HER-2 Positive Breast Cancer
Acta Universitatis Tamperensis, No. 1567
By Katri Köninki
Tampere University Press
Distributed by Coronet Books
$77.50 Paper Original
Breast cancer is the most common cancer and an important cause of mortality in women. There is, however, vast variation in the aggressiveness of different tumor types. HER-2 (human epidermal growth factor) amplification is shown to correlate with poor prognosis in breast cancer. Despite its prognostic and predictive importance, until now the precise incidence of HER-2 amplification in population-based cohorts of breast cancer has not been known. Currently two targeted drugs (humanized monoclonal antibody trastuzumab and dual kinase inhibitor lapatinib) are accepted for treatment of HER-2 positive breast cancer. Although these two drugs are of significant clinical importance, not all patients benefit from the treatment. The resistance mechanisms have been studied but are until now unclear.
The proportion of HER-2 positive breast cancers was studied during years 1982-2005 in the Pirkanmaa hospital district. The incidence of all breast cancers increased by 40% during the study period when the proportion of HER-2 positive breast cancer of all diagnosed invasive breast cancers declined by third. This indicates that the incidence of tumors with HER-2 amplification had remained almost stable. The results also showed that HER-2 positive breast cancers were underrepresented among the tumors diagnosed by mammography screenings.
Trastuzumab resistance mechanisms were studied in detail using the JIMT-1 breast cancer cell line. This model of intrinsic resistance was compared with a panel of trastuzumab sensitive breast cancer cell lines. All cell lines were characterized for several molecular resistance mechanisms and the potency of the ADCC (antibody-dependent cellular cytotoxicity) reaction evoked by trastuzumab. Trastuzumab induced inhibition of growth in most of the HER-2 positive cell lines studied. Lapatinib produced a more significant action on the HER-2 positive cell lines and the IC50 effect (half maximal inhibitory concentration) was achieved with this drug in all the HER-2 positive cell lines. JIMT-1 being the most resistant to both drugs did also express several co-existing resistance mechanisms while in the more sensitive cell lines these features were present at variable levels. ADCC reaction by normal lymphocytes was nearly equally strong in all HER-2 positive cell lines.
Results of the cell line study further confirmed the role of aberrant PI3K-PTEN signaling in resistance to HER-2 targeted drugs. These defects were studied in more detail in clinical breast tumors. PIK3CA mutations were found in third of the analyzed tumor samples. In HER-2 positive cancers the mutation rate was only 14.5% but according to survival analysis this tumor type showed to be aggressive. When considering all breast cancers analyzed, the results indicated that mutated PIK3CA is associated with the trend towards late mortality, also in the estrogen receptor positive tumors.
The study indicated that HER-2 amplification is not as common among breast cancer patients as has been estimated. The results also suggested that the common breast cancer risk factors presumably affect more the HER-2 negative tumor type. The in vitro analyses showed that the HER-2 positive cell lines expressed trastuzumab and lapatinib resistance mechanisms at different levels, which proposes that drug resistance is a complicated phenomenon resulting from different biological properties. This study also emphasized the role of aberrant PI3K and PTEN signaling in resistance to both HER-2 targeted agents studied. The results may also implicate that the patients with PIK3CA mutated breast cancer are in higher risk of late breast cancer mortality.
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