Highlights
- •gBRCA1/2 mutation did not increase overall toxicities after the first or all cycles.
- •gBRCA1/2 mutation did not affect severe haematological toxicities.
- •Difference in febrile neutropenia according to gBRCA status was negligible.
- •Severe thrombocytopaenia was increased in the subgroup of gBRCA1-mutant patients.
- •gBRCA1/2 mutation status did not impact the total dose intensity of chemotherapy.
Abstract
Background
BRCA1 and BRCA2 play a central role in DNA repair. Therefore, patients harbouring germline (g) BRCA1/2 mutations (m) treated with chemotherapy might be at higher risk of haematological toxicities.
Methods
Patients from German Breast Group (GBG) and Arbeitsgemeinschaft Gynäkologische Onkologie-breast
group studies with early triple-negative breast cancer (TNBC) and known gBRCA1/2m status treated with anthracycline-taxane-based neoadjuvant chemotherapy were analysed.
Primary objective was the rate of neutropenia grade (G)III–IV in cycle 1 (C1). Secondary
objectives included effects on overall and other haematological toxicities GIII-IV
in C1, cumulative haematological toxicity across all cycles, relative total dose intensity,
and granulocyte-colony stimulating factor prophylaxis. Haematological toxicities under
taxanes, carboplatin, and cyclophosphamide were explored.
Results
Two hundred nine of 1171 (17.8%) evaluated patients had gBRCA1/2m. In C1, 37.4% gBRCA1/2m versus 35.7% wild-type patients had neutropenia GIII-IV (P = 0.683). For C1, gBRCA1/2m predicted neither for neutropenia GIII-IV (odds ratio [OR]: 1.26, 95% confidence
intervals [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 gBRCA1m patients. In patients treated with taxanes, the rate of haematological toxicities
GIII-IV was higher in gBRCA1/2m compared with wild-type (59.5% versus 43.1%; p < 0.001). No difference was seen
under cyclophosphamide or platinum-containing chemotherapies.
Conclusions
gBRCA1/2m was not associated with higher risk of overall severe haematological toxicities
in the first cycle or cumulatively across all cycles under standard chemotherapy for
TNBC. Under taxane, patients with gBRCA1/2m might have a higher risk of haematological toxicities GIII-IV, requiring further
research.
Keywords
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References
- BRCA2 is required for homology-directed repair of chromosomal breaks.Mol Cell. 2001; 7: 263-272
- Genome maintenance mechanisms for preventing cancer.Nature. 2001; 411: 366-374
- Comprehensive molecular portraits of human breast tumours.Nature. 2010; 490: 61-70
- German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history.BMC Canc. 2018; 18: 265
- Germline mutation status and therapy response in high-risk early-stage 2 breast cancer: a secondary analysis of the GeparOcto randomized clinical trial.JAMA Oncol. 2020; 1 (6): 744-748
- Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response-final results from GeparSixto.Ann Oncol. 2018; 29: 2341-2347
- BRCA1/2 mutations and bevacizumab in the neoadjuvant treatment of breast cancer: response and prognosis results in patients with triple-negative breast cancer from the GeparQuinto study.J Clin Oncol. 2018; 36: 2281-2287
- Distinct Brca1 mutations differentially reduce hematopoietic stem cell function.Cell Rep. 2017; 18: 947-960
- Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia.Blood Rev. 2017; 31: 93-99
- Brca1 deficiency causes bone marrow failure and spontaneous hematologic malignancies in mice.Blood. 2016; 127: 310-313
- Hematologic toxicity in BRCA1 and BRCA2 mutation carriers during chemotherapy: a retrospective matched cohort study.Cancer Med. 2019; 8: 5609-5618
- BRCA1/BRCA2 germline mutations and chemotherapy-related hematological toxicity in breast cancer patients.Breast Canc Res Treat. 2019; 174: 775-783
- BRCA mutation status is not associated with increased hematologic toxicity among patients undergoing platinum-based chemotherapy for ovarian cancer.Int J Gynecol Canc. 2018; 28: 69-76
- Acute chemotherapy-related toxicity is not increased in BRCA1 and BRCA2 mutation carriers treated for breast cancer in the United Kingdom.Clin Canc Res. 2006; 12: 7033-7038
- Is BRCA mutational status a predictor of platinum-based chemotherapy related hematologic toxicity in high-grade serous ovarian cancer patients?.Gynecol Oncol. 2019; 154: 138-143
- Toxicity of (neo)adjuvant chemotherapy for BRCA1- and BRCA2-associated breast cancer.Breast Canc Res Treat. 2016; 156: 557-566
- The influence of BRCA1/BRCA2 mutations on toxicity related to chemotherapy and radiotherapy in early breast cancer patients.Oncology. 2013; 85: 278-282
- Chemotherapy toxicity in BRCA mutation carriers undergoing first-line platinum-based chemotherapy.Oncol. 2019; 24: e1471-e1475
- Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer.N Engl J Med. 2012; 366: 299-309
- Neoadjuvant chemotherapy with paclitaxel and everolimus in breast cancer patients with non-responsive tumours to epirubicin/cyclophosphamide (EC) ± bevacizumab - results of the randomised GeparQuinto study (GBG 44).Eur J Canc. 2013; 49: 2284-2293
- Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial.Lancet Oncol. 2014; 15: 747-756
- Germline mutation status, pathological complete response, and disease-free survival in triple-negative breast cancer: secondary analysis of the GeparSixto randomized clinical trial.JAMA Oncol. 2017; 3: 1378-1385
- dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for neoadjuvant treatment of high-risk early breast cancer (GeparOcto-GBG 84): a randomised phase III trial.Eur J Canc. 2019; 106: 181-192
https://www.ago-online.de/leitlinien-empfehlungen/leitlinien-empfehlungen/kommission-mamma assessed 27.08.2020.
- Direct effect of Taxol on free radical formation and mitochondrial permeability transition.Free Radic Biol Med. 2001; 31: 548-558
- Clinical outcome and toxicity from taxanes in breast cancer patients with BRCA1 and BRCA2 pathogenic germline mutations.Breast J. 2020; 26: 1572-1582
- Targeting BRCA deficiency in breast cancer: what are the clinical evidences and the next perspectives?.Cancers. 2018; 10: 506
- Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance).J Clin Oncol. 2015; 33: 13-21
- Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial.Lancet Oncol. 2018; 19: 497-509
Article Info
Publication History
Published online: January 07, 2021
Accepted:
December 4,
2020
Received in revised form:
December 2,
2020
Received:
October 1,
2020
Identification
Copyright
© 2020 Elsevier Ltd. All rights reserved.
