Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy

Furlanetto, Jenny; Möbus, V.; Schneeweiß, Andreas; Rhiem, Kerstin; Tesch, Hans; Blohmer, Jens-Uwe; Lübbe, Kristina; Untch, Michael; Salat, Christoph; Huober, Jens; Klare, Peter; Schmutzler, Rita K.; Couch, Fergus J.; Lederer, Bianca; Gerber, Bernd; Zahm, Dirk M.; Bauerfeind, Ingo; Nekljudova, Valentina; Hanusch, Claus; Jackisch, Christian; Link, Theresa; Hahnen, Eric; Loibl, Sibylle; Fasching, Peter A.

doi:10.1016/j.ejca.2020.12.007

Cited by 7 publications

(6 citation statements)

References 27 publications

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“…Analysing neutrophils counts at their nadir (mid-cycle), our group recently reported that gBRCA1 heterozygotes but not gBRCA2 heterozygotes with breast cancer tend to be associated with a significantly higher rate of developing grade 4 and febrile agranulocytosis during their first cycle of chemotherapy [35]. Our observation is consistent with a recent report highlighting increased haematological toxicity in gBRCA1 but not gBR-CA2 heterozygotes [36]. Furthermore, gBRCA1 heterozygotes require more granulocyte colony-stimulating factor (G-CSF) support than non-heterozygotes [35].…”

Section: Introductionsupporting

confidence: 91%

“…Because haematological cells in gBRCA heterozygotes harbour one defective allele, it has been hypothesised that gBRCA haematological cells could exhibit increased sensitivity to agents inducing DNA-DSBs (e.g., chemotherapy and radiotherapy). Several groups attempted to elucidate this question using mixed breast cancer populations and heterogeneous methodologies, leading to inconsistent results [25][26][27][28][29][30][31][32][33][34][35][36]. Analysing neutrophils counts at their nadir (mid-cycle), our group recently reported that gBRCA1 heterozygotes but not gBRCA2 heterozygotes with breast cancer tend to be associated with a significantly higher rate of developing grade 4 and febrile agranulocytosis during their first cycle of chemotherapy [35].…”

Section: Introductionmentioning

confidence: 99%

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Chemotherapy-related agranulocytosis as a predictive factor for germline BRCA1 pathogenic variants in breast cancer patients: a retrospective cohort study

Lang¹,

Ayme²,

Ming³

et al. 2023

Swiss Med Wkly

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BACKGROUND: Carriers of germline pathogenic variants of the BRCA1 gene (gBRCA1) tend to have a higher incidence of haematological toxicity upon exposure to chemotherapy. We hypothesised that the occurrence of agranulocytosis during the first cycle of (neo-)adjuvant chemotherapy (C1) in breast cancer (BC) patients could predict gBRCA1 pathogenic variants. PATIENTS AND METHODS: The study population included non-metastatic BC patients selected for genetic counselling at Hôpitaux Universitaires de Genève (Jan. 1998 to Dec. 2017) with available mid-cycle blood counts performed during C1. The BOADICEA and Manchester scoring system risk-prediction models were applied. The primary outcome was the predicted likelihood of harbouring gBRCA1 pathogenic variants among patients presenting agranulocytosis during C1. RESULTS: Three hundred seven BC patients were included: 32 (10.4%) gBRCA1, 27 (8.8%) gBRCA2, and 248 (81.1%) non-heterozygotes. Mean age at diagnosis was 40 years. Compared with non-heterozygotes, gBRCA1 heterozygotes more frequently had grade 3 BC (78.1%; p = 0.014), triple-negative subtype (68.8%; p <0.001), bilateral BC (25%; p = 0.004), and agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy (45.8%; p = 0.002). Agranulocytosis and febrile neutropenia that developed following the first cycle of chemotherapy were independently predictive for gBRCA1 pathogenic variants (odds ratio: 6.1; p = 0.002). The sensitivity, specificity, positive predictive value, and negative predictive value for agranulocytosis predicting gBRCA1 were 45.8% (25.6–67.2%), 82.8% (77.5–87.3%), 22.9% (6.1–37.3%), and 93.4% (88.9–96.4%), respectively. Agranulocytosis substantially improved the positive predictive value of the risk-prediction models used for gBRCA1 evaluation. CONCLUSION: Agranulocytosis following the first cycle of (neo-)adjuvant chemotherapy is an independent predictive factor for gBRCA1 detection in non-metastatic BC patients.

