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

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.

Trastuzumab Given Prior to Surgery Improves the Chance of Survival in HER2-positive Breast Cancer

Primary efficacy analysis of the NeOAdjuvant Herceptin trial (NOAH) presented at the 31st Annual CRTC-AACR San Antonio Breast Cancer Symposium (SABCS, December 10 - 14, 2008) by Professor Luca Gianni, MD, from the Istituto Nazionale Tumori in Milan, a leading investigator of the NOAH trial, demonstrated that standard one year treatment with trastuzumab (Herceptin®, Genentech, 1 DNA Way South San Francisco, CA 94080-4990/F. Hoffmann-La Roche, Grenzacherstrasse 124, CH-4070 Basel, Switzerland) provides long-term benefit to patients with high risk of recurrence of their breast cancer.

Incidence, Mortality and Prevalence
Breast cancer is, according to the World Health Organization (WHO), the most common cancer among women. Based one the GLOBOCAN 2002 data, each year more than one million new cases of breast cancer are diagnosed worldwide, and nearly 400,000 people will die of the disease annually.

Poor response
In HER2-positive breast cancer, increased quantities of the HER2 protein are present on the surface of the tumour cells. This is known as ‘HER2-positivity’ breast cancer. High levels of HER2 are present in a particularly aggressive form of the disease which responds poorly to chemotherapy. Research shows that HER2-positivity affects approximately 20 percent of women with breast cancer.

Mode of Action
Trastuzumab is a humanised antibody, designed to target and block the function of HER2, a protein produced by a specific gene with cancer-causing potential. The mode of action of trastuzumab is unique in that it activates the body’s immune system and suppresses HER2 to target and destroy the tumour. Trastuzumab has demonstrated unprecedented efficacy in treating both early and advanced (metastatic) HER2-positive breast cancer. Given on its own as monotherapy as well as in combination with or following standard chemotherapy, trastuzumab has been shown to improve response rates, disease-free survival and overall survival while maintaining quality of life in women with HER2-positive breast cancer.

Locally advanced breast cancer or LABC, including inflammatory breast cancer, is more common in Europe than in the US and accounting for about 10% of all new cases. The median survival time remains low, ranging from 3 years (for inflammatory breast cancer) to 6 years. Thus, new treatment approaches are critically important.

The largest neoadjuvant trial
The NeOAdjuvant Herceptin trial (NOAH) is the largest multicentre, randomised, open-label, Phase III trial, evaluating the benefits of giving neoadjuvant trastuzumab in combination with anthracycline- and taxane-based chemotherapy versus chemotherapy alone to women with locally advanced HER2-positive breast cancer.

A total of 228 patients with centrally confirmed locally advanced HER2-positive breast cancer, a particularly aggressive form of the disease, participated in this neoadjuvant study. 115 patients received standard chemotherapy plus trastuzumab (for one year) and 113 patients received chemotherapy alone before surgery. The primary end point was event-free survival (EFS), defined as the time between randomisation and disease recurrence or progression, or death from any cause. Secondary end points were pathological complete response (pCR), overall response rate (ORR), overall survival (OS) and safety.

Improving event free survival
The results of this study show that trastuzumab plus chemotherapy improved event free survival at 3 years to 70% vs 53% with chemotherapy alone - the addition of trastuzumab to chemotherapy reduced the relative risk of recurrence by about half (HR 0.56, p=0.006). In addition, trastuzumab plus chemotherapy was shown to completely eradicate the tumor (a pathological complete response to treatment) in nearly twice as many patients, 39%, compared with only 20% of patients treated with chemotherapy alone (p=0.002). The overall response rate was also significantly increased (89% vs 77%, p=0.02).

