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

Oral Bisphosphonates May Significantly Reduce Breast Cancer

Results of a new analysis of data from the Women's Health Initiative (WHI) observational study showed that women who used bisphosphonates, which are commonly prescribed bone-strengthening pills, had significantly fewer invasive breast cancers than women who did not use bisphosphonates. These findings were presented at the CRTC-AACR San Antonio Breast Cancer Symposium.

In the 150,000-plus cohort of generally healthy postmenopausal women, the researchers found that women who used bisphosphonates, mostly alendronate, which is sold as Fosamax (alendronate sodium) by Merck, had 32% fewer cases of invasive breast cancer compared to women who did not use such drugs.

"The idea that bisphosphonates could reduce breast cancer incidence is very exciting because there are about 30 million prescriptions for these agents written annually in the United States targeting bone health, and more could easily be used to counteract both osteoporosis and breast cancer," said the study's lead investigator, Rowan Chlebowski, M.D., Ph.D., medical oncologist at the Los Angeles Biomedical Research Institute at Harbor-University of California, Los Angeles Medical Center.

The concept arose from findings in a report on an adjuvant breast cancer trial where use of the bisphosphonate zoledronic acid given intravenously every six months resulted in fewer contralateral breast cancers.

"It appeared to make bone less hospitable to breast cancer," Chlebowski said.

However, since bisphosphonates are prescribed for women with low bone mineral density and low bone mineral density has been associated with lower breast cancer incidence, a means to control for potential differences between women prescribed bisphosphonate and those not prescribed bisphosphonate in the cohort was needed.

Given that, Chlebowski and colleagues devised a way to control for use of bisphosphonates in the WHI. About 10,000 of the participants had bone mineral density analysis as part of the study, and for the rest they used a 10-item hip fracture predictive score to measure bone density. The researchers were able to correlate the findings from the women who had bone mineral density tests to findings from the predictive score in order to correct for any potential difference in bone density in women using bisphosphonates compared to non-users.

Studying 2,216 WHI participants who were using bisphosphonates when they entered the study, the researchers found that only 64 women developed breast cancer, and most of those cases (50) were estrogen receptor positive. Overall, there was a mean 32 percent fewer breast cancers in women using bisphosphonates compared to women who did not. There were 30 percent fewer estrogen receptor-positive cancers and 34 percent fewer entry receptor-negative cancers in bisphosphonate users. The latter finding was not statistically significant as there were very few receptor-negative cases.

"Bisphosphonates reduce angiogenesis and stimulate immune cells responsible for tumor cell surveillance as potential mediators," Chlebowski said. "This association needs to be studied further. While we currently have several options for reducing receptor-positive breast cancers, none are available for receptor-negative cancers."

Several ongoing adjuvant breast cancer trials evaluating oral and intravenous bisphosphonate will be available in the near future to provide randomized clinical trial evidence regarding their influence on new contralateral breast cancer risk, Chlebowski said.

For more information:

•  Onco'Zine - The International Cancer Network

Bisphosphonates and the Risk of Postmenopausal Breast Cancer

Bisphosphonates are routinely given to women with postmenopausal breast cancer, but new data suggest that these agents may play an important role in reducing recurrent breast cancer as well. Results of a new trial demonstrated that the use of bisphosphonates was associated with a 29% reduction in the risk of postmenopausal breast cancer. The results were presented at the CTRC-AACR San Antonio Breast Cancer Symposium.

Link between Bisphosphonates and Breast Cancer
When breast cancer metastasizes, it often spreads first to the bones. Bone metastases can lead to complications such as pain, fractures, spinal cord compression, bone marrow suppression, and hypercalcemia. The primary reason for this link is that breast cancer cells stimulate bone cells called osteoclasts, and these osteoclasts in turn stimulate the growth of breast cancer cells.

Bisphosphonates have emerged as a highly effective therapeutic option for the prevention of skeletal complications secondary to bone metastases. They interrupt the relationship between osteoclasts and breast cancer cells in early stage breast cancer, slowing the progression of bone metastases while, at the same time, reducing the skeletal complications in women with metastatic breast cancer. Research has also demonstrated that bisphosphonates may prevent the development of bone metastases in newly diagnosed patients with no evidence of metastasis.

