the types of endometrial hyperplasia -- simple hyperplasia, complex hyperplasia, and atypical hyperplasia -- was to progress," senior author Dr. James V. Lacey, Jr., from City of Hope, Duarte, California, told Reuters Health.

Dr. Lacey and his colleagues conducted a case-control study nested in a cohort of 7947 women with endometrial hyperplasia. Case patients (n = 138) were diagnosed with carcinoma an average of 6 years after their diagnosis of hyperplasia. Control patients (n = 241) were matched to case patients on age at hyperplasia diagnosis, date of diagnosis, duration of follow-up, and hyperplasia severity. Original slides and medical records of cases and controls were reviewed.

In the January 10th online issue of the Journal of Clinical Oncology, the researchers report that in women without atypical endometrial hyperplasia (i.e., women with simple or complex hyperplasia), the cumulative risk of progression to cancer after the index biopsy increased from 1.2% through 4 years, to 1.9% through 9 years, to 4.6% through 19 years. For atypical hyperplasia, the cumulative risk increased from 8.2% through 4 years, to 12.4% through 9 years, to 27.5% through 19 years.

Hormonal treatment for endometrial hyperplasia and follow-up biopsies were similar between case patients and controls. All case patients with atypical hyperplasia who were diagnosed with carcinoma at least 5 years after index biopsy received hormonal treatment, and 89% received at least one follow-up biopsy.

"For women who are diagnosed with endometrial hyperplasia and the health care providers who treat them, our data provide the most accurate estimates to date of how likely those women are to clinically progress to carcinoma in the 5, 10, and 20 years after being diagnosed with endometrial hyperplasia," Dr. Lacey noted.

"Numbers like that, expressed as absolute risks," he added, "can be especially helpful in weighing the pros and cons of whether to pursue a course of definitive treatment, like hysterectomy, or whether to pursue a course of nonsurgical clinical management that includes progestin-based therapy and continued observation."

J Clin Oncol 2010.

CETUXIMAB IN NSCLC

J Clin Oncol. 2010 Jan 25. [Epub ahead of print]

Cetuximab and First-Line Taxane/Carboplatin Chemotherapy in Advanced Non-Small-Cell Lung Cancer: Results of the Randomized Multicenter Phase III Trial BMS099.

Lynch TJ, Patel T, Dreisbach L, McCleod M, Heim WJ, Hermann RC, Paschold E, Iannotti NO, Dakhil S, Gorton S, Pautret V, Weber MR, Woytowitz D.

Yale School of Medicine, New Haven; Bristol-Myers Squibb, Wallingford, CT; Mid Ohio Oncology/Hematology, Columbus, OH; Desert Hematology Oncology Medical Group, Rancho Mirage, CA; Florida Cancer Specialists, Fort Myers; Hematology-Oncology Associates of The Treasure Coast, Port Saint-Lucie, FL; Hematology & Oncology Associates of Northeastern Pennsylvania, Dunmore, PA; Northwest Georgia Oncology Centers, Marietta, GA; Piedmont Hematology Oncology Associates, Winston-Salem, NC; Cancer Center of Kansas, Wichita, KS; Western Washington Oncology, Lacey, WA; and Bristol-Myers Squibb, Braine l'Alleud, Belgium.

PURPOSE: To evaluate the efficacy of cetuximab plus taxane/carboplatin (TC) as first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This multicenter, open-label, phase III study enrolled 676 chemotherapy-naïve patients with stage IIIB (pleural effusion) or IV NSCLC, without restrictions by histology or epidermal growth factor receptor expression. Patients were randomly assigned to cetuximab/TC or TC. TC consisted of paclitaxel (225 mg/m(2)) or docetaxel (75 mg/m(2)), at the investigator's discretion, and carboplatin (area under the curve = 6) on day 1 every 3 weeks for