Response-guided neoadjuvant chemotherapy prolonged DFS in early-stage breast cancer

Issue: November 25, 2013

Response-guided neoadjuvant chemotherapy may improve survival in patients with early-stage breast cancer, particularly women with hormone receptor-positive tumors, according to results of a phase 3 study.

Perspective from Douglas Yee, MD

The GeparTrio study included 2,072 patients with early breast cancer were assigned to two cycles of docetaxel, doxorubicin and cyclophosphamide (TAC).

Patients who demonstrated an early response then were randomly assigned to four (n=704) or six (n=686) additional TAC cycles. Nonresponders were assigned to four TAC cycles (n=321) or vinorelbine and capecitabine (Xeloda, Hoffmann-LaRoche; n=301) prior to surgery.

Median follow-up was 62 months.

Among early responders, those assigned to eight total cycles of TAC demonstrated a higher rate of DFS compared with those who underwent the conventional six total cycles (HR=0.78; 95% CI, 0.62-0.97).

Results of an exploratory analysis suggested OS and DFS were prolonged among those who received response-guided therapy (HR=0.71; 95% CI, 0.60-0.85) compared with those who received conventional therapy (HR=0.79; 95% CI, 0.63-0.99).

Researchers reported extended DFS after response-guided therapy among all patients with hormone receptor-positive tumors, with HRs of 0.55 for luminal A tumors, 0.40 for luminal B tumors, and 0.56 for luminal B, HER-2–positive tumors. Researchers did not observe improved DFS among patients with hormone receptor-negative tumors, with HRs of 1.01 for HER-2–positive, nonluminal tumors, and 0.87 for triple-negative tumors.

Pathologic complete response predicted improvements in DFS among patients with triple-negative (HR=6.67), HER-2–positive (HR=5.24) and HER-2–negative tumors (HR=3.74), according to researchers.

Responders who received eight cycles of TAC demonstrated a trend toward longer OS compared with those who received the conventional six cycles (HR=0.76; 95% CI, 0.57-1.01). Nonresponders who were assigned to vinorelbine and capecitabine demonstrated no OS advantage compared with those who received six total TAC cycles (HR=0.85; 95% CI, 0.57-1.27). Response-guided chemotherapy conferred a significant but marginal OS benefit compared with conventional chemotherapy (HR=0.79; 95% CI, 0.63-0.99), according to researchers.

“Because treatment effect was mainly observed in hormone receptor-positive tumors, 5-year follow-up was probably too short to show similar effects on OS, which is longer in such patients,” researchers wrote.

In an accompanying editorial, Melinda L. Telli, MD, of the Stanford University School of Medicine, said the unexpected finding — that response-guided therapy influences DFS in HR-positive breast cancer but not HR-negative disease — emerged from a secondary exploratory subgroup analysis and must be interpreted with caution.

“The challenge now is to put this result in the appropriate context,” Telli wrote. “As we look to the future, does this result provide important insight or leave us more confused? Does response-guided chemotherapy lead to improved outcomes only in patients who are, in principle, the least chemosensitive?”

Results of the exploratory analysis suggest that intensifying treatment in responders, or switching nonresponders to vinorelbine and capecitabine, did not affect long-term outcomes, Telli noted.

“Though we still lack effective targeted therapies for this group of patients, we now understand that this group of patients is highly heterogeneous, and emerging data suggest that DNA-damaging chemotherapeutic approaches may be particularly effective in some triple-negative breast cancers with underlying DNA repair defects,” Telli wrote. “We can only speculate as to whether the results would have been different if nonresponders [were] sequenced on to a different chemotherapy combination. Nonetheless, this result strongly suggests that the answers we are seeking in triple-negative breast cancer lie beyond standard chemotherapy.”

For more information:

Telli ML. J Clin Oncol. 2013;doi:10.1200/JCO.2013.51.0313.
Von Minckwitz G. J Clin Oncol. 2013;doi:10.1200/JCO.2013.51.0313.

