Denosumab Superior to Zoledronic Acid in Reducing Incidence of Skeletal-Related Events in Breast Cancer Patients with Bone Metastases

Data Presented at earlier this month at the San Antonio Breast Cancer Symposium demonstrates that treatment with denosumab, a new drug in late stage clinical development, is superior to the standard of care in advanced breast cancer patients. Among patients with bone metastasis from breast cancer, denosumab was superior to zoledronic acid in reducing the incidence of complications from bone metastases.

"Denosumab prevented more events, was better tolerated and is more convenient for patients," said Alison Stopeck, M.D., associate professor of medicine at the University of Arizona Cancer Center who presented the results of this phase III, double blind study at the 2009 CTRC-AACR San Antonio Breast Cancer Symposium.

Stopeck and colleagues enrolled 2,048 patients with bone metastasis who had never received treatment with intravenous bisphosphonates. They randomly assigned patients to treatment with 120 mg subcutaneous denosumab (Amgen) or 4 mg intravenous zoledronic acid (Zometa, Novartis) every four weeks.

Denosumab, is an investigational first fully human monoclonal antibody developed by Amgen. It works differently from existing bone treatments by specifically targeting a protein called RANK Ligand (RANKL), which plays an important role in regulating osteoclast activity and function and has been linked with increased bone loss and complications from bone metastases.

Stopeck presented data confirming that denosumab significantly delayed time to first on-study skeletal-related event compared with zoledronic acid (HR=0.82; 95% CI, 0.71-0.95), as well as time to first, and subsequent, on-study skeletal-related event (rate ratio=0.77; 95% CI, 0.66-0.89). In this study, patients assigned to denosumab had 491 skeletal-related events compared with 623 for patients assigned to zoledronic acid.

"In clinical trials testing new medications for bone metastases, treatment success is measured by whether the bone complications, or skeletal related events, caused by the tumor are reduced or delayed," Stopeck explained. "Skeletal complications from bone metastases are a critical and painful health concern for patients with advanced breast cancer, and can increase the risk of mortality. Patients who have a first skeletal related event are twice as likely to experience a subsequent SRE, so it is imperative to treat these advanced breast cancer patients."

“Denosumab resulted in a considerable delay in the development of moderate-to-severe pain compared to zoledronic acid,” Stopeck said.

Additional data from this study showed that denosumab significantly reduced the mean annual skeletal morbidity rate (SMR) (the ratio of the number of skeletal complications to the time on trial) compared with Zometa (0.45 vs. 0.58, respectively; p=0.004).

Overall, the incidence of adverse events (96% denosumab, 97% zoledronic acid) and serious adverse events (44% denosumab, 46% zoledronic acid) was consistent with what has previously been reported for these two agents. Adverse events potentially associated with acute phase reactions during the first three days of the study were reported in 10.4 percent of the denosumab arm and 27.3% of the zoledronic acid arm. Adverse events potentially associated with renal toxicity occurred in 4.9% of patients treated with denosumab compared to 8.5% in patients treated with zoledronic acid.

Osteonecrosis of the jaw (ONJ) was seen infrequently in both treatment groups (20 patients receiving denosumab [2.0%] as compared with 14 patients [1.4%t] receiving Zometa). Rates of new primary malignancies were similar between treatment arms (5 patients receiving denosumab [0.5%] and 5 receiving zoledronic acid [0.5%]). Time to disease progression or overall survival was balanced between the study arms.

At 34 months, 30.7% of patients treated with denosumab arm experienced at least one skeletal-related event (95% CI, 33.5%-39.4%) compared with 36.5% of those treated with zoledronic acid. Denosumab also reduced mean skeletal morbidity rate (0.45 vs. 0.58; P=.004).

Clinical relevance
Bone metastases, cancer cells that separate from tumors and migrate to bone tissue where they settle and grow, occur in more than 1.5 million people worldwide. With improvements in cancer care, including earlier diagnosis and new treatment options, leading to increases in survival rates, the number of patients developing metastatic disease secondary to a primary cancer is increasing. Bone metastases are a significant problem for patients with certain types of advanced cancer, with incidence rates of nearly 100 percent in myeloma patients and as high as 75 percent in breast and prostate cancer patients.

With bone metastases the growing cancer cells weaken and destroy the bone around the tumor. The damage the tumor has caused to the bone can result in a number of serious complications, collectively called SREs. These include fracture of a bone, the need for radiation to bone, the need for bone surgery, or spinal cord compression. All are serious complications for advanced cancer patients.

The economic burden of United States (U.S.) patients with bone metastases is significant and was estimated to be $12.6 billion last year. Patients with bone metastases who experience an SRE incur significantly higher medical costs compared with those who do not experience an SRE.

The results of this study are therefore clinically relevant. Before the availability of bisphosphonates 64% patients with breast cancer with bone metastases generally developed a skeletal-related event, including fracture or pain. With the introduction of Bisphosphonates, this was reduced this to 43%. Today, with more potent agents such as zoledronic acid, the development of skeletal-related event are less than 34%. The results of this trial comparing denosumab vs zoledronic acid shows further improvement with a 27% reduction of incidence rate.

This oral presentation of the denosumab 136 data by Dr. Alison Stopeck was presented at the 2009 CTRC-AACR San Antonio Breast Cancer Symposium. on Thursday, December 10 at 3:15 PM (CT) in Exhibit Hall D of the Henry B. Gonzalez Convention Center, San Antonio, Texas.

For more information

• Downey L, Livingstone R, Stopeck A. Diagnosing and treating breast cancer in elderly women: a call for improved understanding. J Am Geriatr Soc 2007 Oct;55(10):1636-44. Epub 2007 Aug 28.
• Coleman R. Potential use of bisphosphonates in the prevention of metastases in early-stage breast cancer. Clin Breast Cancer 2007 Jul;7 Suppl 1:S29-35
• Coleman R. On the horizon: can bisphosphonates prevent bone metastases? Breast. 2007 Dec;16 Suppl 3:S21-7. Epub 2007 Nov 7. Review.
• Coleman RE. The benefits and costs of bisphosphonates. J Support Oncol 2007 Nov-Dec;5(10):483-4.
• Brown JE, Coleman RE. The present and future role of bisphosphonates in the management of patients with breast cancer. Breast Cancer Res. 2002;4(1):24-9. Epub 2001 Nov 26. Review.
• Rosen LS, Gordon D, Kaminski M, Howell A, Belch A, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J. 2001 Sep-Oct;7(5):377-87.
• Coleman RE. Metastatic bone disease: clinical features, pathophysiology and treatment strategies. Cancer Treat Rev. 2001 Jun;27(3):165-76. Review.
• Capanna R, Coia LR, Coleman R. et al. eds. Textbook of Bone Metastases Hoboken, NJ: Edition: John Wiley and Sons; 2005:105.
• Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002 Aug;2(8):584-93. Review
• Schulman KL, Kohles J. Economic burden of metastatic bone disease in the U.S. Cancer. 2007 Jun 1;109(11):2334-42.
• Mortimer JE, Schulman K, Kohles JD. Patterns of bisphosphonate use in the United States in the treatment of metastatic bone disease. Clin Breast Cancer. 2007 Aug;7(9):682-9.

Also follow

• Onco'Zine - The International Cancer Network

TEAM Study of Adjuvant Endocrine Treatment for Breast Cancer Reveals the Cost of Patient Non-compliance

The largest study in the world of treatments for post menopausal, hormone positive breast cancer has shown that patients who continue to take exemestane or tamoxifen do significantly better than patients who start to take one drug (or tamoxifen followed exemestane) but then stop.

Professor Cornelis van de Velde, principal investigator at the central data office for TEAM (tamoxifen exemestane adjuvant multinational) trial told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany, that differences in compliance between the nine countries involved in the trial shed light on the role that it played in patient outcome.

In the Dutch/Belgian part of the TEAM trial, more patients were node positive compared to those in other countries (and were therefore at higher risk of recurrences), because the existing Dutch treatment guidelines (which have since been changed) indicated that only ‘high risk’ patients should receive chemotherapy, endocrine treatment or both. Yet despite this handicap, recurrences of breast cancer in The Netherlands and Belgium were 12% for patients using tamoxifen and 9% of patients using exemestane compared to 8% and 7% internationally. This is probably due to better compliance with treatment in The Netherlands, which was significantly better than in other countries.

“Across the whole study, up to a cut-off point of two years nine months, non-compliance amongst women on tamoxifen was 19.8% and 12.9% for women on exemestane. However, these percentages were considerably lower in the Dutch/Belgian part of the TEAM trial where non-compliance was 14% for tamoxifen and 9% for exemestane Patients who stopped study treatment (tamoxifen or exemestane) had significantly higher chance of a recurrence; the chance was between four and five times higher among this group than among those who continued their treatment. This underlines the need for good information for patients concerning the side-effects of drugs and treatment efficacy,” said Prof van de Velde, who is Professor of Surgery at the Leiden University Medical Centre (Leiden, The Netherlands) and President of the European Society of Surgical Oncology. Compliance with medication in the TEAM study was lower than in any previous study of adjuvant aromatase inhibitors.

