GeparQuattro: Neoadjuvant trastuzumab improved response rate for HER-2–positive breast cancer

Trastuzumab, when added to anthracycline-taxane–based neoadjuvant chemotherapy, resulted in a high rate of pathologic complete response in patients with HER-2–positive breast cancer, results from the German GeparQuattro study showed.

A separate analysis of GeparQuattro data demonstrated that capecitabine (Xeloda, Hoffmann La Roche) did not confer a similar benefit when added to chemotherapy with epirubicin and cyclophosphamide.

GeparQuattro is a phase-3 trial looking into the effect of simultaneous or sequential capecitabine with docetaxel administered after epirubicin/cyclophosphamide and simultaneous trastuzumab on pathologic complete response of previously untreated stage I to stage III breast cancers. Both sets of results were recently published online in the Journal of Clinical Oncology.

In the first study, Untch and colleagues evaluated 1,509 patients with an indication for enoadjuvant chemotherapy. All patients were assigned to four cycles of epirubicin/cyclophosphamide and then randomly treated with four cycles of 100 mg/m² docetaxel (Group A), or 75 mg/m² docetaxel plus 1,800 mg/m² capecitabine (Group B, concomitant arm) or 75 mg/m² docetaxel, followed by four cycles of 1,800 mg/m² capecitabine (Group C, sequential arm).

Patients with HER-2–positive tumors (n=445) received 6 mg/kg IV trastuzumab (Herceptin, Genentech) every three weeks concomitant with all chemotherapy cycles.

The researchers observed pathologic complete response (no invasive tumor cells in the breast and the axilla) in 31.7% of patients with HER-2–positive disease treated with trastuzumab compared with 15.7% in the HER-2–negative group. Sensitivity analysis showed that 34.7% of patients with HER-2–positive tumors had pathologic complete response. An additional 14.2% of those patients and 5.2% of patients with HER-2–negative disease showed only in situ residuals at surgery.

In summary, the researchers found no invasive residual tumor in the breast and no histologic nodal involvement in 40% of patients in the HER-2–positive group vs. 17.3% in the HER-2–negative reference group after neoadjuvant therapy. There was no evidence of nodal involvement in 70.3% of patients in the HER-2–positive group vs. 52.3% in the HER-2–negative reference group.

“In patients with no change in tumor diameter measured by ultrasonography after four cycles of [epirubicin/cyclophosphamide], the [pathologic complete response] rate in HER-2–positive group was five times of that in the HER-2–negative reference group (16.7% vs. 3.3%),” the researchers wrote.

In a second analysis with the same cohort, von Minckwitz and colleagues found no difference in the pathologic complete response rate when capecitabine was added to chemotherapy in the intent-to-treat population or by the per-protocol analysis.

Researchers observed pathologic complete response in 22.3% of 471 patients randomly assigned to Group A, 19.5% of 471 patients assigned to Group B and 22.3% of 479 patients assigned to Group C.

“The difference in [pathologic complete response] between the regimens with and without capecitabine was 2.8% (95% CI, 2.4%-8%),” the researchers wrote.

Researchers observed no invasive residual in the breast and lymph nodes at nearly identical rates among the HER-2 negative groups; 25.7% in Group A, 25.3% in Group B and 26.3% in Group C. Patients evidenced clinical partial or complete response in 81.3% of Group A, 81.7% of Group B and 77.7% of Group C.

Nearly all patients (98.5%) underwent breast surgery after enoadjuvant therapy. Breast conserving surgery was possible in 67.7% of Group A compared with 66.9% for Group B and 63.5% of Group C.

Untch and colleagues said the addition of trastuzumab did not lead to a clinically relevant increase in toxicity. In contrast, von Minckwitz and colleagues said the addition of capecitabine necessitated a 25% dose reduction in docetaxel to maintain tolerability, from 100 mg/m² to 75 mg/m². Time to progression was similar with the lower dose, but researchers said the response rate was significantly better with the higher dose.

“In conclusion, adding capecitabine to or prolonging duration of neoadjuvant epirubicin/cyclophosphamide plus docetaxel does not result in higher efficacy at surgery but might impair the safety profile of this regimen. Therefore, it cannot be recommended unless the long-term outcome or other ongoing studies . . . show different results,” von Minckwitz and colleagues said.

The pathologic complete remission rate in patients with HER-2 overexpressing tumors in this multicenter trial with the addition of trastuzumab showed that a relatively short treatment with chemo- and antibody therapy is very effective and future trials addressing the duration of trastuzumab have great potential, including the idea of postneoadjuvant targeted treatment in patients without pathologic complete response.

For more information:

• Untch M. J Clin Oncol. 2010;doi:10.1200/JCO.2009.23.8451.
• Von Minckwitz G. J Clin Oncol. 2010;doi:10.1200/JCO.2009.23.8303.

It’s no surprise that adding neoadjuvant trastuzumab results in a higher response rate and a slightly higher pathologic complete response rate. Clearly, in the neoadjuvant setting, in HER-2-neu—positive breast cancer, trastuzumab is clearly beneficial and should be part of the regimens. With capecitabine, they were addressing the question, “In HER-2-neu—negative cancer, is adding more chemotherapy or administering a different class of chemotherapy better?” It looks like the answer is “No” in the case of capecitabine. That doesn’t mean we shouldn’t explore other biological agents, but adding chemotherapy with a different mechanism may not be the way to go.

– Adam M. Brufsky, MD, PhD

Medical Director, Women’s Cancer Center, Magee Women’s Hospital, Pittsburgh