A number of agents are now approved in both Europe and the US. They included Clodronate, Pamidronate, Ibandronate, Zoledronic acid.

New and ongoing research
Lead researcher Gad Rennert, M.D., Ph.D., chairman of the Department of Community Medicine and Epidemiology at the Carmel Medical Center of Clalit Health Services and a faculty member at the Technion-Israel Institute of Technology in Israel, said these data help shed light on a possible new pathway for breast cancer prevention.

"We have identified a new class of drugs that is associated with a reduced risk of breast cancer, and if proven in randomized trials, we may be able to recommend it to postmenopausal women for this purpose," said Rennert.

Rennert and colleagues extracted data from the Breast Cancer in Northern Israel Study, which is a population-based, case-control study. They evaluated the use of bisphosphonates for at least five years in 4,575 postmenopausal study participants using a structured interview. The self-reported, long-term use of bisphosphonates prior to diagnosis was associated with a significant reduced relative risk for breast cancer by approximately 34%.

This reduction remained significant, at 29%, even after adjusting for a large variety of risk factors for breast cancer such as age, fruit and vegetable consumption, sports activity, family history of breast cancer, ethnic group, body mass index, calcium supplement and hormone replacement therapy use, number of pregnancies, months of breastfeeding and age at first pregnancy.

Moreover, the breast tumors identified among patients who used bisphosphonates were more often estrogen receptor positive and less often poorly differentiated.

"These tumors are the type that are associated with a better prognosis," said Rennert.

While most experts are cautiously optimistic about the results of this study, several of them said that more information is necessary, and as of now, they would not suggest the use of bisphosphonates for women who do not have osteoporosis.

For more information:

• Coleman RE. Bisphosphonates in breast cancer. Ann Oncol 2005 May;16(5):687-95. Epub 2005 Mar 31.
• Logman JF, Heeg BM, Botteman MF, Kaura S, van Hout BA. Economic evaluation of zoledronic acid for the prevention of osteoporotic fractures in postmenopausal women with early-stage breast cancer receiving aromatase inhibitors in the UK. Ann Oncol. 2009 Dec 2. [Epub ahead of print]
• Ghazi M, Roux C. Hormonal deprivation therapy-induced osteoporosis in postmenopausal women with breast cancer. Best Pract Res Clin Rheumatol. 2009 Dec;23(6):805-11.
• Theriault RL. Bisphosphonates: ready for use as adjuvant therapy of breast cancer? Curr Opin Obstet Gynecol. 2009 Nov 19. [Epub ahead of print]

Also see:

• Onco'Zine - The International cancer Blog

BSI-201, an Investigational Drug, plus Chemotherapy May Offer New Treatment Option for Triple-Negative Breast Cancer

A randomized Phase II study, featured during the plenary session of the 45th Annual Meeting of the American Society of Clinical Oncology (ASCO) , shows that women with metastatic triple-negative breast cancer who received the investigational PARP inhibitor BSI-201, in combination with conventional chemotherapy, lived significantly longer and experienced significantly better progression-free survival than women who received standard chemotherapy alone.

“The results of this study provide early evidence that BSI-201, a potent inhibitor of PARP1, or poly (ADP-ribose) polymerase-1, is a promising treatment for women with triple-negative breast cancer, an aggressive form of the disease for which we need new, more effective therapies,” said Joyce O’Shaughnessy, MD, co-director of the Breast Cancer Research Program at Baylor-Charles A. Sammons Cancer Center in Dallas, Texas.

Triple-negative breast cancers (TNBC) are particularly hard to treat since they lack receptors for estrogen, progesterone and HER2, which are targeted by widely available and effective drugs. African American women are 3 times more likely than white or Hispanic women to be diagnosed with triple-negative breast cancer.

In this study, clinical benefit rate (defined by complete and partial responses and stable disease of at least 6 months), response rate, progression-free survival (the time it takes for cancer to progress), and overall survival were compared among 116 women with metastatic triple-negative breast cancer who were randomly assigned to receive a standard chemotherapy treatment (gemcitabine and carboplatin) plus BSI-201, or standard treatment alone.