The TEAM study is a randomised phase III clinical trial comparing the efficacy of the aromatase inhibitor exemestane versus the current “gold standard” treatment tamoxifen as adjuvant endocrine therapies for hormone sensitive early breast cancer in postmenopausal women. After two years nine months a total of 9,779 women had been included in the trial from nine countries: France (1230 patients), Germany (1480), Greece (211), Japan (184), The Netherlands (2753), Belgium (414), UK/Ireland (1275), and the USA (2232).

The trial was started in 2001 but in 2004, based on results from another trial (Intergroup Exemestane Study) that showed a significant survival advantage for patients on exemestane, the TEAM study was changed so that patients receiving tamoxifen were switched to exemestane after having been in the trial for between two and a half to three years. The results presented today relate to data on disease-free survival in patients on the trial for no longer than two years nine months and they focus particularly on issues of compliance in the Dutch/Belgian TEAM patients, as well as on side effects, and disease-free and overall survival across the whole of the study.

Prof van de Velde noted: “Adverse side effects were the main reasons why patients discontinued their treatment – about half of all patients who discontinued did so because of side effects. Out of all the patients in the study, 6.3% discontinued tamoxifen and 4.4% discontinued exemestane because of side effects."

Adverse side effects included heart, skin, hormonal, digestive, metabolic, neurological, muscle and skeletal problems. Exemestane was associated with significantly higher rates of arthralgia, carpal tunnel syndrome, diarrhoea and high cholesterol levels, but with significantly lower rates of hot flushes, vaginal bleeding and discharge, and thromboembolism than tamoxifen. Fractures and heart problems were similar between the two groups.

“The safety profile has been better for exemestane than for tamoxifen and I think this is a contributory factor to the lower discontinuation rates amongst the patients on exemestane,” Van de Velde said.

After two and three-quarter years of follow-up, among the women on exemestane there were 11% fewer cases of a local recurrence of the tumour, distant metastases, breast cancer in the other breast (contralateral breast cancer) and deaths occurring without a relapse of the disease,than among the women on tamoxifen (352 in the exemestane patients and 388 in the tamoxifen patients). There were no differences between the two groups for time to contralateral breast cancer or overall survival, and no unexpected safety issues were reported. Patients aged 70 or over and women with breast cancer that had spread to only one to three lymph nodes had a significantly better disease-free survival on exemestane than on tamoxifen.

“The current analysis covers a short period of time with relatively few deaths occurring and this makes it difficult to see significant differences between the two groups. However, the data from TEAM indicate that early use of exemestane in these high risk patients appears to be safe and a more effective endocrine treatment than tamoxifen for reducing breast cancer recurrence,” said Prof van de Velde. “The study is continuing and the next end point has already been reached, so that we now have enough events to conclude whether starting with tamoxifen and switching to exemestane is better or worse than starting with exemestane. These results will be presented at the San Antonio breast cancer symposium in December.”

For more information:

• Abstract no: 2BA. Presidential session, Tuesday 12.30-14.30 hrs CEST (Hall 1)

Also read these PubMed Abstracts:

• Fallowfield LJ, Bliss JM, Porter LS, Price MH, et al. Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol. 2006 Feb 20;24(6):910-7

Post-menopausal Early Breast Cancer Patients May Benefit From Switching to Exemestane After Two Years of Treatment with Tamoxifen

New research has found that switching post-menopausal women with early breast cancer to the drug exemestane (Aromasin®, Pfizer, USA) after two or three years of tamoxifen rather than keeping them on tamoxifen for five years improves the chance of remaining cancer free and reduces the risk of death for at least the next six years.

“These findings have confirmed that the strategy of switching to exemestane mid-way through the five-year tamoxifen treatment plan provides a clear and durable benefit for relapse and overall survival,” the study’s leader, Professor Charles Coombes, head of oncology at Imperial College in London, told Europe’s largest cancer congress, ECCO 15 – ESMO 34, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin, Germany. “We found that six years after changing treatment, women who got exemestane were 18% more likely to remain disease free and were 14% less likely to die than those who stayed on tamoxifen.”

Breast cancer is the leading cancer in women, with 1.29 million cases diagnosed worldwide every year. About 75% of breast cancers are oestrogen-receptor positive, meaning that oestrogen plays in important role in promoting the growth. Such tumours are usually treated with anti-oestrogen drugs.

Tamoxifen, also known by the trade names Nolvadex, Istubal, and Valodex, is the oldest of these. The drug blocks the tumour’s ability to use oestrogen and is the standard treatment after surgery in women who have early-stage breast cancer. It is normally taken for five years.

Exemestane belongs to a newer class of anti-oestrogen drugs known as aromatase inhibitors, which interfere with the function of aromatase, an enzyme responsible for the production of oestrogen. Aromatase inhibitors are accepted as an alternative to tamoxifen for post-menopausal women, but the question of how best to use these drugs remains under investigation.

The study tested whether switching to exemestane after two or three years of tamoxifen was more effective in the long term than continuing with tamoxifen for the remainder of the five years of treatment. The results presented in Berlin update findings reported previously, providing evidence based on a longer follow-up to produce a more robust estimate of the strategy’s effect on survival and disease recurrence and give a clearer picture of the long-term side effects.

“Our earlier analysis, based on a shorter follow-up, had shown a clear relapse advantage but until now, the magnitude and duration of the overall survival benefit had been uncertain. These updated results show that the relapse improvement does not seem to diminish over time and have clarified that the survival advantage is robust and enduring.”

The study, which has the longest follow-up of any trial to date investigating the impact of switching from tamoxifen to an aromatase inhibitor, involved 4,724 postmenopausal women from 37 countries with oestrogen-receptor-positive or unknown receptor status breast cancer who had their tumours cut out and had remained disease free after two or three years on tamoxifen. About half continued with tamoxifen until they had completed a total of five years of treatment, while the other half were switched to exemestane for the remaining period of treatment. The women were followed for an average of 91 months.

The 18% improvement in disease-free survival is derived from a hazard ratio of 0.82, while the 14% improvement in overall survival is calculated from a hazard ratio of 0.86.

“Practice changed in many countries after our early findings were released in 2004, from using five years of tamoxifen to the current recommended treatment strategy of switching these patients to exemestane or another aromatase inhibitor after two or three years of tamoxifen. The issue that has yet to be clarified is whether starting with tamoxifen and then switching is better than starting with an aromatase inhibitor,” Coombes said.

Cancer Research UK and Pfizer Ltd., which makes exemestane, funded the study.

For more information:

• Abstract no: 5010. Breast Cancer proffered papers session, Tuesday 09.00-11.00 hrs CEST (Hall 1)

Also read these PubMed Abstracts

• Eisen A, Trudeau M, Shelley W, Messersmith H, Pritchard KI. Aromatase inhibitors in adjuvant therapy for hormone receptor positive breast cancer: a systematic review. Cancer Treat Rev. 2008 Apr;34(2):157-74. Epub 2007 Dec 31. Review.
• Spicer J, Ellis P. Towards optimal endocrine therapy for hormone-sensitive breast cancer: initial versus sequential adjuvant aromatase inhibition.
  Cancer Lett. 2007 Apr 1 8;248(2):165-74. Epub 2006 Aug 21. Review.

Sorafenib (Nexavar®) Significantly Improves the Length of Time Before Breast Cancer Worsens: Results From First, Large Randomized Trial

Approximately 30 studies evaluating the use of sorafenib (Nexavar®, Bayer Healthcare Pharmaceuticals/Onyx Pharmaceuticals)tablets across tumor types – as a single agent or in combination with other therapies – were presented at Europe’s largest cancer congress, the joint 15th European CanCer Organisation (ECCO) and 34th European Society for Medical Oncology (ESMO) Multidisciplinary Congress, September 20 – 24 in Berlin.

“The presentations at the ECCO/ESMO conference continue to build on our large body of data in unresectable liver cancer and advanced kidney cancer where sorafenib has a proven track record,” said Dimitris Voliotis, Vice President, Global Clinical Development Oncology. “Additionally, we are very enthusiastic about the presented Phase 2 studies evaluating the safety and efficacy of sorafenbib in other tumor types, including breast and thyroid cancers.”

One of the first of a series of trials to investigate the use of sorafenib – a targeted anti-cancer drug – for the treatment of advanced breast cancer has found that if it is combined with the chemotherapy drug, capecitabine (Xeloda®, Roche, Basel, Switzerland), it makes a significant difference to the time women live without their disease worsening.