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Section: Introductionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Chemotherapy-related agranulocytosis as a predictive factor for germline BRCA1 pathogenic variants in breast cancer patients: a retrospective cohort study

Lang¹,

Ayme²,

Ming³

et al. 2023

Swiss Med Wkly

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“…A recent publication exploring safety issues in the neoadjuvant setting concludes that g BRCA 1/2 mutated patients show a higher risk of hematological toxicity when treated with regimens including a taxane [ 55 ]. On the contrary, our study demonstrates higher adverse hematological AEs with the addition of anthracyclines, PARPi and anti-VEGF to a standard regimen with platin.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of different neoadjuvant treatment regimens in BRCA-mutated triple negative breast cancer: a systematic review and meta-analysis

Caramelo¹,

Silva

Caramelo

et al. 2022

Hered Cancer Clin Pract

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Purpose Triple negative breast cancer (TNBC) is an aggressive breast cancer strongly associated with BRCA mutation. Standard neoadjuvant chemotherapy remains the standard of care for early stage TNBC, the optimal chemotherapy regimen is still a matter of discussion. Other agents, such as poly-ADP-ribosyl polymerase inhibitors (PARPi) and anti-vascular endothelial growth factor (VEGF) antibodies were evaluated in the neoadjuvant setting. This systematic review and meta-analysis intend to evaluate the impact of neoadjuvant treatments in pCR rates in TNBC gBRCA mutation, beyond traditional standard chemotherapy. Methods PubMed, Clinicaltrials.gov, Cochrane CENTRAL, Embase and key oncological meetings for trials were searched for studies reporting neoadjuvant chemo-immunotherapy in BRCA positive TNBC. Results Out of 1238 records reviewed, thirty-one trials were included, resulting in a total 619 BRCA-mutated TNBC patients. In BRCA mutated TNBC patients who received cisplatin in monotherapy the proportion of patients who achieved pCR was 0.53 (95%CI [0.30, 0.76]), and when treatment combined standard chemotherapy and platin derivatives the proportion of pCR increased to 0.62 (95% CI [0.48, 0.76]). The group of patients treated with platin derivatives, anthracyclines ± taxanes achieved the highest proportion of pCR, 0.66. Patients treated with PARPi alone show a pCR proportion of 0.55 (95% CI [0.30, 0.81]); and when standard chemotherapy and platin derivatives were combined with PARPi the proportion of pCR did not vary. Conclusions Patients with BRCA mutated TNBC treated with cisplatin in monotherapy demonstrate inferior proportion in the pCR achievement when compared with standard chemotherapy plus platin derivates. The best pCR was achieved with platin derivates in association with anthracyclines ± taxanes. No difference in pCR was found between PARPi alone vs PARPi with standard chemotherapy.

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“…Huszno et al reported that more frequent neutropenia was detected in breast cancer with BRCA1/2 mutation after one cycle of chemotherapy [50]. Furlanetto et al found that breast cancer with germline BRCA1/2 mutations had higher risk of hematologic toxicities under taxane [51]. Tomao et al demonstrated that germline BRCA1/2 mutations were associated with higher hematologic toxicity for ovarian cancer undergoing platinumbased chemotherapy [49].…”

Section: Discussionmentioning

confidence: 99%

Association of Neo-Family History Score with pathological complete response, safety, and survival outcomes in patients with breast cancer receiving neoadjuvant platinum-based chemotherapy: An exploratory analysis of two prospective trials

Xu¹,

Lin²,

Wang³

et al. 2021

eClinicalMedicine

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Background: Homologous recombination deficiency is associated with platinum-based chemosensitivity, whereas few studies reported the predictive value of family history of cancer for breast cancer in the neoadjuvant setting. This study aimed to construct a novel family history scoring system and to explore its association with clinical outcomes for patients with breast cancer receiving neoadjuvant platinum-based chemotherapy. Methods: This study included 262 patients with locally advanced breast cancer enrolled in the SHPD001 and SHPD002 trials from October 2013 to June 2018. The Neo-Family History Score (NeoFHS) was calculated according to cancer type, age at diagnosis, kinship, and number of affected relatives. Findings: Clinical tumor stage (p=0¢048), estrogen receptor status (p=0¢001), progesterone receptor status (p=0¢036), human epidermal growth factor receptor 2 status (p=0¢013), and molecular subtype (p=0¢016) were significantly related to NeoFHS. NeoFHS could serve as an independent predictive factor of pathological complete response (pCR) (OR=2¢262, 95% CI 1¢159-4¢414, p=0¢017) and an independent prognostic factor of relapse-free survival (adjusted HR=0¢305, 95% CI 0¢102-0¢910, p=0¢033). Alopecia (p=0¢001), nausea (p=0¢001), peripheral neuropathy (p=0¢018), diarrhea (p=0¢026), constipation (p=0¢037) of any grade and leukopenia of grade 3 or greater (p=0¢005) were more common in patients with higher NeoFHS. Interpretation: NeoFHS is a practical and effective biomarker for predicting not only pCR and survival outcomes but also chemotherapy-induced adverse events for neoadjuvant platinum-based chemotherapy in breast cancer. It may help screen candidate responders and guide safety managements.

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Germline BRCA1/2 mutations and severe haematological toxicities in patients with breast cancer treated with neoadjuvant chemotherapy

Cited by 7 publications

References 27 publications

Chemotherapy-related agranulocytosis as a predictive factor for germline BRCA1 pathogenic variants in breast cancer patients: a retrospective cohort study

Chemotherapy-related agranulocytosis as a predictive factor for germline BRCA1 pathogenic variants in breast cancer patients: a retrospective cohort study

Efficacy of different neoadjuvant treatment regimens in BRCA-mutated triple negative breast cancer: a systematic review and meta-analysis

Association of Neo-Family History Score with pathological complete response, safety, and survival outcomes in patients with breast cancer receiving neoadjuvant platinum-based chemotherapy: An exploratory analysis of two prospective trials

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