Approximately 62 percent of patients receiving BSI-201 showed clinical benefit, compared with 21 percent in the chemotherapy only group. The overall response rate to treatment with the drug combination containing BSI-201 was significantly greater (48 percent) than in the group receiving only standard chemotherapy (16 percent). Women who received BSI-201 had a median survival of 9.2 months and median progression-free survival of 6.9 months compared with 5.7 months and 3.3 months, respectively, in women who received standard treatment alone.

Efficacy and Safety
BiPar Sciences Inc, a California-based subsidiary of French drug maker Sanofi–Aventis involved in the development of novel cancer therapies, reported interim safety data from this trial during the annual San Antonio Breast Cancer Symposium (SABCS) in December 2008, showing that the drug was well tolerated with no added toxicities compared with chemotherapy alone.

While inhibition of PARP has demonstrated significant anti-tumor effects in several cancers, its activity does not appear to be critical for normal, non-cancerous cells. Thus, PARP inhibition has the potential to impair a fundamental mechanism of tumor growth without rendering damage to normal cells, implying a lower risk for side effects in patients who receive PARP-inhibitor-based therapies

In general, BSI-201 has shown a strong safety profile and no significant toxicities attributable to drug in studies of more than 200 patients treated to date with monotherapy, as well as in combination with chemotherapeutic regimens.

In the trial, the incidence of side effects was similar between the two groups. BSI-201 itself was well-tolerated and did not contribute any new side effects nor add to the known side effects of gemcitabine and carboplatin.

Future research
The researchers believe that BSI-201 has first-in-class and best-in-class potential as targeted therapy for several types of cancer. The trial drug is a leading candidate in the field of PARP inhibitors and is the furthest along in clinical development of this novel therapeutic approach.

Based on the results of the Phase II trial, California based BiPar Sciences Inc will be initiating a Phase III clinical trial in triple negative metastatic breast cancer in the second half of 2009. This Phase III program has been guided by preliminary safety and efficacy data from a Phase II study in the same patient population.

ASCO 2009 abstract:

• O'Shaughnessy J, Osborne C, Pippen J, Yoffe M, et al. Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol 27:18s, 2009 (suppl; abstr 3).

For more information (posters):

• Preclinical Activity of BSI-201 + Chemotherapy in Triple Negative Breast Cancer, American Association for Cancer Research, April 2009
• O’Shaughnessy J, Osborne C, Blum J, Pippen J, Yoffe M, et al. Triple Negative Metastatic Breast Cancer: A Phase 2, Multi-Center, Open-Label, Randomized Trial of Gemcitabine/Carboplatin (G/C) With or Without BSI-201, a PARP Inhibitor. SABCS Poster 2120, December 2008.

Also read these Pubmed abstracts:

• Stead LA, Lash TL, Sobieraj JE, Chi DD, Westrup JL, et al. Triple-negative breast cancers are increased in black women regardless of age or body mass index. Breast Cancer Res. 2009;11(2):R18. Epub 2009 Mar 25.

Help your Patient to better understand:

• Triple Negative Breast Cancer Foundation

Photo courtesy of the American Society of Clinical Oncology.

Test Identifies Low-risk Subgroup in HER2-positive Breast Cancer

HER2, human epidermal growth factor receptor 2, is a protein found on the surface of breast cancer cells. When functioning normally, HER2 is a key component in regulating cell growth. However, when altered, extra HER2 protein receptors may be produced.

This overexpression of HER2 is considered a negative prognostic factor and associated with increased cell growth and reproduction, often resulting in a more aggressive form of breast cancer with increased disease recurrence and worse prognosis. Studies show that HER2/neu is overexpressed in approximately 15-20% of invasive breast cancers. Because HER2+ tumors tend to grow and spread more quickly than tumors that are not HER2+, accurate and timely diagnostic procedures are crucial.