Principal investigator of the study, Professor José Baselga told his audience: “This is the first, large, randomized study that demonstrates significant clinical activity of sorafenib in breast cancer when given in combination with chemotherapy. Our results showed that patients who received sorafenib plus capecitabine had a 74% percent improvement in the time they lived without their disease worsening compared to those who received the chemotherapy alone. This is a very positive study and the magnitude of the benefit is such that it suggests that this agent will be an important addition to our therapeutic armory in breast cancer.”

Sorafenib is a potent multi-kinase inhibitor, which works by interfering with the growth of cancer cells and slowing the growth of new blood vessels within the tumor. Until now, it has only been used in the treatment of kidney and liver cancer.

Prof Baselga, who is head of the oncology department at Vall d’Hebron University Hospital (Barcelona, Spain), president of ESMO (European Society for Medical Oncology) and a member of the ECCO (European CanCer Organization) executive committee, and his colleagues in Spain, France and Brazil enrolled 229 patients with locally advanced or metastatic breast cancer in the double-blind, randomized phase II clinical trial between June 2007 and December 2008. They randomized the patients to receive capecitabine (1000 mg/m2 pill taken twice daily for 14 of every 21 days) and a placebo (114 women), or capecitabine and sorafenib (400 mg pill taken twice daily continuously) for 115 women.

The very first results from the trial only became available in time for the ECCO 15 – ESMO 34 congress, and they show that the average progression free survival (the time that elapses without the cancer getting worse) was 6.4 months for women on capecitabine and sorafenib compared to 4.1 months for women taking the placebo. It is too early for data on overall survival to be available. The only death that occurred was in the placebo arm of the trial, attributed to the effect of capecitabine. The number of patients discontinuing treatment due to adverse side-effects was nine (8%) in the placebo arm and 15 (13.4%) in the sorafenib arm of the trial.

Prof Baselga said: “The regimen was tolerable and the side-effects were mostly manageable. No new or unexpected side effects were observed with this combination. The fact that this treatment could be taken orally may represent a unique and convenient treatment option for patients with breast cancer.

“This trial is an example of good academia and industry partnership. It was designed and conducted by the Spanish breast cooperative group SOLTI with the participation also of Brazilian and French groups. The trial was fully supported by Onyx and Bayer. Based on the encouraging data from this trial so far, Onyx and Bayer are evaluating various strategies for sorafenib in breast cancer.

“This trial is the first of a series of randomized phase II studies with sorafenib that are currently underway in breast cancer. Based on our results, we believe that the drug shows considerable promise for the treatment of the disease.”

For more information:

• Jose Baselga, M.D., Vall d'Hebron University Hospital in Barcelona, Spain. A double-blind, randomized phase 2b study evaluating the efficacy and safety of sorafenib (SOR) compared to placebo (PL) when administered in combination with capecitabine (CAP) in patients (pts) with locally advanced (adv) or metastatic (met) breast cancer (BC). Late-breaking abstract 3LBA, Presidential Session III, Wednesday, September 23, 1:30 p.m., Hall 1

Other trial results:

Hepatocellular Carcinoma

• Jean-Luc Raoul, M.D., Centre Eugène Marquis, Rennes, France. Effect of Macroscopic Vascular Invasion (MVI), Extrahepatic Spread (EHS), and ECOG Performance Status (ECOG PS) on Outcome in Patients with Advanced Hepatocellular Carcinoma (HCC) Treated with Sorafenib: Analysis of Two Phase 3, Randomized Double-Blind Trials. Abstract 6621, Poster 309, Wednesday, September 23, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Josep Llovet, M.D., Barcelona Clinic Liver Cancer (BCLC) Group, Liver Unit, CIBERehd, IDIBAPS, Hospital Clinic Barcelona, Barcelona, Spain. Efficacy and Safety of Sorafenib in Patients with Advanced Hepatocellular Carcinoma (HCC): Collective Results from the Phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) and Asia-Pacific (AP) Trials. Abstract 6519, Poster 13, Tuesday, September 22, 2009, 8 a.m. – 11 a.m., Poster Discussion, 11:15 a.m. – 12:15 p.m., Central Lobby (Outside Hall 3)

Renal Cell Carcinoma

• Joachim Beck, M.D., Johannes-Gutenberg-Universität III. Medizinische Klinik, Mainz, Germany. Final Analysis of a Large Open-label, Noncomparative, Phase 3 Study of Sorafenib in European Patients with Advanced RCC (EU-ARCCS). Abstract 7137, Poster 150, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Hideyuki Akaza, M.D., Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan. Efficacy and Safety of Long-term Use of Sorafenib: Final Report of a Phase II Trial of Sorafenib in Japanese Patients with Unresectable/Metastatic Renal Cell Carcinoma. Abstract 7147, Poster 160, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Ronald M. Bukowski, M.D., Cleveland Clinic Taussig Cancer Center, Cleveland, OH. Efficacy and Safety of Sorafenib in Patients with Advanced Clear-Cell Renal-Cell Carcinoma (RCC) with Bone Metastases: Results from the Phase III TARGET Study Abstract 7130, Poster 143, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1
• Dirk Jäger, M.D., National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany. PREDICT (Patient characteristics in REnal cell carcinoma and Daily practICe Treatment with Nexavar) Global Non-interventional Study: First interim results. Abstract 7128, Poster 141, Monday, September 21, 2009, 2 p.m. – 5 p.m., Hall 14.1

Thyroid Cancer

• Marcia Brose, M.D., Ph.D. Department of Medicine, Division of Hematology/Oncology and Department of Otorhinolaryngology: Head and Neck Surgery, Abrahamson Cancer Center of the University of Pennsylvania, Philadelphia, PA, U.S.A. Completion of a Phase II study of sorafenib for advanced thyroid cancer. Late-breaking poster 51LBA, Poster 276, Tuesday, September 22, 11 a.m. – 1:00 p.m. Hall 14.1

Highlights of Prescribing Information:

• Sorafenib (Nexavar ®)
• Capecitabine (Xeloda®)

Also read these Pubmed Abstracts:

• Higgins MJ, Forastiere A, Marur S. New directions in the systemic treatment of metastatic thyroid cancer. Oncology (Williston Park). 2009 Aug;23(9):768-75.
• Bianchi G, Loibl S, Zamagni C, Salvagni S, Raab G, et al. Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer Drugs. 2009 Aug;20(7):616-24.
• Hill KL Jr, Lipson AC, Sheehan JM. Brain magnetic resonance imaging changes after sorafenib and sunitinib chemotherapy in patients with advanced renal cell and breast carcinoma. J Neurosurg. 2009 Sep;111(3):497-503.
  Pytel D, Sliwinski T, Poplawski T, Ferriola D, Majsterek I. Tyrosine kinase blockers: new hope for successful cancer therapy Anticancer Agents Med Chem. 2009 Jan;9(1):66-76. Review.
• Schraml C, Schwenzer NF, Martirosian P, Bitzer M, et al. Diffusion-weighted MRI of advanced hepatocellular carcinoma during sorafenib treatment: initial results. AJR Am J Roentgenol. 2009 Oct;193(4):W301-7.
• Sugawara M, Geffner DL, Martinez D, Hershman JM. Novel treatment of medullary thyroid cancer. Curr Opin Endocrinol Diabetes Obes. 2009 Oct;16(5):367-72.

Effective Cancer Drugs May Increase Risk of Adverse Effects, Report Says

Three drugs, including tamoxifen, reduce a woman's chance of getting breast cancer, but each drug carries distinct potential harms of its own, according to a new report from HHS' Agency for Healthcare Research and Quality.

Drugs to reduce the risk of breast cancer can be prescribed to women with a family history of breast cancer or other risk factors, but prescribing practices vary widely. The comparative effectiveness review found that all three drugs, tamoxifen (Nolvadex®; an antagonist of the estrogen receptor in breast tissue), raloxifene, (Evista; an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator or SERM that belongs to the benzothiophene class of compounds), and tibolone (Xyvion; a synthetic anabolic steroid with estrogenic, androgenic and progestagenic activities), significantly reduce invasive breast cancer in midlife and older women but that benefits and adverse effects can vary depending on the drug and the patient.

"Taking medicine to avoid breast cancer in the first place is an attractive notion, but the decision to do so must be made by patients in consultation with their clinicians with benefit of the best evidence available," said AHRQ Director Carolyn M. Clancy, M.D. "These drugs are not necessarily for everyone. This report sheds important light on their advantages and potential harms."

The report is the first to make a direct, comprehensive comparison of the drugs so that women and their health care providers can assess the medications' potential effectiveness and adverse effects. The report compares the use of the three drugs to reduce the risks of getting breast cancer in women who have not previously had breast cancer.

Breast cancer is the second most commonly diagnosed cancer of women (after skin cancer), with more than 190,000 new cases diagnosed each year in the United States. It is estimated to cause more than 40,000 deaths per year. The National Cancer Institute estimates that nearly 15 percent of women born today will develop breast cancer in their lifetimes. Most cases of breast cancer occur in women with no specific risk factors other than age and gender, although family history of breast and ovarian cancer is associated with higher risk.