Treatment options
Standard treatment for locally advanced breast cancer currently includes neoadjuvant chemotherapy. In this study, outcomes were assessed in HER2-positive patients with locally advanced breast cancer treated with chemotherapy (3 cycles of doxorubicin and paclitaxel, 4 cycles of paclitaxel, 3 cycles of CMF; n=113) or with chemotherapy + trastuzumab (n=115). A control group of HER2-negative patients with LABC received chemotherapy only (n=99). The primary endpoint was event-free survival (EFS), with a median follow-up time of 3 years. For HER2-positive patients who received chemotherapy and trastuzumab, EFS was significantly improved compared with HER2-positive patients who only received chemotherapy (70.1% vs 53.3%, respectively; HR=0.56, P=.006). Overall survival, a secondary endpoint, was also improved in patients receiving trastuzumab, but the difference was not significant (85.3% vs 80.4%, respectively; HR=0.65, P=.18). EFS was similar in the HER2-positive arm treated with chemotherapy alone and the HER2-negative control arm over the first 18 months, but showed a divergence in favor of HER2-negative patients over a longer period of time. Adverse events from the 2 therapy regimens were within acceptable limits. Cardiac toxicity, as reflected by changes in left ventricular ejection fraction (LVEF), was minimal in the majority of patients (>95% of patients with CTC grade 0 or 1), with 2 cardiac events reported in the group receiving trastuzumab.

About 70% of women with locally advanced HER2-positive breast cancer were free of their disease three years after initiation of therapy when treated with trastuzumab plus chemotherapy before surgery, compared to only around 50% of patients receiving pre-operative chemotherapy alone.

The results from the final analysis of the NOAH (NeOAdjuvant Herceptin) phase III study offer welcome news as patients with this early, but locally advanced breast cancer whose disease has spread to tissues around the breast such as the skin, muscle or lymph nodes generally face a high chance of recurrence and short life-expectancy.

‘The positive results of the NOAH study show that starting trastuzumab treatment prior to surgery offers long-term benefits to women with HER2-positive breast cancer,’ said William M. Burns, CEO Division Roche Pharmaceuticals. ‘Herceptin continues to provide women with early breast cancer a much improved prognosis, even if their cancer has advanced locally.’

Commenting on the results, Professor Gianni explained: ‘Women with locally advanced HER2-positive breast cancer are difficult to treat,’ ‘The results of the NOAH study imply that starting chemotherapy with one year of Herceptin should become the standard of care for women with locally advanced HER2-positive breast cancer’.

The aim of pre-surgery (neoadjuvant) therapy given to women with breast cancer is to improve the local control of the tumour to facilitate surgery. At the same time, the objective is to determine the sensitivity of the tumour towards a specific treatment. The results of this study demonstrate that starting trastuzumab treatment prior to surgery helps shrink locally advanced breast cancer and improve long term outcomes.

For more information, read:

• Gianni L, Eiermann W, Semiglazov V, et al. Neoadjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer: primary efficacy analysis of the NOAH trial. (General Session 3) Abstract 31 San Antonio Breast Cancer Symposium

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
• Structural Bioinformatics / Protein NMR Structure Gallery
• Ferlay J., Bray F., Pisani P. and Parkin D.M. GLOBOCAN 2002. Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No.5, Version 2.0. IARCPress, Lyon, 2004.

Also read PubMed abstract:

• Glück S, McKenna EF Jr, Royce M. XeNA: capecitabine plus docetaxel, with or without trastuzumab, as preoperative therapy for early breast cancer. Int J Med Sci. 2008;5(6):341-6. Epub 2008 Nov 4
• Sánchez-Muñoz A, García-Tapiador AM, Martínez-Ortega E. et al. Tumour molecular subtyping according to hormone receptors and HER2 status defines different pathological complete response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. Clin Transl Oncol. 2008 Oct;10(10):646-53. Contact the authors.
• Madarnas Y, Trudeau M, Franek JA. et al. Adjuvant/neoadjuvant trastuzumab therapy in women with HER-2/neu-overexpressing breast cancer: a systematic review. Cancer Treat Rev. 2008 Oct;34(6):539-57. Epub 2008 May 27. Contact the authors.
• Kulkarni S, Hicks DG. HER2-positive early breast cancer and trastuzumab: a surgeon's perspective. Ann Surg Oncol. 2008 Jun;15(6):1677-88. Epub 2008 Apr 9. Contact the authors.
• Lazaridis G, Pentheroudakis G, Pavlidis N. Integrating trastuzumab in the neoadjuvant treatment of primary breast cancer: accumulating evidence of efficacy, synergy and safety. Crit Rev Oncol Hematol. 2008 Apr;66(1):31-41. Ep.ub 2007 Sep 4. Review

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.

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.