High Risk
There are a number of different kinds of breast cancer and each is treated differently. Patients with Her2+ breast cancer are generally classified as high risk. As a result, current treatment guidelines recommend adjuvant trastuzumab (Herceptin®, Genentech, 1 DNA Way South San Francisco, CA 94080-4990, co-marketed by F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland) and chemotherapy as the best treatment option for all HER2-positive breast cancer patients at high risk of relapse, increasing their chance of living longer. At the same time, results from the HERA-trial (HERceptin Adjuvant), a randomized, two-arm, open label study of the efficacy, safety and tolerability of trastuzumab compared to observation in women who have completed standard adjuvant treatment of HER2 positive primary breast cancer, showed that 74% of patients remained distant recurrence-free at 3 years without trastuzumab.

A highly sensitive prognostic tool
Dr. Michael Knauer, MD, from the Netherlands Cancer Institute presented the results from a study investigating the benefits of a highly sensitive diagnostic assay during the 2008 San Antonio Breast Cancer Symposium (SABCS). In the study, researchers used MammaPrint®, (Agendia BV, Amsterdam Science Park, Kruislaan 406, NL-1098 SM Amsterdam, The Netherlands), a prognostic genomic test developed with micro-array technology that has the potential to greatly improve risk assessment and treatment decision making for early breast cancer, to identify a subgroup of patients with low risk and favorable outcome. This test looks at the expression of 70 genes linked to breast cancer with an accuracy level of 96.7% as determined by a study published in the New England Journal of Medicine. This prognostic signature of genetic 'fingerprint' is validated as an independent prognostic indicator for patients with up to three positive lymph nodes.

Knauer showed that the highly accurate MammaPrint was able to differentiate between patients at high risk for recurrence and a low risk subgroup of HER2+ patients. The assay helped uncover a substantial group of traditionally miscategorized low risk HER2+ patients.

Study results
In the study population of 169 HER2+ patients, Mammaprint, the first ‘in vitro diagnostic multivariate index assay’ (IVDMIA) cleared by the U.S. Food and Drug Administration (FDA) designed to identify patients with early metastasis, classified 16 percent of patients as having a good prognosis signature with a 10-year distant disease-free survival (DDFS) of 89 percent, even in the absence of (neo)adjuvant trastuzumab and chemotherapy, compared to 84 percent of patients classified as having a poor prognosis signature with a DDFS of 64 percent. Additionally, in a subgroup of highly endocrine responsive HER2/neu positive patients, MammaPrint low risk patients had no relapse.

All 169 patients with HER2-positive breast cancer were selected from a pooled dataset of 1280 patients with known HER2-status. Patients had a unilateral T1-3, N0-1 tumor and were treated with either breast-conserving therapy or mastectomy. Samples were analyzed and classified by the 70-gene signature as good or poor prognosis by Agendia Laboratories.

The strength of the assay is underscored by the 70 gene panel unique to the test and a resulting gene profile that covers all molecular pathways associated with breast cancer.

Personalized medicine
MammaPrint accurately identified a subgroup of patients with a good clinical outcome in HER2+ early breast cancer. These patients will be further studied in the ongoing MINDACT-trial (EORTC 10041/ BIG 3-04), a multicentre, prospective, phase III trial coordinated by the EORTC (European Organisation for Research and Treatment of Cancer) and run under the BIG and TRANSBIG network, which will accrue 6000 node-negative patients designed to determine the prospects of withholding chemotherapy and/or trastuzumab in HER2+, MammaPrint low risk patients.

This study compares MammaPrint to traditional clinical-pathological methods to assess the risk of breast cancer recurring in women with lymph node negative disease. Since breast cancer tumors with similar clinicopathological characteristics can have strikingly different outcomes, the traditional selection for adjuvant chemotherapy is far from accurate.

Based on the initial results with MammaPrint, it is hypothesized that using the genomic test in addition to traditional methods will result in more accurate risk assessment. It is expected that 10% to 20% of patients with node negative breast cancer will, in the future, safely be able to avoid chemotherapy and its potential side effects.

The current trend in research cancer is to develop ways of individualizing breast cancer treatment. This goal toward ‘personalized medicine’ requires better identification of type of systemic treatment and better identification of patients who are highly likely to develop distant metastases, and therefore, may benefit the most from adjuvant chemotherapy.

MammaPrint may be one of the tools helping to realize these goals.

