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December 2020: Effect of germline BRCA1/2 mutations on haematological toxicities after neoadjuvant chemotherapy.


A retrospective analysis investigating the effect of germline BRCA1/2 mutations on severe haematological toxicities in TNBC patients treated with chemotherapy has been published in European Journal of Cancer.

BRCA1 and BRCA2 proteins are involved in the homologous recombination (HR), playing a crucial role in DNA repair of double-strand breaks. Germline (g)BRCA1/2 mutations are associated with increased sensitivity to chemotherapy leading to higher pathologic complete response (pCR) rates and better disease-free survival in the neoadjuvant setting. This increase in efficacy may also result in increased toxicity. Hypothetically, the amount of functional protein in patients with gBRCA1/2 mutation could be too low to ensure adequate DNA repair of the damage caused by cytotoxic agents, leading to higher rates of haematological toxicities compared with wild-type patients. The aim of this study was to investigate the effect of gBRCA1/2 mutations on severe haematological toxicities in patients with early triple-negative breast cancer (TNBC) receiving anthracycline-taxane-based neoadjuvant chemotherapy.

Overall, 1171 patients with TNBC and known gBRCA1/2 status from three GBG randomised neoadjuvant trials (GeparQuinto, GeparSixto and GeparOcto) were included in the analysis. All patients had received at least one dose of chemotherapy. Haematological toxicities were defined based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0. Primary objective was the rate of neutropenia grade (G) III-IV in cycle 1. Secondary objectives included effects on overall and other haematological toxicities GIII-IV in cycle 1, cumulative haematological toxicity across all cycles, relative total dose intensity, and granulocyte-colony stimulating factor (G-CSF) prophylaxis. Haematological toxicities under taxanes, carboplatin, and cyclophosphamide were also analyzed. Overall, 209 (17.8%) patients had gBRCA1/2 mutations; 37.1% of patients with gBRCA1/2 mutations versus 48.5% wildtype received primary G-CSF prophylaxis (p=0.088), and 39.6% with gBRCA1/2 mutations versus 39.2% wildtype patients received secondary G-CSF prophylaxis (p=1.000). Relative total dose intensity was analyzed in 674 patients enrolled in the GeparSixto and GeparOcto study (gBRCA1/2 mutations N=118, wild-type N=556). Of all, 38.1% of patients with gBRCA1/2 mutations versus 44.2% wild-type received full dose of chemotherapy (p=0.260). In the first cycle, 37.4% of patients with gBRCA1/2 mutations versus 35.7% wild-type had neutropenia GIII-IV (p=0.683); gBRCA1/2 mutations predicted neither for neutropenia GIII-IV (OR 1.26, [95% CI 0.87-1.82], p=0.226) nor for other haematological toxicities GIII-IV (OR 0.91 [95% CI 0.64-1.31], p=0.625) in multivariable regression models. Analyses of cumulative toxicities across all cycles yielded similar results except thrombocytopaenia GIII-IV, which was increased in patients with gBRCA1 mutation compared to wild-type (10.7% versus 6.1%, p=0.034). In patients treated with taxanes, the rate of haematological toxicities GIII-IV was higher in patients with gBRCA1/2 mutations compared to wild-type (59.5% versus 43.1%; p<0.001). In the multivariate analysis, gBRCA1/2 mutation was predictive for severe haematological toxicities (OR 2.91 [95% CI 1.55-5.45]; p=0.001), especially severe leucopenia, neutropenia and thrombocytopaenia. No difference was seen under cyclophosphamide or platinum-containing chemotherapies.
In conclusion, gBRCA1/2 mutations were not associated with higher risk of overall severe haematological toxicities in the first cycle or cumulatively across all cycles under standard chemotherapy for TNBC. In particular, the difference in febrile neutropenia was negligible. These findings suggested that patients with gBRCA1/2 heterozygous mutations have an adequate haematopoietic regenerative capacity. However, under taxane, patients with gBRCA1/2 mutations might have a higher risk of haematological toxicities GIII-IV, requiring further research.

Furlanetto J, Möbus V, Schneeweiss A, et al. Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy. Eur J Cancer. 2021 Jan 7;145:44-52.


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