Tamoxifen, a selective estrogen receptor modulator (SERM), was approved by the U.S. Food and Drug Administration in 1998 to prevent breast cancer in women at high risk of developing the disease. Tamoxifen's use to reduce the risk of breast cancer is accepted clinical practice, although the drug is primarily used for treatment rather than risk reduction.

The AHRQ report compared tamoxifen with another SERM, raloxifene, which is primarily used to prevent and treat osteoporosis and was approved by the FDA for breast cancer risk reduction in 2007. A third drug, tibolone, which has not been approved by the FDA for use in the United States but is commonly used in other countries to treat menopausal symptoms and osteoporosis, also was included in the study.

The report found that all three drugs reduce the occurrence of breast cancer but have various side effects. The most common side effects for tamoxifen are flushing and other vasomotor symptoms (e.g., night sweats, hot flashes), vaginal discharge and other vaginal symptoms such as itching or dryness; for raloxifene, side effects include vasomotor symptoms and leg cramps; and for tibolone, side effects include vaginal bleeding.The report also found that each drug carried the risk of adverse effects. It found that tamoxifen increases risk for endometrial cancer, hysterectomies, and cataracts compared with the other drugs. Tamoxifen and raloxifene increase risk of blood clots, although tamoxifen's risk is greater. Tibolone carries an increased risk of stroke.

The report also examined the drugs' effectiveness and harms based on such factors as age, menopausal status, estrogen use, and family history of breast cancer and sought to identify the kinds of women who might be good candidates for prevention therapy, although the evidence is limited in this area. The report called for more research to more clearly identify characteristics of patients who would benefit from these drugs while suffering the least harm.

AHRQ's new report, Comparative Effectiveness of Medications to Reduce Risk of Primary Breast Cancer in Women, is the latest analysis from the Agency's Effective Health Care Program. That program, authorized by the Medicare Prescription Drug Improvement and Modernization Act of 2003, represents an important federal effort to compare alternative treatments for health conditions and make the findings public. The program is intended to help patients, doctors, nurses, and others choose the most effective treatments.

For more information:

• National Cancer Institute: Study of Tamoxifen and Raloxifene (STAR) Trial

PubMed abstracts:

• Cummings SR, Ettinger B, Delmas PD, Kenemans P, et al. The effects of tibolone in older postmenopausal women. N Engl J Med. 2008 Aug 14;359(7):697-708
• Escande A, Servant N, Rabenoelina F, Auzou G, Kloosterboer H et al. Regulation of activities of steroid hormone receptors by tibolone a.... J Steroid Biochem Mol Biol. 2009 Aug;116(1-2):8-14. Epub 2009 Apr 2.

Study Points to Possible Reasons Why African-Americans Fare Worse With Cancer.

Among man and women with sex-specific cancers, including breast, ovarian, and prostate cancer, African Americans have a higher mortality rate than Caucasian. This is the conclusion of an analysis of clinical trial data which implicates biological factors behind worse outcomes for African-Americans.

After analyzing almost 20,000 patient records from the Southwest Oncology Group's (SOG) database of clinical trials finds, the researchers, for the first time, noted potential biological factors as an explanation why African-American patients with sex-specific cancers tend to die earlier than patients of other races. This despite identical medical treatment regimens for all patients involved and enrollment in the same phase III SWOG trials with uniform stage, treatment, and follow-up. Other confounding socioeconomic factors were also controlled.

Breast cancer
In unrelated earlier studies, observed variations in breast cancer survival by racial/ethnic background had been attributed to a number of varying factors, including differences in clinical and pathologic disease features at diagnosis and economic resource inequities that may affect treatment access and quality.

Whether African-American women have biologically more aggressive breast carcinoma compared with women of other races and whether race acts as a significant independent prognostic factor for was a question that for many years remained unanswered. The general consensus was that race could be a surrogate for socioeconomic status (SES). Researchers in often concluded that a mortality deficit for African-American women relative to Caucasian women, was due to greater mortality from noncancer causes among African-Americans. A retrospective literature review in 2002 by Cross et al demonstrated that while socioeconomic factors replaced race as a predictor of worse outcome after women were diagnosed with breast carcinomas, black women generally presented more advanced disease that appeared more aggressive biologically at a younger age compared with white women.

Prostate cancer
Similar racial/ethnic disparities have been observed in prostate cancer rates. Large population-based cross-sectional studies show the highest incidence and mortality rates among African-Americans followed by non-Hispanic Whites, Hispanics, and Asian/Pacific Islanders. In many studies African-Americans men have two- to fivefold increased risk of prostate cancer deaths in comparison to non-Hispanic Whites across all levels of their socioeconomic status (SES). Based on these results, many researchers felt that socioeconomic status alone could account for the greater burden of prostate cancer among African-American men.

Non Sex-specific cancers
Furthermore, various key studies into other major cancers, including non sex-specific cancer such as colon cancer, generally attributed to the disparity in survival in racial/ethnic settings to a number of varying causes, including diagnosis at later disease stage and other unfavorable disease features, inadequate treatment, and socioeconomic factors.

After analyzing the results of the Eastern Cooperative Oncology Group's E3200 trial, Dr Paul Catalano, D.Sc.,of the Harvard School of Public Health and the Dana-Farber Cancer Institute in Boston found that African Americans with metastatic colorectal cancer (MCC) do not fare as well as Caucasians when, in a specific treatment, bevacizumab (Avastin), a targeted vascular endothelial growth factor inhibitor, is added to the FOLFOX regimen.

In analyzing the data accumulated in the trial that included 713 Caucasians and 66 African Americans, Dr. Catalano and colleagues determined that, in the E3200 trial, African Americans had a lower objective response rate - 3% versus 12.5% (P=0.02), a non-significant shorter time of progression-free survival (P=0.08) and a significantly shorter overall survival (10.2 months versus 11.8 months, (P=0.03). They noted that and this difference remained after adjustment for treatment, gender, age and performance status.

Analytical outcome
The SOG analyses for the first time, shows overwhelming evidence pointing to biological or host genetic factors as the potential source of the survival gap between African Americans and Caucasian patients.

Of 19 457 patients registered, 2308 (11.9%, range = 3.9%–21.6%) were African American. After adjustment for prognostic factors, African American race was associated with increased mortality in patients with early-stage premenopausal breast cancer (hazard ratio [HR] for death = 1.41, 95% confidence interval [CI] = 1.10 to 1.82; P = .007), early-stage postmenopausal breast cancer (HR for death = 1.49, 95% CI = 1.28 to 1.73; P < .001), advanced-stage ovarian cancer (HR for death = 1.61, 95% CI = 1.18 to 2.18; P = .002), and advanced-stage prostate cancer (HR for death = 1.21, 95% CI = 1.08 to 1.37; P = .001).

No statistically significant association between race and survival for lung cancer, colon cancer, lymphoma, leukemia, or myeloma was observed. Additional adjustments for socioeconomic status did not substantially change these observations. Ten-year (and median) overall survival rates for African American vs all other patients were 68% (not reached) vs 77% (not reached), respectively, for early-stage, premenopausal breast cancer; 52% (10.2 years) vs 62% (13.5 years) for early-stage, postmenopausal breast cancer; 13% (1.3 years) vs 17% (2.3 years) for advanced ovarian cancer; and 6% (2.2 years) vs 9% (2.7 years) for advanced prostate cancer.

Access to Quality treatment
"When you look at the dialogue about the issue of race and cancer survival that's gone on over the years," says the paper's lead author, Kathy Albain, M.D., a breast and lung cancer specialist at Loyola University's Cardinal Bernardin Cancer Center, "it always seems to come down to general conclusions that African-Americans may in part have poorer access to quality treatment, may be diagnosed in later stages, and may not have the same standard of care delivered as Caucasian patients, leading to a disparity in survival."

The study, published online by the Journal of the National Cancer Institute (JNCI), found that when treatment was uniform and differences in tumor prognostic factors, demographics, and socioeconomic status were controlled, there was in fact no statistically significant difference in survival based on race for a number of other cancers -- lung, colon, lymphoma, leukemia, and multiple myeloma.

"The good news is that for most common cancers," Albain says, "if you get good treatment, your survival is the same regardless of race. But this is not the case for breast, ovarian, and prostate cancers."

Even with good treatment by the same doctors, African-American patients with one of these three cancers faced a significantly higher risk of death than did other patients, ranging from a 21% higher risk for those with prostate cancer to a 61% higher risk for ovarian cancer patients.
The elimination of treatment and socioeconomic factors as the cause of this higher mortality "implicates biology," says study co-author Dawn L. Hershman, M.D., of the Columbia University College of Physicians and Surgeons.

"There may be differences in genetic factors by race that alter the metabolism of chemotherapy drugs or that make cancers more resistant or more aggressive," she adds.