For more information, read:

• Knauer M, Cardoso F, Mook S. et al. Identification of a low risk subgroup in Her2-positive breast cancer by the 70-gene prognosis signature. SABCS, Saturday, December 13, 2008 - 7:00 AM Poster Session IV: Late Acceptances (7:00AM-9:00AM). Abstract 4171.

Watch:

• Options for HER2+ Breast Cancer (video).

Also review PubMed abstracts:

• Haibe-Kains B, Desmedt C, Piette F, et al. Comparison of prognostic gene expression signatures for breast cancer. BMC Genomics. 2008 Aug 21;9:394. Free Full Text Article (PDF);
• Mook S, Schmidt MK, Viale G, et al. The 70-gene prognosis-signature predicts disease outcome in breast cancer patients with 1-3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2008 Jul 27. [Epub ahead of print];
• Cardoso F, Van't Veer L, Rutgers E, et al. Clinical application of the 70-gene profile: the MINDACT trial. J Clin Oncol. 2008 Feb 10;26(5):729-35.
• Marchionni L, Wilson RF, Marinopoulos SS et al. Impact of gene expression profiling tests on breast cancer outcomes. Evid Rep Technol Assess (Full Rep). 2007 Dec;(160):1-105;
• Mook S, Van't Veer LJ, Rutgers EJ et al. Individualization of therapy using Mammaprint: from development to the MINDACT Trial. Cancer Genomics Proteomics. 2007 May-Jun;4(3):147-55;
• Van de Vijver MJ, He YD, van't Veer LJ, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002 Dec 19;347(25):1999-2009.

More information:

• EORTC – The Mindact brochure.
• EORTC – The Mindsact website.
• Clinical trial: Trastuzumab in Treating Women With Primary Breast Cancer (EORTC, NCIC, BIG); Phase III.

HER2-Positive, Small Tumors Linked with Poor Prognosis

Patients with breast cancer whose tumors were HER2-positive and one centimeter or smaller, also caled T1a,bN0M0 tumors, have a significant risk of relapse compared with other tumor types, according to a new study presented at the 31st Annual CRTC-AACR San Antonio Breast Cancer Symposium (SABCS, December 10 - 14, 2008).

HER2-positive breast cancer is a breast cancer that tests positive for a protein called human epidermal growth factor receptor-2 (HER2). HER2 promotes the growth of cancer cells and its presence generally correlates with a poorer prognosis at any state of cancer. While approximately 15 – 20% of every breast cancers is HER2-positive, overexpression of the protein also occurs in other cancers such as ovarian cancer and stomach cancer.

A targeted therapy
In the past few years many encouraging advancements have been made in understanding the molecular mechanisms underlying carcinogenesis and tumor progression. These improvements have led to the identification of promising new targets for cancer therapy. Patients with HER2-positive breast cancer can now be effectively treated with targeted drugs, a humanized monoclonal antibody (MAb) called trastuzumab (Herceptin®, Genentech, 1 DNA Way South San Francisco, CA 94080-4990/F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland). Studies have shown that, in the treatment of early stage and metastatic breast cancer, this drug reduces the recurrence of HER2-positive breast cancers by anout 50%.

Mechanism of Action
Some breast cancer cells divide and grow when human epidermal growth factor or EGF, a protein that naturally occurs in the body, attaches itself to another protein known as HER2, which is found on the surface of some breast cancer cells. Trastuzumab interferes with this process by attaching itself to the HER2 protein.

This interfering antitumor activity induces HER2 receptor downmodulation and, as a result, inhibits critical signalling pathways (i.e. ras-Raf-MAPK and PI3K/Akt) and blocks cell cycle progression by inducing the formation of p27/Cdk2 complexes. Trastuzumab also inhibits HER2 cleavage, preceding antibody-induced receptor downmodulation, and this effect might contribute to its antitumor activity in some cancers. Additionally, trastuzumab inhibits, in vivo, angiogenesis and induces antibody-dependent cellular cytotoxicity.

Studies have shown that because trastuzumab works on both the extracellular and the intracellular domains of the HER2 receptor, it continuously suppresses HER2 activity that may lead to tumor proliferation, leads to cell stasis and death, may enhanced the effects of chemotherapy and provides constant inhibition of the HER2 receptor.

