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

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.

Triple-negative breast cancer: risk factors to potential targets

Breast cancer is not one single disease, but knows different subgroups originating in the breast. Triple-negative breast cancer, one of these subgroups, has recently been recognized as an important subgroup of breast cancer with a distinct outcome and therapeutic approach when compared with other subgroups of breast cancer. Triple-negative breast cancer comprises primarily, but not exclusively, of the basal-like subtype and refers to a specific subtype of breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor (PR) or Her2/neu.

Depending on its stage of diagnosis, triple-negative breast cancer can be extremely aggressive and is more likely to recur and metastasize than other subtypes of breast cancer. It typically is responsive to chemotherapy, although it can be more difficult to treat because it is unresponsive to the most effective receptor targeted treatments

Late last year, researchers from the Indiana University Department of Medicine, Melvin and Bren Simon Cancer Center, Indianapolis, led by Dr. Bryan Paul Schneider MD, reported details of a new studies and findings in the area of breast cancer risk factors. The results were published in the journal Clinical Cancer Research.

Commenting on the research results, Schneider explained: ‘We do not yet have an assay to identify basal-like breast cancer in clinical samples, so triple-negative breast cancer has become a commonly used proxy for this subtype. The molecular biology and pathophysiology of triple-negative breast cancer are not completely understood, but understanding is improving rapidly with the advent of sophisticated molecular biology platforms.’

The established risk factors of breast cancer as a whole may not apply to this unique subgroup of patients. Because triple-negative breast cancer is defined by the absence of a target, there are currently limitations to using a tailored therapeutic approach, leaving conventional cytotoxic therapies as the mainstay.

‘Active preclinical and clinical research programs focus on defining the clinical behavior, delineating the risk factors, and more completely understanding the molecular biology of triple-negative breast cancer to improve prevention, optimize conventional agents, and unveil novel therapeutic targets,' Schneider said.

For more information, read:

• Schneider BP, Winer EP, Foulkes WD, Garber J, et al. Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res. 2008 Dec 15;14(24):8010-8
• Click here to contact the author.

Also read PubMed abstracts:

• Liu ZB, Liu GY, Yang WT, Di GH, et al. Triple-negative breast cancer types exhibit a distinct poor clinical characteristic in lymph node-negative Chinese patients Oncol Rep. 2008 Oct;20(4):987-94.
• Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review. Histopathology. 2008 Jan;52(1):108-18. Review.
• Sasa M, Bando Y, Takahashi M, Hirose T, Nagao T Screening for basal marker expression is necessary for decision of therapeutic strategy for triple-negative breast cancer. J Surg Oncol. 2008 Jan 1;97(1):30-4.
• Rakha EA, El-Sayed ME, Green AR, Lee AH, et al. Prognostic markers in triple-negative breast cancer. Cancer. 2007 Jan 1;109(1):25-32

See online video:

• CNN's Dr. Sanjay Gupta looks into tripple-negative breast cancer, an aggressive and drug-resistant form of cancer affecting black women.
• About tripple-negative breast cancer on Truveo.