Earlier this year, Hershman, et al published a smaller study that found that, at least with breast cancer, disparities in survival based on race persist even after adjusting for differences in treatment. That study, published in the May 2009 issue of Journal of Clinical Oncology, analyzed data on 634 breast cancer patients.

"Our study of multiple cancers is distinguished from others that have looked at race-based disparities by its size and by the source of its data," says Joseph Unger of the Southwest Oncology Group's Statistical Center, who was statistician and co-author on the new JNCI study.
The study analyzed records from 35 clinical trials - going back as far as 1974 - that had been conducted by the Southwest Oncology Group, an NCI-sponsored cooperative group headquartered at the University of Michigan. Using data from clinical trials, which are already controlled for a range of potentially confounding factors such as differences in diagnosis, treatment, and follow-up, helps throw the remaining factors into sharper relief, according to Frank L. Meyskens, Jr., M.D.

"It's because of the similar way that people are treated on clinical trials that these differences are even detectable," he says. Meyskens is associate chair for Cancer Control and Prevention for the Southwest Oncology Group and director of the University of California-Irvine's Chao Family Comprehensive Cancer Center.

Long term prediction
The urgency of addressing the reasons for racial disparities in outcomes - both sociological and biological - is amplified by another recent study in the Journal of Clinical Oncology. In this study, Benjamin Smith and colleagues predict that cancer incidence among minorities will nearly double in the coming decades, increasing 99% by 2030 compared to an expected 31% increase among whites. Overall, from 2010 to 2030, the percentage of all cancers diagnosed in older adults will increase from 61% to 70%, and the percentage of all cancers diagnosed in minorities will increase from 21% to 28%

Disparities in Cancer Care
In 2008, the American Society of Clinical Oncology (ASCO), the world’s leading professional organization representing physicians who treat people with cancer, published a ‘Disparities in Cancer Care’ policy statement that recommends a set of strategies designed to address the disparities of cancer care experienced by underserved and minority populations.

The recommendations offered by ASCO suggest that strategies should focus on education, prevention, diagnosis, and treatment and should discuss issues regarding the resources and funding routinely available, talk about misconceptions regarding clinical trials and cancer research, address lack of minority representation among oncologists. The authors of the ASCO policy statement feel that addressing these topics, coupled with improved access to care, are likely to yield improved outcomes for minority cancer patients.

"The elimination of socioeconomic and healthcare access disparities must be a priority in the United States," says Lisa Newman, M.D., director of the Breast Care Center at the University of Michigan Comprehensive Cancer Center. "However, Dr. Albain's landmark study demonstrates that further investigation of race- or ethnicity-associated differences in primary tumor biology is also important."

John Crowley, Ph.D., of the Southwest Oncology Group Statistical Center and Charles A. Coltman, M.D., of the University of Texas Health Science Center were also coauthors of the study, which was funded by the National Cancer Institute.

The Southwest Oncology Group is one of the largest cancer clinical trials cooperative groups, with a network of almost 5,000 physician-researchers practicing at more than 500 institutions, including 19 of the National Cancer Institute-designated cancer centers. The Group is headquartered at the University of Michigan in Ann Arbor, Mich. The Group has an operations office in San Antonio, Texas and a statistical center in Seattle, Washington.

For more information:

• Albain KS, Unger JM, Crowley JJ, Coltman, Jr CA, Hershman DL, Racial Disparities in Cancer Survival Among Randomized Clinical Trials Patients of the Southwest Oncology Group Journal of the National Cancer Institute Advance Access published online on July 7, 2009 JNCI Journal of the National Cancer Institute.
• Raghavan, D, Perez EA, Harvey HA. Disparities in Cancer Care (2008 educational handbook)
• Cancer Care in Minority Populations (Educational session, ASCO 2008 Annual meeting, chair Raghavan D, Genitourinary cancer Track).
• Catalano PJ, Mitchell EP, Giantonio BJ, Meropol NJ Benson AB. Outcomes differences for African Americans and Caucasians treated with bevacizumab, FOLFOX4 or the combination in patients with metastatic colorectal cancer (MCRC): Results from the Eastern Cooperative Oncology Group Study E3200. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 4100

Also read these PubMed Abstracts:

• Albain KS, Unger JM, Crowley JJ, Coltman CA Jr, Hershman DL. Racial Disparities in Cancer Survival Among Randomized Clinical Trials Patients of the Southwest Oncology Group. J Natl Cancer Inst. 2009 Jul 7. [Epub ahead of print].
• Hershman DL, Unger JM, Barlow WE, Hutchins LF, Martino S, et al. Treatment quality and outcomes of African American versus white breast cancer patients: retrospective analysis of Southwest Oncology studies S8814/S8897. J Clin Oncol 2009 May 1;27(13):2157-62. Epub 2009 Mar 23.
• Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol. 2009 Jun 10;27(17):2758-65. Epub 2009 Apr 29.
• McKoy JM, Samaras AT, Bennett CL. Providing cancer care to a graying and diverse cancer population in the 21st century: are we prepared? J Clin Oncol 2009 Jun 10;27(17):2745-6. Epub 2009 Apr 29
• Breslin TM, Morris AM, Gu N, Wong SL, Finlayson EV, Banerjee M, Birkmeyer JD. Hospital Factors and Racial Disparities in Mortality After Surgery for Breast and Colon Cancer. J Clin Oncol. 2009 May 26. [Epub ahead of print]
• Sloane D. Cancer epidemiology in the United States: racial, social, and economic factors. Methods Mol Biol. 2009;471:65-83.
• Resnick MJ, Canter DJ, Guzzo TJ, Brucker BM, Bergey M, Sonnad SS, Wein AJ, Malkowicz SB. Does race affect postoperative outcomes in patients with low-risk prostate cancer who undergo radical prostatectomy? Urology. 2009 Mar;73(3):620-3. Epub 2008 Dec 18
• Cheng I, Witte JS, McClure LA, Shema SJ, Cockburn MG, John EM, Clarke CA. Socioeconomic status and prostate cancer incidence and mortality rates among the diverse population of California. Cancer Causes Control. 2009 Jun 13. [Epub ahead of print]
• Lamb DS, Bupha-Intr O, Bethwaite P, Murray J, Nacey J, Russell G, Delahunt B. Prostate cancer--are ethnic minorities disadvantaged? Anticancer Res. 2008 Nov-Dec;28(6B):3891-5.
• Lathan CS, Neville BA, Earle CC. The effect of race on invasive staging and surgery in non-small-cell lung cancer. J Clin Oncol. 2006 Jan 20;24(3):413-8. Epub 2005 Dec 19.
• Norton KS, Johnson LW, Li BD. Compliance and outcomes: do African Americans with advanced breast cancer fare worse? J La State Med Soc. 2005 Jan-Feb;157(1):28-30.
• Dignam JJ, Colangelo L, Tian W, Jones J, Smith R, et al. Outcomes among African-Americans and Caucasians in colon cancer adjuvant therapy trials: findings from the National Surgical Adjuvant Breast and Bowel Project. J Natl Cancer Inst. 1999 Nov 17;91(22):1933-40.
• Henson DE, Chu KC, Levine PH. Histologic grade, stage, and survival in breast carcinoma: comparison of African American and Caucasian women. Cancer 2003 Sep 1;98(5):908-17.
• Dignam JJ, Redmond CK, Fisher B, Costantino JP, Edwards BK. Prognosis among African-American women and white women with lymph node negative breast carcinoma: findings from two randomized clinical trials of the National Surgical Adjuvant Breast and Bowel Project (NSABP). Cancer 1997 Jul 1;80(1):80-90.
• Cross CK, Harris J, Recht A. Race, socioeconomic status, and breast carcinoma in the U.S: what have we learned from clinical studies. Cancer 2002 Nov 1;95(9):1988-99.
• Dignam JJ. Efficacy of systemic adjuvant therapy for breast cancer in African-American and Caucasian women. J. Natl. Cancer Inst Monogr. 2001;(30):36-43.
• Dignam JJ. Differences in breast cancer prognosis among African-American and Caucasian women. CA cancer J. Clin 2000 Jan-Feb;50(1):50-64.
• Joslyn SA, West MM. Racial differences in breast carcinoma survival. Cancer 2000 Jan 1;88(1):114-23.
• Eojcik BE, Spinks MK, Optenberg SA. Breast carcinoma survival analysis for African American and white women in an equal-access health care system. Cancer 1998 Apr 1;82(7):1310-8.
• Mayberry RM, Coates RJ, Hill HA, Click LA, Chen VW, et al. Determinants of black/white differences in colon cancer survival. J Natl Cancer Inst. 1995 Nov 15;87(22):1686-93.

Images courtesy American Society of Clinical oncology (ASCO)

A New and Advanced Imaging Technique Allows Researchers to Monitor Protein Changes in Mouse Tumors

A new imaging technique can monitor, in living mice, the HER2 protein found in above-normal amounts in many cases of breast cancer as well as some ovarian, prostate and lung cancers. This new approach, once validated in mice and pending further experiments, could provide a real-time noninvasive method for identifying tumors in women who express HER2 and who would be candidates for targeted therapy directed against this protein.

