Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors.

BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.

Exploring the Prescribing Process of Domperidone for Low Milk Supply: A Qualitative Study Among Mothers, IBCLCs, and Family Doctors.

BACKGROUND: When mothers are confronted with milk supply problems, taking domperidone is regularly suggested. However, domperidone has been associated with sudden cardiac death and caution in prescribing is advised. In 2016, a multidisciplinary group of authors from a tertiary academic hospital (Erasmus MC) published a clinical protocol in a leading Dutch physicians' journal to support Dutch family physicians in prescribing domperidone to stimulate lactation. RESEARCH AIM: To explore consumer and health care provider perspectives and experiences regarding the prescribing of domperidone for lactation insufficiency following publication of a national clinical protocol. METHODS: A cross-sectional qualitative study was performed using semi-structured interviews (N = 40) based on a topic list covering the prescribing process. Participants were mothers (n = 18) who had been advised to try domperidone to boost their milk supply between November 2016 and May 2018, their International Board Certified Lactation Consultants (n = 9), and their family physicians (n = 15). Another group of participants (mothers; n = 6) answered short questionnaires. All interviews were recorded, transcribed and analyzed using ATLAS.ti software. The resulting list of codes was organized according to the topics. RESULTS: In the process leading to domperidone use to stimulate lactation, participant family physicians relied on the IBCLC, pharmacist, or mother to guide the prescription of domperidone, often citing the published national clinical protocol as back up. The medical safeguards incorporated in the protocol (e.g., taking medical history, physical exam, performing electrocardiograms, limiting dosage) were usually not implemented. CONCLUSIONS: Though the availability of a national clinical protocol in which the prescribing of domperidone for lactation is supported appeared to increase the willingness of participant family physicians to prescribe, gaps were identified between clinical practice and this clinical protocol for prescribing domperidone.