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The Lancet Oncology

Saturday, January 10, 2009

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.

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