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Ann Oncol. 2018 Oct 18. doi: 10.1093/annonc/mdy460. [Epub ahead of print]

Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response - final results from GeparSixto.

Author information

1
German Breast Group, Neu-Isenburg, Germany.
2
Myriad Genetics Inc., Salt Lake City, UT, USA.
3
The Permanente Medical Group, Inc., Oakland, CA, USA.
4
Center for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, Germany.
5
Department of Gynecology and Obstetrics, University Hospital Erlangen, Germany.
6
Institute of Pathology, Charité University Hospital and German Cancer Consortium (DKTK), Berlin, Germany.
7
National Center for Tumor Diseases, University Hospital Heidelberg.
8
Brustzentrum, Sana Kliniken Offenbach, Germany.
9
Hämatoonkologische Schwerpunktpraxis, Munich, Germany.
10
Luisenkrankenhaus Düsseldorf, Germany.
11
Klinik für Gynäkologie mit Brustzentrum, Charité, Berlin, Germany.
12
Brustzentrum, SRH Waldklinikum Gera, Germany.
13
Frauenklinik, Universität Rostock, Germany.
14
Praxisklinik Berlin, Germany.
15
Breast Unit, Kliniken Essen-Mitte, Essen, Germany.
16
Mammazentrum am Krankenhaus Jerusalem, Hamburg, Germany.
17
Klinikum rechts der Isar der Technischen Universität München, Frauenklinik,München, Germany.
18
GRAIL, Menlo Park, CA, USA.
19
Helios-Klinikum, Berlin-Buch, Berlin, Germany.

Abstract

Background:

In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD).

Patients and Methods:

Patients were randomized to paclitaxel plus non-pegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study endpoints disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in FFPE tumor samples of 193/315 (61.3%) participants with TNBC. HR deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA).

Results:

A significantly better DFS (hazard ratio 0.56, 95%CI 0.34-0.93; P=0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) (odds ratio (OR) 2.60, 95%CI 1.26-5.37, P=0.008). Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P=0.001), but only marginally in HR non-deficient tumors (from 20.0% to 29.6%, P=0.540; test for interaction P=0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P=0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR non-deficient (hazard ratio 0.44, 0.17-1.17, P=0.086) and HR deficient tumors (hazard ratio 0.49, 0.23-1.04, P=0.059).

Conclusions:

The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.

PMID:
30335131
DOI:
10.1093/annonc/mdy460

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