Disclosure: The researchers report research funding and honoraria from, consultant or advisory roles with, or stock ownership in Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Genomic Health International, GlaxoSmithKline, Novartis, Roche, Sanofi-Aventis and Sividon Diagnostic. Telli reports no relevant financial disclosures.

Perspective

Douglas Yee, MD

The GeparTrio study reported by von Minckwitz and colleagues asked a key question in the neoadjuvant treatment of breast cancer: When is it appropriate to “switch horses in midstream?” Pre-surgical systemic therapy (TAC) was utilized for women with high-risk breast cancer, defined as tumor greater than 2 cm, with one or more other poor risk factors (young age, hormone receptor (HR) negative, clinically involved axillary nodes, or undifferentiated tumor grade). After two cycles, tumors were determined to be responders or nonresponders.

Although the technique for determining response (>50% reduction in two largest perpendicular diameters) was not standardized — clinical, radiographic or ultrasonographic methods were all acceptable — the nonresponders were randomly assigned to receive the same TAC therapy or switch to vinorelbine and capecitabine (NX) for four cycles. For responders, patients were assigned to receive a total of eight cycles of TAC vs. six cycles. The “response-guided” therapy arms were defined as the TACx8 arm for the responders (two extra “bonus” cycles) and the TAC-NX therapy for the nonresponders (“midstream” switch).

Although there was an improvement in DFS for the response-guided therapy group, it was disappointing that the OS benefits were quite modest. For the responders, the two additional cycles of TAC did not result in a statistically significant improvement in OS. Similarly, the addition of the NX regimen to the nonresponders did not improve OS. However, when the response-guided therapy was applied to entire cohort, there was a “marginal OS benefit” compared with TACx6.

The authors also explored whether subgroups of breast cancer benefitted from the response-guided therapy. Surprisingly, they discovered that response-guided therapy was most beneficial in prolonging DFS for HR-positive tumors, and there was no benefit in the HR-negative and nonluminal tumors. As with other studies, pathologic complete response (pCR) did not predict benefit in HR-positive breast cancer, whereas achieving a pCR in HR-negative tumors improved DFS. However, response-guided therapy did not increase the probability of achieving a pCR.

The authors should be congratulated for completing a large phase 3 study of response-guided neoadjuvant therapy, but unfortunately, the results were negative: Response-guided therapy did not increase OS. Although subgroup analysis revealed some potential interesting leads, the study was not designed to test hypotheses in specific subgroups. As the authors clearly state, their analyses “strongly suggest that the various breast cancer phenotypes require different chemotherapy approaches.” It could also be added that better response criteria are needed to know when to switch therapies. Anatomic response is only a poor surrogate for biological response; other technologies (functional imaging, genomic and proteomic analysis, proliferation and apoptotic markers, etc) could all be employed to identify a meaningful immediate surrogate response that correlates with OS.

Moreover, just switching isn’t enough. We need to switch to therapies that address a specific vulnerability of the nonresponding tumor. Although NX is different and noncross-resistant compared with TAC, there is no compelling reason for NX to address the biological properties of TAC-resistant tumors. It is just different cytotoxic chemotherapy. Treating tumor biology is key — witness the success of adding systemic HER-2–targeted therapy in the neoadjuvant setting, where the addition of trastuzumab increases both pCR and DFS (Gianni L. Lancet. 2010;375:377-384). Recently, the FDA’s Oncology Drug Advisory board recommend a new neoadjuvant indication for pertuzumab (in combination with trastuzumab and docetaxel) based on the increased pCR rate observed in the NEOSPHERE and TRYPHAENA trials. Thus, the remaining challenge is not to just switch, but to switch to a strategy that will address the underlying cellular and molecular features of the tumor to target to increase pCR. Despite the limitations of this study, one thing is clear: The only way to effectively switch horses is in the neoadjuvant setting. We just need to know which horse to get on.

Douglas Yee, MD

HemOnc Today Editorial Board member

Disclosures: Yee reports no relevant financial disclosures.