Gerber, Bernd

Abstract Background: BRCA1/2 genes play a central role in DNA repair. Therefore, pts harboring gBRCA1/2m treated with chemotherapy might be at higher risk of acute hematological toxicities due to the lower level of functional BRCA1/2 protein potentially resulting in more toxicity. Published results are discordant, further data are needed. Methods: Pts with early TNBC and known gBRCA1/2m treated with anthracycline-taxane based NACT in the GeparQuinto (n=487), GeparSixto (n=291) and GeparOcto (n=393) studies were included. Primary G-CSF prophylaxis was foreseen only for the iddETC arm in GeparOcto. Primary objective was the rate of neutropenia grade (G)3-4 after cycle 1; secondary objectives were the rate of other hematological toxicities G3-4 and the overall toxicity rate after cycle 1 as well as hematological toxicities in gBRCA1/2 pts during the taxane part of chemotherapy. Results: 209/1171 evaluated pts (17.8%) had a gBRCA1/2m (177 gBRCA1m, 33 gBRCA2m). Median age was 48yrs [21-78]. The rate of neutropenia G3-4 after cycle 1 in gBRCA1/2 wildtype (wt) pts was 35.7% vs 37.4% in gBRCA1/2m (p=0.683), 35.9% in gBRCA1m (p=1.000), 44.8% in gBRCA2m (p=0.330). gBRCA1/2 mutational status did not predict neutropenia G3-4 at univariate (OR=1.08, 95%CI 0.78-1.48 p=0.658) or multivariate analysis adjusted for age, BMI and treatment (OR=1.26, 95%CI 0.87-1.82 p=0.226). The overall rate and the rates of other hematological toxicities are shown in the table. gBRCA1/2 mutational status did also not predict for any other hematological toxicities G3-4 (univariate OR=0.94, 95%CI 0.64-1.40 p=0.773; multivariate OR=0.94, 95%CI 0.62-1.43 p=0.779). gBRCA1/2 mutational status predicted for hematological toxicities G3-4 under taxane treatment (univariate OR=1.94, 95%CI 1.35-2.77 p<0.001; multivariate OR=2.91, 95%CI 1.55-5.45 p=0.001). During taxane treatment, the overall rate of hematological toxicities G3-4 in wt pts was 43.1% (n=270) vs 59.5% (n=91) in gBRCA1/2m, p<0.001; anemia G3-4 2.6% (n=16) vs 3.3% (n=5), p=0.584; leucopenia G3-4 32.7% (n=203) vs 47.1% (n=72), p=0.001; neutropenia G3-4 35.8% (n=219) vs 49.3% (n=73), p=0.003; thrombopenia G3-4 1.4% (n=9) vs 4.6% (n=7), p=0.024; febrile neutropenia 5.9% (n=37) vs 4.6% (n=7), p=0.696. Conclusions: Overall, gBRCA1/2 mutation is not associated with a significantly higher risk of severe hematological toxicities. Under taxane therapy, pts with gBRCA1/2 demonstrate a higher rate of hematological toxicities G3-4, especially neutropenia, compared to wildtype pts, and should therefore be carefully monitored. Hematological toxicities after cycle 1wildtypegBRCA1/2mp-valuegBRCA1mp-valuegBRCA2mp-valueN%N%N%N%neutropenia G3-432635.77437.40.6836135.91.0001344.80.330febrile neutropenia171.831.41.00010.60.33726.10.130leucopenia G3-424425.83818.20.0212815.80.0041030.30.548anemia G3-420.200.01.00000.01.00000.01.000thrombopenia G3-4111.210.50.70510.60.70400.01.000any hematological toxicities G1-477782.617081.70.76314180.10.4533090.90.344any hematological toxicities G3-442846.38843.60.5337241.90.3171651.60.587 Citation Format: Jenny Furlanetto, Volker Möbus, Andreas Schneeweiss, Kerstin Rhiem, Hans Tesch, Jens-Uwe Blohmer, Kristina Lübbe, Michael Untch, Christoph Salat, Jens Huober, Peter Klare, Rita Schmutzler, Fergus J Couch, Bianca Lederer, Bernd Gerber, Dirk-Michael Zahm, Ingo Bauerfeind, Valentina Nekljudova, Claus Hanusch, Christian Jackisch, Theresa Link, Sibylle Loibl, Peter A Fasching. Germline (g)BRCA1/2 mutations (m) and hematological toxicities in patients (pts) with triple negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NACT) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-10-03.

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression‐free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2‐negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre‐planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF‐A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49–3.75), 1.20 (95% CI, 0.88–1.64) and 0.61 (95% CI, 0.34–1.12). Notably, some SNPs in VEGF‐A exhibited a more pronounced effect in the triple‐negative subgroup. Several SNPs in VEGF‐A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.