Neoadjuvant Carboplatin Improves Disease-Free Survival in Triple-Negative Breast Cancer

Gunter von Minckwitz, MD, PhD

Adding carboplatin to neoadjuvant chemotherapy improves disease-free survival (DFS) significantly in women with triple-negative breast cancer (TNBC) but not HER2-positive breast cancer, according to a new analysis of the GeparSixto clinical trial.¹

The favorable impact of carboplatin on DFS in TNBC was predicted by improvement found previously with carboplatin on pathologic complete response (pCR) in GeparSixto, said Gunter von Minckwitz, MD, PhD, at the 2015 San Antonio Breast Cancer Symposium.

“GeparSixto supports the use of carboplatin as part of neoadjuvant treatment in all patients with TNBC,” said Minckwitz, president of the German Breast Group and professor of gynecology, University of Frankfurt, Germany. “Unexpectedly, a strong positive effect of carboplatin on pCR and DFS was observed in patients with wild-type BRCA status.”

Platinum compounds had previously not been thought to be active in patients without germline BRCA mutation.

GeparSixto is a phase II study in which the benefit of adding carboplatin to weekly paclitaxel plus non-pegylated liposomal doxorubicin for 18 weeks was evaluated in 595 women with early breast cancer. Patients with TNBC received concurrent bevacizumab; patients with HER2-positive disease received concurrent trastuzumab. After 330 patients were enrolled, the carboplatin dose was reduced from area under the curve (AUC) 2.0 to AUC 1.5 to improve tolerability.

Carboplatin improved the pCR rate from 36.9% to 53.2% (P = .005) in patients with TNBC, with no statistically significant difference in pCR in the HER2-positive subgroup (36.8% vs 32.8%, respectively; P = .6). The test for interaction by cancer subtype was significant (P = .015).

After a median of 35 months of observation, in the overall study population, DFS was 84.7% in patients randomized to carboplatin compared with 81.0% in the control arm (P = .3115).

When the patients with HER2-positive breast cancer were analyzed separately, there was again no different in the rate of DFS between the carboplatin and control arms (83.4% vs 86.7%; P = .3719).

In contrast, the results in TNBC showed a significant improvement in DFS with the addition of carboplatin to chemotherapy compared with controls (85.8% vs 76.1%; HR, 0.56; P = .0350). The test for interaction for the endpoint of DFS by disease subtype was again significant (P = .046).

Fifty patients in the study had known germline BRCA mutations. In assessing pCR rates by germline BRCA status, in patients with BRCA wild-type, the odds ratio (OR) for pCR was 2.09 in favor of carboplatin treatment compared with controls (50.8% vs 33.1%; P = .005). In the BRCA-mutant patients, the OR for pCR was 1.6 in favor of carboplatin, but the difference was not statistically significant (61.5% vs 50.0%; P = .413).

The DFS analysis by germline BRCA status was similar to the pCR findings in that carboplatin improved DFS in patients with BRCA wild-type disease but not in BRCA-mutant tumors. “My hypothesis why carboplatin does not add efficacy in the BRCA-mutant tumors is because highly DNA unstable tumors maybe get enough DNA-damaging treatment already in the control arm with the doxorubicin,” said von Minckwitz. “From that, you can hypothesize that maybe another DNA-damaging agent like cyclophosphamide could also have the same effect in the wild-type patients as carboplatin.”

The favorable prognosis after pCR was confirmed and was independent of germline BRCA status. “The DFS effect of carboplatin was correctly predicted by its extensive effect on pCR, and this trial is therefore supporting the surrogacy of pCR,” von Minckwitz said. “The effect on pCR and DFS and the size of the study is very much comparable to the NOAH study,² where also trastuzumab showed in a small neoadjuvant study a significant large increase in pCR rate and an improvement in DFS, and that was later then confirmed by the large adjuvant trastuzumab studies.”

References

1. von Minckwitz G, Loibl S, Schneeweiss A, et al. Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). Presented at the 2015 San Antonio Breast Cancer Symposium; San Antonio, Texas, December 8-12, 2015. Abstract S2-04.
2. Semiglazov V, Eiermann W, Zambetti M, et al. Surgery following neoadjuvant therapy in patients with HER2- positive locally advanced or inflammatory breast cancer participating in the NeOAdjuvant Herceptin (NOAH) study. Eur J Surg Oncol. 2011;37(10):856-863.

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