Dataset Information

Chemotherapy Regimens Received by Women With BRCA1/2 Pathogenic Variants for Early Stage Breast Cancer Treatment.

ABSTRACT:

Background

Genetic testing is widespread among breast cancer patients; however, no guideline recommends using germline genetic testing results to select a chemotherapy regimen. It is unknown whether breast cancer patients who carry pathogenic variants (PVs) in BRCA1 and/or 2 (BRCA1/2) or other cancer-associated genes receive different chemotherapy regimens than noncarriers.

Methods

We linked Surveillance, Epidemiology, and End Results registry records from Georgia and California to germline genetic testing results from 4 clinical laboratories. Patients who 1) had stages I-III breast cancer, either hormone receptor (HR) positive and HER2 negative or triple negative (TNBC), diagnosed in 2013-2017; 2) received chemotherapy; and 3) were linked to genetic results were included. Chemotherapy details were extracted from Surveillance, Epidemiology, and End Results text fields completed by registrars. We examined whether PV carriers received more intensive regimens (HR-positive,HER2-negative: ≥3 drugs including an anthracycline; TNBC: ≥4 drugs including an anthracycline and platinum) and/or less standard breast cancer agents (a platinum). All statistical tests were 2-sided.

Results

Among 2293 patients, 1451 had HR-positive, HER2-negative disease, and 842 had TNBC. On multivariable analysis of women with HR-positive, HER2-negative disease, receipt of a more intensive chemotherapy regimen varied statistically significantly by genetic results (P = .02), with platinum receipt more common among BRCA1/2 PV carriers (odds ratio = 2.44, 95% confidence interval = 1.36 to 4.38; P < .001). Among women with TNBC, chemotherapy agents did not vary significantly by genetic results.

Conclusion

BRCA1/2 PV carriers with HR-positive, HER2-negative breast cancer had twofold higher odds than noncarriers of receiving a platinum, as part of a more intensive chemotherapy regimen. This likely represents overtreatment and emphasizes the need to monitor how genetic testing results are managed in oncology practice.

SUBMITTER: Kurian AW

PROVIDER: S-EPMC9305849 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel NaV1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that NaV1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)] and compared them with neurons from an epileptic encephalopathy (EE) patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower NaV1.2 protein levels. In neurons with the frameshift variant, NaV1.2 mRNA and protein levels were reduced by ~ 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying NaV1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced NaV1.2 levels. In contrast, epilepsy neurons displayed no change in NaV1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced NaV1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to NaV1.2 dysfunction and can guide further investigations.