The new technique may also provide real-time information that will help clinicians optimize treatment for individual patients. The study by Kramer-Marek and colleagues, published in the July 2009 issue of The Journal of Nuclear Medicine, was conducted at the National Cancer Institute (NCI) and the National Institute of Biomedical Imaging and Bioengineering, both parts of the National Institutes of Health.

Overexpression of HER2
The HER2 protein is overexpressed in approximately 20 percent to 25 percent of breast cancers. Numerous studies have shown that HER2 is associated with shorter disease-free and overall survival. In breast cancer, HER2 gene amplification was significantly associated with pathologic stage at diagnosis, axillary node involvement, and histologic subtype. In ovarian cancer HER2 has been associated with decreased overall survival and with an increase in relative risk of death.

Tumors that overexpress HER2 are more aggressive and more likely to recur than tumors that do not overexpress the protein. Targeted therapies directed against HER2 can slow or stop the growth of tumors that overexpress it.

Determining HER2
HER2 expression can be determined by any of several methods. The most commonly used methods include Fluorescence in situ hybridization or FISH, which detects gene amplification by measuring the number of copies of the HER2 gene in the nuclei of tumor cells and Immunohistochemistry or IHC, which measures the number of HER2 receptors on the cell surface and therefore detects receptor overexpression.

Chromogenic in situ hybridization or CISH, which measures gene amplification using a light microscope rather than a fluorescent microscope required for FISH and reverse-transcriptase polymerase chain reaction or RT-PCR, which detects HER2 gene amplification are among some other methods of HER2 testing whicj have been used increasingly in clinical studies and may eventually be incorporated into routine practice.

Not Perfect
In 2007, Wolff et al showed that Immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH) test results can be affected by testing conditions including the use of suboptimally fixed tissue, failure to use specified reagents, deviation from specific instructions, and failure to include appropriate controls. Therefore, in order to increase the accuracy of HER2 testing results, testing should be performed by laboratories with demonstrated aptitude in the specific test requested. Even if tested in these high-end laboratories, expression of HER2 in test samples may still not accurately represent HER2 expression in the tumor as a whole. Moreover, follow-up biopsies are not always routinely performed after the initial diagnosis, and there are no means to evaluate how long a targeted therapy takes to reach its target, how effective it is, and how long its effects last.

In this study, the researchers used an imaging compound that consists of a radioactive atom (fluorine-18) attached to an Affibody molecule, a small protein that binds strongly and specifically to HER2. Affibody molecules are developed by Affibody AB, (Bromma, Sweden), a Swedish biotech company focused on developing next generation products for therapy, diagnostic imaging, and other applications based on its unique proprietary Affibody® molecules and albumin binding technology platforms. The Affibody molecules are much smaller than antibodies and can reach the surface of tumors more easily. The radioactive atom allows the distribution of the Affibody molecules in the body to be analyzed by positron emission tomography (PET) imaging.

The researchers first used the radiolabeled Affibody molecule to visualize tumors that expressed HER2 in mice. The mice were injected under the skin with human breast cancer cells that varied in their levels of HER2 expression, from no expression to very high expression. After three to five weeks, when tumors had formed, the mice were injected with the Affibody molecule and PET images were recorded. The levels of HER2 expression as determined by PET were consistent with the levels measured in surgically removed samples of the same tumors using established laboratory techniques.

To determine whether their method could be used to monitor possible changes in HER2 expression in response to treatment, the team next injected the Affibody molecule into mice with tumors that expressed very high or high levels of HER2 and then treated them with the drug 17-DMAG, which is known to decrease HER2 expression. PET scans were performed before and after 17-DMAG treatment. The researchers found that HER2 levels were reduced by 71 percent in mice with tumors that expressed very high levels of HER2 and by 33 percent in mice with tumors that expressed high levels of HER2 in comparison with mice that did not receive 17-DMAG. The researchers confirmed these reductions by using established laboratory techniques to determine the concentrations of HER2 in the tumors after they were removed from the mice.

"Our work shows that PET imaging using Affibody molecules was sufficiently sensitive to detect a twofold to threefold decrease in HER2 expression," said senior author Jacek Capala, Ph.D., of NCI’s Center for Cancer Research. "Therefore, PET imaging may provide a considerable advantage over current methods. Our technique would allow a better selection of patients for HER2-targeted therapies and also early detection of tumors that either do not respond to or acquire resistance to these therapies."

"This approach might easily be extended to forms of cancer other than breast cancer," Capala continued. "Because Affibody molecules may be selected to target specific cell proteins, similar compounds can be developed to target proteins that are unique to other types of tumors."

For more information:

• Kramer-Marek G, Kiesewetter DO, Capala J. Changes in HER2 Expression in Breast Cancer Xenografts After Therapy Can Be Quantified Using PET and 18F-Labeled Affibody Molecules. J. Nucl Med. 2009 Jun 12. [Epub ahead of print].
• Wållberg H, Ahlgren S, Widström C, Orlova A. Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys(61)]-Z (HER2:2395)-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors. Mol Imaging Biol. 2009 Jun 26. [Epub ahead of print]

Also read PubMed Abstracts:

• Slamon DJ, Godolphin W, Jones LA, Holt JA, Wong SG, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989 May 12;244(4905):707-12
• Ménard S, Tagliabue E, Campiglio M, Pupa SM. Role of HER2 gene overexpression in breast carcinoma. J Cell Physiol. 2000 Feb;182(2):150-62. Review
• Sergina NV, Rausch M, Wang D, Blair J, Hann B, et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature. 2007 Jan 25;445(7126):437-41. Epub 2007 Jan 7
• Konecny GE, Meng YG, Untch M, Wang HJ. et al. Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin Cancer Res. 2004 Mar 1;10(5):1706-16
• Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med. 2007;131(1):18-43.

More information:

• View an animation of how Affibody® molecules will enable cancer specialists to locate and treat tumors and metastases!

Images courtesy of Affibody AB.

The IMPAKT of a New Drug Target in Breast Cancer

New and exciting results presented at the first IMPAKT Breast Cancer Conference (Brussels, Belgium, May 7 - 9) an international medical meeting focusing on IMProving cAre and Knowledge through Translational Research, may help scientists develop treatments for women with a type of breast cancer that currently does not respond to targeted therapies.

Although most people generally think of breast cancer as a single disease, doctors have recently come to understand that it actually comes in a variety of different ‘subtypes’. Each different subtype has different risk factors, different rates of progression, different treatment options, and a different prognosis. They are diagnosed based upon the presence three ‘receptors’ found on cancer cells: estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor 2 (HER2/neu).

Over the years, effective treatments have been developed to target each of these receptors. Some cancers, however, are estrogen receptor-negative, progesterone receptor-negative and HER2-negative, and are better known as ‘triple-negative’ breast cancers.

Triple-negative tumors generally do not respond to receptor-targeted treatments and is clinically characterized as more aggressive and less responsive to standard treatments. This form of breast cancer is generally associated with poorer overall patient prognosis and is more common among women with BRCA1 gene mutations. Furthermore, for reasons not yet well understood, triple-negative breast cancer is also more frequently diagnosed in younger women and African-American women. Researchers include triple-negative breast cancers are part of the subgroup of ‘basal-type’ breast cancers.

The role of androgens (AR)
In recent years, scientists have begun looking for new targets in these triple-negative breast cancers. One of the targets that has been identified is the androgen-receptor.

Studies have shown that the risk of breast cancer is increased in postmenopausal women with high estrogen levels as well as in women with high androgen levels. While the mechanism by which androgens contribute to breast cancer is not well understood, but studies have shown that androgens can induce proliferative changes in breast tissue. Furthermore, animal models have shown that administration of both estrogen and androgens can induce tumor formation.
Other studies have show that BRCA1 is a coactivator of the androgen-receptor (AR), making this an interesting and viable target.

GeparTrio Trial
At the IMPAKT Breast Cancer Conference, Sibylle Loibl MD, PhD, and colleagues report results from the GeparTrio trial (n=1,711) in which all patients with primary breast cancer received treatment with three chemotherapy drugs, including docetaxel, doxorubicin and cyclophosphamide. Almost half of the 682 patients (47.8%) expressed androgen receptor.The patient population in this German Breast Group (GBG) study was made up of patients with histologically confirmed unilateral or bilateral primary carcinoma of the breast (confirmed histologically by core biopsy) and patients with a tumor lesion in the breast with a palpable size of .2 cm in maximum diameter.

The researchers found that among those with triple-negative tumors the expression of the androgen receptor was correlated with a lower likelihood of an effective treatment.