Immune system response
Because antibodies are part of the body's normal defense against bacteria, viruses and abnormal cells such as cancer cells, trastizumab not only blocks the epidermal growth factor from reaching cancer cells, but it also invokes the body’s own immune cells to help destroy them.

Current guidelines
Although the data presented during the SABCS may suggest that women with small, early-stage HER2-positive cancer could possibly benefit from aggressive treatment, current treatment guidelines recommend a different approach for HER2-positive tumors less than one-half centimeter in size. And, until now, there were no study available that investigated the effectiveness of trastuzumab in women with small, HER2-positive, tumors.

Commenting on this, Ana M. Gonzalez-Angulo, M.D., assistant professor in the Departments of Breast Medical Oncology and Systems Biology at the University of Texas M. D. Anderson Cancer Center (MDACC) said: ‘The current guidelines call for no further therapy if the tumors are less than five millimeters or consider therapy if the tumors are from six to 10 millimeters, but this data challenges that thinking and shows this group of women may benefit from additional therapy.’

Gonzalez-Angulo and Ronjay Rakkhit, chief fellow of Hematology-Oncology at M. D. Anderson, and colleagues retrospectively studied 965 patients from MDACC and validated their findings with 350 patients from two European institutions. Patients with a lack of receptor information, and/or who had received adjuvant chemotherapy or trastuzumab at any time were excluded.

‘This is the largest study of its kind in a patient population, and as our ability to detect tumors improves, this patient population will only continue to increase. Further, it answers a common question oncologist have in daily practice – which early stage patients may be in need of additional therapy,’ said Gonzalez-Angulo.

Patients were diagnosed between 1990 and 2003. The median age of these patients at diagnosis was 57 years. All tumors were one centimeter or smaller. Most of the tumors (68 percent) were hormone receptor-positive, while 10 percent were HER2-positive and 23 percent were triple receptor-negative.

Five-year, recurrence-free survival was 77.1 percent and 93.7 percent in patients with HER2-positive and HER2-negative tumors, respectively, and five-year distant recurrenc-free survival was 86.4 percent and 97.2 percent, in patients with HER2-positive and HER2-negative tumors, respectively. Patients with HER2-positive tumors had 2.68 times greater risk of recurrence and 5.3 times higher the risk of distant recurrence than those with HER2-negative tumors.

Patients with HER2-positive tumors had 5.09 times the risk of recurrence and 7.81 times the risk of distant recurrence compared to patients with hormone receptor-positive tumors. 'Data on 350 additional patients treated at two other institutions showed reproducibility,' said Gonzalez.

‘This paper shows that patients with HER2-positive tumors one centimeter or less have a significant risk of relapse and should be considered for clinical trials of systemic anti-HER2 adjuvant therapy, or if a clinical trial is not available, adjuvant therapy should be discussed with them’, Gonzalez-Angulo noted.

For more information, read:

• Rakkhit R, Broglio K, Peintinger F, Cardoso F, et al. Significant increased recurrence rates among breast cancer patients with HER2-positive, T1a,bN0M0 tumors. Poster Discussion Session: HER2 as a Biomarker.

Also read:

• Full Herceptin prescribing information (USA).
• Summary of Product Characteristics (European SPC / EMEA / English Version).
• Description of trastuzumab's mechanism of action.
• The international comprehensive Herceptin resource for healthcare professionals outside the United States of America.
• Roche - Product Information: Herceptin
• Comprehensive Herceptin resourse for the United States of America
• HER2-positive breast cancer: What is it?
• Roche introduces a new global packaging design for prescription medicine
• Structural Bioinformatics / Protein NMR Structure Gallery

Also read PubMed abstracts:

