Human Genome Project research results to the cancer molecular diagnostics and molecular targeted therapy has brought great influence, human beings can go up at the molecular level study of the occurrence and development of malignant tumors such as breast cancer, but also can be designed at the molecular level of new targets for different drugs.
Herceptin (Herceptin) against HER2 monoclonal antibody in breast cancer treatment because of its superior efficacy to obtain as representative of cancer molecular target therapy. With the advances in molecular biology techniques, the tumor, invasion of the mechanism from more and more in-depth understanding of the molecular level to start against cell receptor, the key genes and regulatory elements as the target of treatment, in recent years against the human epidermal growth factor receptor (HER) family of angiogenesis pathway, cell proliferation pathways, cell cycle regulation, apoptosis pathway such as the target of treatment has made gratifying progress.
1 HER receptor family as targets for drug
HER family is a group of transmembrane receptors by the extracellular ligand-binding domain, a transmembrane domain and intracellular tyrosine kinase domains. The family includes four members, namely, HER1, HER2, HER3, and HER4. When the ligand and receptor extracellular domain combination, HER family of the formation of the same type of dimer or heterodimer, leading to intracellular domain tyrosine kinase phosphorylation, thereby activating intracellular signaling pathways, leading to cell proliferation, angiogenesis , apoptosis and other cellular effects.
Pre-clinical studies suggest that, HER2 overexpression is an early event in tumor formation, tumor growth through cell cycle plays an important role in the process. HER1 overexpression of tumor development in the later period of the event. At the same time to express HER1 and HER2 breast cancer, multiple pairs of endocrine therapy resistance. Thus, for the HER family of drugs as the target of R & D hot spots.
(1) HER-2 inhibitors
Trastuzumab (Herceptin) is a recombinant human monoclonal antibody, is the field of breast cancer the first molecular targeted drug. Herceptin monotherapy of efficiency was 15% -30%, in combination with chemotherapy can improve the efficacy. Herceptin, a 469 cases of Her-2 positive metastatic breast cancer recurrence in patients with stage â…¢ clinical study confirmed that, Herceptin plus paclitaxel group compared with single-agent paclitaxel in the treatment, efficiency markedly improved, and can prolong survival. International multi-center clinical study NASBP-31 study, NCCTG N9831, BCIRG006 research and HERA study released preliminary findings have confirmed Herceptin in breast cancer adjuvant therapy in the active role. Four studies enrolled a total of 13000 patients with early breast cancer, all of HER2 IHC detection of 3 + or FISH testing positive. Herceptin can study confirmed that patients with early breast cancer on the basis of conventional radiotherapy and chemotherapy, relapse risk decreased 39% -52%, so Herceptin for early HER2-positive breast cancer patients provides an important therapeutic tool for patients with HER2-positive the treatment of landmark significance.
Should be consistent with the clinical immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) to detect HER-2 quality certification standards of laboratory testing. HER-2 over-expression of the FISH detection of positive or IHC detection of HER-2 (+++), IHC detection of HER-2 (+ +) in patients with FISH should be confirmed. Trastuzumab can be used as after chemotherapy treatment, you can also program in the AC → T with paclitaxel at the same time to start using, taking into account cardiac toxicity, not with anthracycline used simultaneously. Trastuzumab in accordance with the program every week or every three weeks one year of therapy and closely monitor the new features.
Currently considered HER-2 over-expression in patients with lymph node-positive should be given as long as trastuzumab (Herceptin) treatment. However, lymph node-negative tumors larger than 1cm, also proposes to give trastuzumab (Herceptin) treatment. But the organization well-differentiated tubular carcinoma and mucinous carcinoma, regardless of how the lymph nodes and tumor size, are not recommended Herceptin treatment.
(2) HER1 inhibitor
To HER1 Targeted small molecule tyrosine kinase inhibitors Arroyo Imatinib (trade name Tarceva) and Gefitinib (trade name Iressa, Iressa), there are macromolecules cetuximab, a monoclonal antibody monoclonal antibody (Cetuximab, C-225). Gefitinib treatment of breast cancer are more pre-clinical studies, but clinical studies show the majority of single-agent gefitinib treatment of recurrent metastatic breast cancer poorer treatment outcomes, Fountzilas G etc. of gefitinib with paclitaxel and carboplatin in combination therapy studies, and achieved 57.3% efficiency, but past Taxol and carboplatin combination therapy reported similar results, that is, after the joint effect of gefitinib has not increased. Reason for the failure of these studies may be that it would not come to the right gefitinib effectively target populations. In lung cancer studies have shown that gefitinib and EGFR gene mutations, copy number-related, so the treatment may require a number of molecular markers to predict the efficacy of individual treatment guidance. Arroyo imatinib in non-small cell lung cancer and pancreatic cancer treatment achieved good efficacy, but also in the treatment of breast cancer are no more positive results were reported. Monoclonal antibody cetuximab clinically proven to be effective for colon and head and neck tumors, in the field of breast cancer treatment with chemotherapy drugs combined studies are in progress.
(3) HER receptor, an inhibitor of multi-target
Lapatinib is the HER1 and HER2 receptor in two small-molecule inhibitors. Pre-clinical studies have shown that by reducing the two kinds of receptor dimers or heterodimers with the type of the tyrosine kinase domain phosphorylation, blocking signal transduction, thereby inhibiting the expression of HER1 or HER2 breast cancer cell line growth, and induction of wither death. Burris and so conducted a Phase I clinical study, a total of 66 patients enrolled, of which 30 cases were patients with recurrence and metastasis, effective in patients with 4 cases (13%), which are all four cases of Herceptin in patients with treatment failure, and 10 cases of After five months median follow-up condition remained stable. Lapatinib a single agent in advanced breast cancer treatment Herceptin failed Phase II study enrolled 41 patients, efficiency of 10% at 16 weeks when 25% of patients in stable condition. 2006 ASCO meeting, reported on a joint Lapatinib Xeloda Xeloda compared with single-agent Phase III clinical study results. The study enrolled HER2-positive, past had received anthracyclines, yew, and Herceptin treatment of breast cancer recurrence and metastasis. Joint group of 160 cases, 161 cases of single-agent group, two groups of patients with similar baseline characteristics. Combination group received treatment Lapatinib 1250mg / day, Xeloda 2000mg/m2, the first 1-14 days. Xeloda monotherapy group dose 2500mg/m2, the first 1-14 days, 3 weeks a cycle. The results showed that the joint group, the median time to progression was 36.9 weeks, single-drug group was 19.7 weeks (hazard ratio 0.51, P = 0.00016). The combination group and single drug group were progression-free survival was 36.9 weeks and 17.9 weeks (hazard ratio 0.48, P = 0.000045). The total efficiency between the two groups no significant (P = 0.113). It is noteworthy that the transfer of the central nervous system combined treatment group than monotherapy group (4 cases and 11 cases). The study provides the first line of refractory breast cancer, new hope. 2006 ASCO session Lapatinib in HER2 overexpressing advanced breast cancer patients with brain metastases in the efficacy of even more exciting. Ongoing research is now enrolled 39 patients, all occurred in the Herceptin treatment of brain metastases, of which 38 patients after radiotherapy progress. Lapatinib receiving treatment (750mg orally 2 / day). The results showed that 2 patients PR, and maintenance therapy were 158 days and 347 days to prove that Lapatinib can penetrate the blood-brain barrier.