“This group has looked for the expression of androgen receptor in breast cancer and found a sub-group of the population who do express it, and have shown that these patients respond worse to chemotherapy than those whose tumors do not express androgen receptor,” said Professor Jose Baselga, co-chair of the IMPAKT Conference.

The study showed a significant correlation between androgen receptor and tumor grading (PP=.006), expression of estrogen/progesterone status (P<.001) and age, and further revealed a pathological complete response in 14.2% of androgen receptor-positive patients vs. 31.9% of androgen receptor-negative patients (P<.001). The total pathological complete response was 21.4%. Among 86 triple-negative tumors analyzed (12.6% of total), 40.7% had a pathological complete response. 27.9% of the analyzed tumors expressed androgen receptor (AR+). For the remaining triple-negative androgen receptor-negative tumors (AR-), the pathological complete response rate was 43.5% vs. 33.3% for the triple-negative androgen receptor-positive tumors (P=.387). Baselga noted that a clinical trial is currently underway to try and target the androgen receptor in breast cancer. “I think we are seeing the birth of a new concept in breast cancer—the androgen-receptor-positive breast cancer,” Professor Baselga said. “This is an important development in finding new targets that we can attack with new drugs in the future.”

More IMPAKT Results
Unrelated but interesting results presented during the IMPAKT conference, which is designed to present and discuss advances in translational research and ways to quickly transform laboratory discoveries into tools that clinicians can use to help make decisions about the way they treat patients in their daily practice, included a presentation about a genetic test that helps reduce the need for second surgery in Breast cancer treatment.

This new rapid test can confirm quickly and accurately that breast cancer has most likely not spread into adjacent lymph nodes, offering reassurance to patients and reducing the need for a second operation. The test takes roughly 35 minutes to produce results and can be performed while the patient is having the initial surgery to remove the primary tumour.

Earlier studies have shown that the test can detect cancer that has spread to nearby lymph nodes. Currently, when a woman is having surgery to remove a breast cancer, surgeons take a sample from the so-called 'sentinel node.' This is the lymph node most directly connected to the breast, and the place the cancer is likely to spread to first.

The sentinel node biopsy is normally analysed by a pathologist who looks carefully for the presence of cancerous cells, in a process that can take several hours. If these cells have grown to a diameter between 0.2 mm and 2 mm — known as a micro metastasis -- the patient is considered to be at risk of a worse outcome. She would then usually be advised to return to the operating theatre to have all the lymph nodes in that region removed.

“This process of trying to identify micro metastases takes a lot of time and money,” explains conference co-chair Prof Martine Piccart from Institut Jules Bordet in Brussels, Belgium. “The new technique allows you to make the diagnosis of micro metastases while the surgery is underway, meaning the patient does not have to suffer the disruption of undergoing another operation.” To see whether the test results predicted the spread of cancer to other lymph nodes in the armpit, researchers in Belgium, the US and the UK tested sentinel nodes removed from 1,138 patients.

Once removed, each node was cut into thin slices. Alternating slices were then tested using either the new gene test or traditional pathology methods. If either test returned a positive result, the patient then had all lymph nodes from that armpit removed and tested. The new test provided a particularly high 'negative predictive value', they found, meaning that it accurately predicted whether the remaining nodes were free of cancer. “Remarkably, when the new test gives a negative result — meaning it finds no spread of cancer to the sentinel node — it really predicts very well the status of the other lymph nodes,” said Prof Piccart.

Other interesting presentation

• Gene Sinature Identifies Breast Cancer Pahtiens who will respond to chemotherapy. Researchers have identified a genetic signature that can predict which breast cancer patients will respond well to treatment with epirubicin, a widely used form of chemotherapy. Although among the most effective chemotherapies in breast cancer, a small proportion of women suffer severe side-effects. By identifying those women who are most likely to benefit from treatment, doctors may be able to ensure fewer women are unnecessarily exposed to that risk. The new study shows that this goal can be achieved by developing more sophisticated ways to use older drugs.
• Gene Signature predicts good outcome in Breast Cancer. Researchers have identified a genetic signature that can predict an improved clinical outcome in patients with breast cancer, and which could help in the development of new targeted therapies. By analyzing the expression of different genes induced by a specific mutation in a molecule called PIK3CA, a critical part of the pathway commonly deregulated in breast cancer, they found that these genes were correlated with an improved clinical outcome in over 1500 women with the disease.

For more information, see the presentation

• Androgen-Receptor Expression in Triple-negative breast cancer: results from the neoadjuvant Gepartrio trialPresented by Sibylle Loibl MD, PhD, assistant professor at University Frankfurt in Germany and a co-author of the study, at IMPAKT Breast Cancer Conference; May 7-9, 2009; Brussels, Belgium abstract #1270 Abstracts of the IMPAKT Breast Cancer Conference. Brussels, Belgium. May 7-9, 2009. Ann Oncology 2009 May;20 Suppl 2:ii11-70. Follow this link to other IMPAKT webcasts.

Also, read PubMed abstracts:

• Poulin R, baker D, Labrie F. Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line. Breast Cancer Res Treat 1988 Oct;12(2):213-25.
• Labrie F, Simard J, de Launoit Y, et al. Androgens and breast cancer. Cancer Detect Prev. 1992;16(1):31-8.<>
• Hankinson SE, Willett WC, Manson JE, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst. 1998;90:1292-1299.
• Cauley JA, Lucas FL, Kuller LH, et al. Elevated serum estradiol and testosterone concentrations are associated with a high risk for breast cancer: study of Osteoporotic Fractures Research Group. Ann Intern Med. 1999;130:270-277.
• Jongen VH, Hollema H, Van der Zee AG, Heineman MJ. Aromatase in the context of breast and endometrial cancer. A review. Minerva Endocrinol. 2006 Mar;31(1):47-60
• Lin HY, Sun M, Lin C, Tang HY. Androgen-induced human breast cancer cell proliferation is mediated by discrete mechanisms in estrogen receptor-alpha-positive and -negative breast cancer cells. J steroid Biochem Mol Biol. 2009 Feb;113(3-5):182-8. Epub 2008 Dec 30

Also Read:

• What’s new in Breast Cancer Research and Treatment

Progress Against Breast and Gynecologic Cancers: Highlights from ASCO

Advances in the treatment of cancers that primarily affect women, including breast and gynecologic cancers, were presented in Orlando at the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO), the world’s leading professional organization representing physicians who care for people with cancer.

“Studies presented during the 45th Annual Meeting of the American Society of Clinical Oncology demonstrate continued progress against breast, ovarian and cervical cancers, which are major causes of cancer mortality worldwide,” said Eric P. Winer, MD, Chair of ASCO’s Cancer Communications Committee and professor of medicine at Harvard Medical School. “One study tells us that women can safely avoid unnecessary blood tests and can delay toxic treatment for ovarian cancer recurrence without compromising their longevity. Others report on a promising new class of targeted drugs for some of the most difficult-to-treat breast cancers. And others provide more effective and less invasive options for treating cervical cancer, which is a particularly significant problem in developing countries.”

Studies highlighted during ASCO include:

• No survival advantage to treating ovarian cancer relapse based on rising CA125 levels, compared with waiting for symptoms. A study featured in ASCO’s plenary session reports that starting treatment immediately for an ovarian cancer relapse based on CA125 protein levels found in the blood does not improve overall survival, compared with delaying treatment until symptoms arise. The findings should allow women to avoid the anxiety and cost associated with frequent blood testing and the toxicity of early treatment.
• PARP inhibitors show promise for hard-to-treat breast cancers. Two studies, including one featured in ASCO’s plenary session, report promising data on a new class of targeted drugs called PARP inhibitors. Poly (ADP-ribose) Polymerase (PARP) has a well-established role in DNA repair processes, and small molecule inhibitors of PARP have been developed as chemotherapy sensitisers for the treatment of cancer. The subsequent demonstration that PARP inhibition is selective for BRCA1 or BRCA2 deficiency suggests that PARP inhibitors may be particularly useful for the treatment of cancer with BRCA mutations. The plenary study reports that women with hard-to-treat “triple-negative” breast cancer who received the PARP inhibitor BSI-201 (BiPar Sciences Inc) along with conventional chemotherapy had 60% better survival outcomes compared with chemotherapy alone than women who received chemotherapy alone. A second study reports that women with BRCA-deficient advanced breast cancer experienced tumor shrinkage after receiving the PARP inhibitor olaparib as a single agent.
• Gemcitabine plus chemoradiation improves cervical cancer survival. Adding the drug gemcitabine (Gemzar) to cisplatin-based chemotherapy and radiation therapy extends overall survival among women with locally advanced cervical cancer. This study was primarily conducted in developing countries, where cervical cancer screening programs are limited.
• Sentinel node biopsy is an effective option for early-stage cervical cancer. Most women with early-stage cervical cancer can safely undergo sentinel node biopsy – a technique in which only one or two lymph nodes are removed to determine whether cancer has spread – in lieu of the traditional, more invasive pelvic lymph node removal, which can lead to more significant side effects. Sentinel node biopsy was also as effective for detecting cancer spread to atypical areas of the pelvis.

