Primary systemic therapy is the standard of care for locally advanced and inflammatory breast carcinoma, and is progressively more applied also in earlier stages of disease. Nowadays, this strategy can be considered a reasonable alternative to postoperative therapy for all patients who are candidates for adjuvant chemotherapy.In patients with HER2-positive tumors, several trials evaluating adjuvant trastuzumab have shown a clear advantage compared with chemotherapy alone.1-4 Therefore, trastuzumab represents an essential component of the adjuvant treatment of HER2-positive breast cancer. In the preoperative setting, the combination of trastuzumab to sequential chemotherapy with taxanes and anthracyclines resulted in an impressive rate of pathologic complete responses (pCRs),5 which represents a powerful marker of long-term outcome6,7. However, not all the patients equally benefit from trastuzumab therapy, and many different intracellular pathways can contribute to the intrinsic or acquired resistance to HER2 blockade.8 Lapatinib is a smallmolecule dual inhibitor of the tyrosine kinase activity of epidermal growth factor receptor (EGFR) and HER2. The inhibition of these two pathways can affect tumor growth by reducing the EGFR-dependent proliferative stimulus, by restoring apoptosis, and possibly by enhancing sensitivity to chemotherapy.9,10 However, clinical data so far support the activity of lapatinib in patients with HER2-positive/amplified tumors only.11 Furthermore, this agent can also act against tumoral cells that express the truncated form of EGFR and HER2, which are not recognized by antibodies directed to the external domain.12 In metastatic disease, the combination of lapatinib and capecitabine significantly improved the progression- free survival compared with capecitabine alone in patients pretreated with trastuzumab.13 Therefore, lapatinib in combination wtih capecitabine has recently been approved for patients with HER2-positive metastatic breast cancer who have progressed on previous therapy including trastuzumab.The combination trastuzumab/lapatinib is also under development because of the potential additive effect of a combined blockade of the outer and inner part of the HER2 receptor; preliminary safety and activity data seem promising.14 On these premises, the combination of lapatinib with chemotherapy and trastuzumab represents an attractive research tool. Therefore, we have designed a phase II randomized trial to evaluate the activity and safety of chemotherapy plus lapatinib, trastuzumab, or both trastuzumab and lapatinib as preoperative therapy for HER2-positive operable breast cancer.
Preoperative chemotherapy plus lapatinib or trastuzumab or both in HER2-positive operable breast cancer (CHERLOB trial)
FRASSOLDATI, Antonio;
2008
Abstract
Primary systemic therapy is the standard of care for locally advanced and inflammatory breast carcinoma, and is progressively more applied also in earlier stages of disease. Nowadays, this strategy can be considered a reasonable alternative to postoperative therapy for all patients who are candidates for adjuvant chemotherapy.In patients with HER2-positive tumors, several trials evaluating adjuvant trastuzumab have shown a clear advantage compared with chemotherapy alone.1-4 Therefore, trastuzumab represents an essential component of the adjuvant treatment of HER2-positive breast cancer. In the preoperative setting, the combination of trastuzumab to sequential chemotherapy with taxanes and anthracyclines resulted in an impressive rate of pathologic complete responses (pCRs),5 which represents a powerful marker of long-term outcome6,7. However, not all the patients equally benefit from trastuzumab therapy, and many different intracellular pathways can contribute to the intrinsic or acquired resistance to HER2 blockade.8 Lapatinib is a smallmolecule dual inhibitor of the tyrosine kinase activity of epidermal growth factor receptor (EGFR) and HER2. The inhibition of these two pathways can affect tumor growth by reducing the EGFR-dependent proliferative stimulus, by restoring apoptosis, and possibly by enhancing sensitivity to chemotherapy.9,10 However, clinical data so far support the activity of lapatinib in patients with HER2-positive/amplified tumors only.11 Furthermore, this agent can also act against tumoral cells that express the truncated form of EGFR and HER2, which are not recognized by antibodies directed to the external domain.12 In metastatic disease, the combination of lapatinib and capecitabine significantly improved the progression- free survival compared with capecitabine alone in patients pretreated with trastuzumab.13 Therefore, lapatinib in combination wtih capecitabine has recently been approved for patients with HER2-positive metastatic breast cancer who have progressed on previous therapy including trastuzumab.The combination trastuzumab/lapatinib is also under development because of the potential additive effect of a combined blockade of the outer and inner part of the HER2 receptor; preliminary safety and activity data seem promising.14 On these premises, the combination of lapatinib with chemotherapy and trastuzumab represents an attractive research tool. Therefore, we have designed a phase II randomized trial to evaluate the activity and safety of chemotherapy plus lapatinib, trastuzumab, or both trastuzumab and lapatinib as preoperative therapy for HER2-positive operable breast cancer.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