• Fischgräbe J, Wülfing P. Targeted therapies in breast cancer: established drugs and recent developments. Curr Clin Pharmacol. 2008 May;3(2):85-98. Review.
• Lee-Hoeflich ST, Crocker L, Yao E, Pham T. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008 Jul 15;68(14):5878-87
• Arnould L, Gelly M, Penault-Llorca F. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer. 2006;94:259-267.
• Bianco AR. Targeting c-erb2 and other receptors of the c-erB family: rationale and clinical applications. J Chemother. 2004;16:52-54.
• Pegram MD, Konecny GE, O'Callaghan C, Beryt M, Pietras R, Slamon DJ. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Nat Cancer Inst. 2004;96:739-749.
• Albanell J, Codony J, Rovira A, Mellado B, Gascón P. Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4. Adv Exp Med Biol. 2003;532:253-68.
• Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S, Arteaga CL. Herceptin-induced inhibition of phosphatidyli-nositol-3 kinase and Akt is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Research. 2002;62:4132-4141. Full text article (PDF).
• Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology. 2001;61:1-13. Click here to contact the author.
• Harari D, Yarden Y. Molecular mechanisms underlying ErbB2/HER2 action in breast cancer. Oncogene. 2000;19:6102-6114.
• Sliwkowski MX, Lofgren JA, Lewis GD, Hotaling TE, Fendly BM, Fox JA. Nonclinical studies addressing the mechanism of action of trastuzumab (Herceptin). Semin Oncol. 1999;26:60-70.
• Baselga J, Norton L, Albanell J, Kim Y-M, Mendelsohn J. Recombinant humanized anti-HER2 antibody (HerceptinTM) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res. 1998;58:2825-2831. Click here to contact the author.
• Lewis GD, Figari I, Fendly B. Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother. 1993;37:255-263.
• Carter P, Presta L, Gorman CM, et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci. 1992;89:4285-4289. Full text article (PDF).
• Shalaby MR, Shepard HM, Presta L, Rodrigues ML, et al. Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells overexpressing the HER2 protooncogene. J Exp Med. 1992 Jan 1;175(1):217-25.

Zoledronic Acid May Have Anti-Tumor Properties

Early evaluations of the bisphosphonate zoledronic acid (Zometa® , Novartis Oncology) suggest a possible direct anti-tumor effect when combined with neoadjuvant chemotherapy in breast cancer treatment, according to data presented to scientists and other medical professionals gathered at the Henry B. Gonzales Convention Center in San Antonio to hear and present the latest scientific findings in breast cancer research during the CTRC-AACR San Antonio Breast Cancer Symposium (December 10-14, 2008 ).

There is substantial in vitro evidence that zoledronic acid has direct antitumour effects and synergy with chemotherapy agents. Bisphosphonates may therefore be an adjuvant therapeutic strategy of potential importance.

‘Zoledronic acid is primarily targeted to bone and metastasis within the bone marrow microenvironment, but it may also be enhancing the response in the primary breast tumor,’ explained Robert Coleman, M.D., FRCP, professor of medical oncology at the University of Sheffield in the United Kingdom.

Coleman is the lead researcher on the AZURE (Adjuvant Zoledronic Acid to Reduce Recurrence) trial, a prospective, randomised, open label, parallel group trial designed to to evaluate the effect of zoledronic acid on breast cancer. ‘Although the larger AZURE trial is still being evaluated, if the findings in this smaller study are confirmed, the effect could be practice changing,' Coleman said.

The AZURE trial opened to recruitment in September 2003. Patients were recruited from 176 centres worldwide, completing accrual in January 2006, 8 months ahead of schedule, and enrolled 3,360 women with stage II/III breast cancer. The trial was set up to determine whether adjuvant treatment with 4 mg zoledronic acid in addition to adjuvant or neoadjuvant chemotherapy would improve the disease-free and bone metastasis-free survival of women with breast cancer at high risk of relapse.

Analysis of the characteristics of the study population shows that both groups are well
matched across all criteria. 51% of patients have T2 tumour at presentation, with 76.6% being ER positive. 60.6% and 33.2% had 1-3 and ≥4 axillary nodes involved respectively and 6.4% were treated in the neoadjuvant setting. Anthracyclines were administered to 92.6% and 22.7% received taxanes, in large part due to accrual into the TANGO trial concurrent with AZURE. Only 4.6% received endocrine therapy alone. Almost half of the patients (44.6%) were premenopausal at randomisation.

