OzzieSue
10-06-2008, 03:09 PM
HER2 Conversion May Account for Trastuzumab Resistance
Elsevier Global Medical News. 2008 Sept 4, K Wachter
HER2-positive tumors can convert to HER2-negative status in women receiving chemotherapy and the HER2-targeting drug trastuzumab (Herceptin), based on the results of a study of residual tumor tissue from 23 women.
This finding may account for resistance to trastuzumab and the incomplete pathologic response seen in some women.
"We've demonstrated that approximately a third of tumors [in patients who] did not achieve a pathologic complete response will convert from HER2-postive to HER2-negative disease," Dr. Elizabeth A. Mittendorf said during a teleconference held before the start of the American Society of Clinical Oncology's annual Breast Cancer Symposium.
HER2 is overexpressed in about 25%-30% of all breast tumors. These patients have a poor prognosis with a decreased time to relapse and decreased overall survival, noted Dr. Mittendorf of the department of surgical oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
Dr. Mittendorf and her colleagues reviewed clinicopathologic data for 141 patients with HER2-overexpressing breast cancer who were treated at M.D. Anderson between 2004 and 2007. Tumors were determined to be HER2-positive either by demonstrating overexpression of the HER2 protein using immunohistochemistry or by demonstrating amplification of the HER2 gene using fluorescence in situ hybridization (FISH). The women were treated with 12 cycles of weekly paclitaxel (Taxol) with concurrent trastuzumab, followed by four cycles of fluorouracil, epirubicin (Ellence), and cyclophosphamide (Cytoxan), also given with concurrent trastuzumab.
Of 141 patients, 51% achieved pathologic complete response, which was defined as no evidence of invasive disease in the breast and axilla at surgery. At a median follow-up of 10 months, 3% of patients achieving a pathologic complete response experienced a recurrence versus 10% of those achieving less than a pathologic complete response.
Pre- and post-therapy tissue was available for 23 patients with less than a pathologic complete response.
In 16 tumors that were initially HER2-negative, repeat FISH showed that the residual tumor obtained at surgery remained HER2-negative. Seven tumors (30%) that were initially HER2-positive became HER2 negative. The researchers were able to reanalyze the pre-treatment biopsy tissue to confirm initial HER2 amplification of these tumors.
"This could represent a treatment effect in that we've selected out the HER2-negative clones. The HER2-positive clones have been treated and the HER2-negative clones persist," said Dr. Mittendorf. "Alternatively, we're hypothesizing that this could represent a possible mechanism of resistance to trastuzumab therapy."
She added that, "consideration should be given to reassessing HER2 status in the residual tumor of patients, who do not achieve a pathologic complete response, in order to identify those patients that could be enrolled in a clinical trial to further investigate the most appropriate adjuvant therapy for this population."
The researchers reported that they had no significant financial relationships to disclose.
Elsevier Global Medical News. 2008 Sept 4, K Wachter
HER2-positive tumors can convert to HER2-negative status in women receiving chemotherapy and the HER2-targeting drug trastuzumab (Herceptin), based on the results of a study of residual tumor tissue from 23 women.
This finding may account for resistance to trastuzumab and the incomplete pathologic response seen in some women.
"We've demonstrated that approximately a third of tumors [in patients who] did not achieve a pathologic complete response will convert from HER2-postive to HER2-negative disease," Dr. Elizabeth A. Mittendorf said during a teleconference held before the start of the American Society of Clinical Oncology's annual Breast Cancer Symposium.
HER2 is overexpressed in about 25%-30% of all breast tumors. These patients have a poor prognosis with a decreased time to relapse and decreased overall survival, noted Dr. Mittendorf of the department of surgical oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
Dr. Mittendorf and her colleagues reviewed clinicopathologic data for 141 patients with HER2-overexpressing breast cancer who were treated at M.D. Anderson between 2004 and 2007. Tumors were determined to be HER2-positive either by demonstrating overexpression of the HER2 protein using immunohistochemistry or by demonstrating amplification of the HER2 gene using fluorescence in situ hybridization (FISH). The women were treated with 12 cycles of weekly paclitaxel (Taxol) with concurrent trastuzumab, followed by four cycles of fluorouracil, epirubicin (Ellence), and cyclophosphamide (Cytoxan), also given with concurrent trastuzumab.
Of 141 patients, 51% achieved pathologic complete response, which was defined as no evidence of invasive disease in the breast and axilla at surgery. At a median follow-up of 10 months, 3% of patients achieving a pathologic complete response experienced a recurrence versus 10% of those achieving less than a pathologic complete response.
Pre- and post-therapy tissue was available for 23 patients with less than a pathologic complete response.
In 16 tumors that were initially HER2-negative, repeat FISH showed that the residual tumor obtained at surgery remained HER2-negative. Seven tumors (30%) that were initially HER2-positive became HER2 negative. The researchers were able to reanalyze the pre-treatment biopsy tissue to confirm initial HER2 amplification of these tumors.
"This could represent a treatment effect in that we've selected out the HER2-negative clones. The HER2-positive clones have been treated and the HER2-negative clones persist," said Dr. Mittendorf. "Alternatively, we're hypothesizing that this could represent a possible mechanism of resistance to trastuzumab therapy."
She added that, "consideration should be given to reassessing HER2 status in the residual tumor of patients, who do not achieve a pathologic complete response, in order to identify those patients that could be enrolled in a clinical trial to further investigate the most appropriate adjuvant therapy for this population."
The researchers reported that they had no significant financial relationships to disclose.