For more information, read these PubMed abstracts

• Sivanesaratnam V. Third S. S. Ratnam Memorial Lecture 2007. Ovarian cancer: Is there hope for women? J Obstet Gynaecol Res. 2009 Jun;35(3):393-404.
• Gupta D, Lis CG, Vashi PG, Lammersfeld CA. Impact of improved nutritional status on survival in ovarian cancer. Support Care Cancer. 2009 May 31. [Epub ahead of print]
• Turgut O, Tandogan I, Yilmaz MB, Gul I, Gurlek A. CA125 levels among patients with advanced heart failure: An emerging independent predictor for survival. Int. J Cardiol. 2009 May 13. [Epub ahead of print]
• Interim phase 2 results for PARP inhibitor BSI-201 at San Antonio Breast Cancer Symposium. Cancer Biol Ther. 2009 Jan;8(1):2-3.

Help your patients understand:

• For consumer-oriented information about the studies in this article, please refer your patients to ASCO’s patient website.

Lipocalin 2 promotes breast cancer progression: Breast Cancer Biomarker Highlighted as useful in Non-Invasive Diagnostic Assays

Lipocalin-2 (lcn2) a 25 kDa secretory glycoprotein, also called NGAL (neutrophil gelatinase-associated lipocalin) is predominantly expressed in adipose tissue and liver and belongs to the lipocalin superfamily that consists of over 20 small secretory proteins. Lipocalin folds consist of 8 antiparallel ß-sheets that surround a hydrophobic pocket. A common feature of this protein family, following from its structure, is its capacity to bind and transport small lipophilic substancies such as free fatty acids, retinoids, arachidonic acid and various steroids.

Although Lipocalin-2 was identified more than a decade ago, the physiologic function of this protein remained poorly understood. Research now showd that lipocalin-2 appears to be upregulated in cells under the “stress” (e.g. from infection, inflammation, in tissues undergoing involution to ischemia or neoplastic transformation).

Therapeutic importance
Plasma levels of lipocalin-2 rise in inflammatory or infective condition. The protein mediates an immune response to bacterial infection by sequestering iron. Therfore, Lipocalin-2 may represent a promising candidate as a therapeutic agent against bacterial infection.
Several recent reports suggest that lipocalin-2 may also represent a sensitive biomarker for early renal injury. In cardiopulmonary bypass-induced acute renal injury and cisplatin-induced nephrotoxic injury, increased de novo synthesis of lipocalin-2 in proximal tubule cells leads to sharply increased concentration of this protein in both urine and serum.

Lipocalin-2 is also highly expressed after malignant transformation of the lung, colon and pancreatic epithelia. Circulating levels of lipocalin-2 play a causative role in pathogenesis of obesity-induced metabolic disorders such as insulin resistance, Type 2 Diabetes Mellitus and cardiovascular disorders. In addition, serum lipocalin-2 concentrations were positively associated with adipocyte-fatty acid binding protein (A-FABP), a novel serum marker for adiposity and metabolic syndrome.

Role in Breast Cancer
Reserach show that lipocalin-2 plays an important role in breast cancer, in complex with matrix metalloproteinase-9 or MMP-9, by protecting MMP-9 from degradation thereby enhancing its enzymatic activity and facilitating angiogenesis and tumor growth.

Researchers demonstrated that the binding of neutrophil gelatinase-associated lipocalin (NGAL) to matrix metalloproteinase-9 (MMP-9) protects the extracellular matrix remodeling enzyme from autodegradation. Although breast cancer cells express MMP-9 and not the NGAL protein, clinical researchers hypothesized that the addition of NGAL to breast cancer cells, result in a more aggressive phenotype in vivo. Based on previous reports that MMPs can be detected in the urine of cancer patients, researchers wondered whether MMP-9/NGAL could be detected in the urine of breast cancer patients and whether it might be predictive of disease status.

In an article by Yang, Bielenberg, Rodig and colleagues published in the Proceedings of the National Academy of Sciences (PNAS) investigating the function of lipocalin 2 in breast cancer progression, the research team identified the mechanisms in which lipocalin 2 promotes breast cancer progression.

Yang and colleagues noted that lipocalin-2 levels were consistently associated with invasive breast cancer in human tissue and urine samples. In research designed to unravel the role of Lipocalin 2 was overexpressed in human breast cancer cells and was found to up-regulate mesenchymal markers, including vimentin and fibronectin, down-regulate the epithelial marker E-cadherin, and significantly increase cell motility and invasiveness.

These changes in marker expression and cell motility are hallmarks of an epithelial to mesenchymal transition (EMT). Reserachers also noted that Lcn2 silencing in aggressive breast cancer cells inhibited cell migration and the mesenchymal phenotype. Furthermore, reduced expression of estrogen receptor (ER) α and increased expression of the key EMT transcription factor Slug were observed with lipocalin-2 expression.

Overexpression of ERα in Lcn2-expressing cells reversed the EMT and reduced Slug expression, suggesting that ERα negatively regulates Lcn2-induced EMT. Finally, orthotopic studies demonstrated that Lcn2-expressing breast tumors displayed a poorly differentiated phenotype and showed increased local tumor invasion and lymph node metastasis.

A non-invasive biomarker for advanced breast cancer
In this research, Yang demonstrated that lipocalin 2 promotes breast cancer progression by inducing the epithelial to mesenchymal transition (EMT), one of the key processes involved in tumor progression and metastasis. The team further showed that lipocalin-2 levels can be measured in urine samples, and high levels are correlated with cancer cell migration and invasiveness in women with advanced or metastatic estrogen-receptor (ER)-negative breast cancer.

These findings suggest the potential for lipocalin 2 as a non-invasive biomarker for advanced breast cancer. lipocalin-2, along with other urine biomarkers for various cancers discovered at Children’s Hospital Boston, is exclusively licensed to Predictive Biosciences for diagnostic assay development. Predictive Biosciences is an emerging molecular diagnostics company developing non-invasive diagnostic products for informed cancer management™.

"Estrogen-receptor negative breast tumors are among the most difficult to treat," said Marsha A. Moses, Ph.D., Professor of Surgery at Harvard Medical School and interim Director of the Vascular Biology Program at Children’s Hospital Boston, and co-author of the PNAS publication. Dr. Moses, a co-founder of Predictive Biosciences / , added, "We are excited by this research showing a strong correlation between high levels of Lcn2 and the aggressiveness of breast cancer. These studies suggest the potential for a simple, urine-based assay to measure Lcn2 as a way of monitoring cancer development and progression on an individual basis, and to determine if more aggressive treatment is needed. This would be an important step towards more accurate and personal cancer management for these patients."

Utilizing its portfolio of patented biomarkers and proprietary clinical approaches (such as Clinical Intervention Determining Diagnostic™ or CIDD); Predictive Biosciences is developing novel diagnostic assays that have exceptionally high negative predictive value (NPV) and positive predictive value (PPV) for cancer development and progression. This information, incorporated into current standard clinical practice, should lead to more effective utilization of existing tools and ultimately better outcomes for patients. Predictive aims to deliver highly accurate, convenient diagnostics to provide physicians with actionable information for personalized diagnostic follow-up and treatment plans – avoiding expensive, invasive procedures and increasing patient compliance and comfort.

"We are very pleased to be collaborating with Professor Marsha Moses and Children’s Hospital Boston on developing a number of urine-based cancer diagnostic assays," said Peter Klemm, Ph.D., President and Chief Executive Officer of Predictive.

"Already, Predictive is advancing novel bladder cancer assays, with plans to commercialize these tests via our CLIA lab. In addition, we have a rich pipeline of biomarkers poised for diagnostic assay development, including this very compelling breast cancer biomarker, Lcn2. Leveraging our deep clinical development and scientific capabilities, we are building a robust portfolio of innovative cancer assays, in collaboration with others who share our interest in delivering highly accurate and convenient cancer diagnostics for informed cancer management™."

For more information also read these PubMed abstracts:

• Yang J, Bielenberg DR, Rodig SJ, Doiron R, et al. Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):3913-8. Epub 2009 Feb 23.
• Fernández CA, Yan L, Louis G, Yang J et al. The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clin Cancer Res.2005 Aug 1;11(15):5390-5 (Full article)
• Søiland H, Skaland I, Varhaug JE, Kørner H, et al. Co-expression of estrogen receptor alpha and Apolipoprotein D in node positive operable breast cancer--possible relevance for survival and effects of adjuvant tamoxifen in postmenopausal patients. Acta Oncol. 2009;48(4):514-21.
• Shi H, Gu Y, Yang J, Xu L, Mi W, Yu W. Lipocalin 2 promotes lung metastasis of murine breast cancer cells. J Exp Clin Cancer Res. 2008 Dec 12;27:83.