Coleman and colleagues performed a retrospective pathology analysis on 205 patients who received neoadjuvant chemotherapy to determine zoledronic acid’s impact on the primary tumor. Zoledronic acid appeared to reduce tumor size from 30 mm in the chemotherapy alone group to 20.5 mm in the combination group.

After adjusting for variables like estrogen receptor status and treatment duration, the difference remained at 42.4 mm in the chemotherapy group and 28.2 mm in the combination group. The pathological complete response rate was 5.8 percent in the chemotherapy arm and 10.9 percent in the zoledronic acid group.

The number of patients requiring mastectomy was 77.9 percent in the chemotherapy group and 65.3 percent in the combination group. ‘Zoledronic acid is currently approved for the treatment of bone metastasis and osteoporosis. If the AZURE trial remains positive, then we’ll file for an additional indication,’ Coleman said.

For more information, read:

• Winter MC, Thorpe HC, Burkinshaw R, Beevers SJ, Coleman RE. The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response exploratory evidence for direct anti-tumor activity in breast cancer. Abstract 5101. Poster Session V: Treatment: Neoadjuvant Therapy. San Antonio Breast Cancer Symposium.

Also read:

• Click here for full prescribing information.
• The Institute of Cancer Research

Also read PubMed Abstracts:

• Lyseng-Williamson KA. Zoledronic Acid: a review of its use in breast cancer. Drugs. 2008;68(18):2661-82
• Brufsky A. Management of cancer-treatment-induced bone loss in postmenopausal women undergoing adjuvant breast cancer therapy: a Z-FAST update. Semin Oncol. 2006 Apr;33(2 Suppl 7):S13-7.

Reduction in Breast Density Predicts Potential Benefit of Tamoxifen

Reduction in breast density appears to be a strong indicator of a woman’s response to tamoxifen, an agent used to decrease breast cancer risk. Increased breast density is the leading risk factor for breast cancer, apart from age.

At the CTRC-AACR San Antonio Breast Cancer Symposium, the British researchers said that if their findings are validated in follow-up studies, women at risk for developing breast cancer should have a baseline mammogram before starting use of tamoxifen, and then a follow-up scan a year or two later to monitor breast density.

If there is a reduction, the agent is having an effect; if density is the same, it may not be a beneficial drug for the individual woman, said the study’s lead investigator, Jack Cuzick, Ph.D., head of the Cancer Research UK Centre for Epidemiology, Mathematics and Statistics in London.

“It is important to find a way to predict who will respond to tamoxifen, and changes in breast density may constitute an early indicator of benefit,” said Cuzick. “This is important to know because other preventive options now exist or are being tested.” Cuzick led the International Breast Intervention Study I (IBIS-I), a trial of tamoxifen for breast cancer prevention that involved more than 7,000 participants. Results of the study found the agent reduces the risk of estrogen-positive (ER) breast cancer by 30 to 40 percent among women at high risk. During that study, researchers collected baseline mammograms, as well as mammograms at 18, 36, and 54 months to check for breast cancer development. Based on analysis of these mammograms, Cuzick and his colleagues later found a strong correlation between reduction of breast density in women who use tamoxifen and lowered breast cancer risk.

In this study, the investigators examined a subpopulation of the IBIS-I participants (120 women who developed breast cancer and 943 who didn’t), to see if their mammograms changed over time and if tamoxifen treatment reduced breast density. They also looked at changes in other variables, such as hormone status, body weight and familial factors. They found that only change in mammographic density predicted reduction of risk for ER-positive breast cancer.

For the 46 percent of women in the tamoxifen-treatment group whose breast density was reduced by 10 percent or more, the risk of breast cancer was reduced by 52 percent relative to the control group (women who did not develop breast cancer). Conversely, the 54 percent of women whose density was not reduced by 10 percent only had a non-significant, 8 percent reduction in breast cancer risk. The findings suggest that the impact of tamoxifen on risk reduction is predictable by changes it induces on breast density after 12 to 18 months of treatment, Cuzick said.

For more information:
Cuzick J, Warwick J, Pinney L, Warren R, Cawthorn S, et al. Change in breast density as a biomarker of breast cancer risk reduction; results from IBIS-1. Abstract 61; SABCS, December 10-14, 2008.