PARP Inhibitors in Breast Cancer: Why, How, and When

Breast cancer is the most common malignancy in young women worldwide, accounting for an estimated 30% of new cancer diagnoses and 25% of cancer deaths. Approximately two thirds of young women with breast cancer have hormone receptor–positive (HR+)/human epidermal growth receptor 2–negative (HER2−) tumors. Numerous studies, primarily in early‐stage breast cancer, have demonstrated that young age is an independent risk factor for more aggressive disease and worse outcomes. Although more limited data are available regarding outcomes in young patients with advanced disease, these age‐related disparities suggest that breast cancer in premenopausal women has distinct clinicopathologic and molecular features that can impact treatment outcomes. Until recently, limited data were available on the intrinsic molecular subtypes and genetics of young patients with HR+/HER2− metastatic breast cancer (mBC). In this review, we explore insights into the clinical and pathologic features of HR+/HER2− mBC in younger women derived from recent clinical trials of the cyclin‐dependent kinase 4/6 inhibitors palbociclib (PALOMA‐3), ribociclib (MONALEESA‐7), and abemaciclib (MONARCH 2) and the implications of these findings for clinical practice, guideline development, and future research. Implications for Practice This review provides clinicians with an overview of emerging data on the unique clinicopathologic and molecular features of hormone receptor–positive/human epidermal growth receptor 2–negative metastatic breast cancer (mBC) in premenopausal women, summarizes findings from the most recent clinical trials of endocrine‐based treatment in this patient population, and explores the implications of these findings for clinical practice, guideline development, and future research. Improved understanding of the key factors influencing disease course and treatment response in premenopausal patients with mBC may lead to more timely incorporation of evidence‐based treatment approaches, thereby improving patient care and outcomes.

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“…These agents currently are recommended as second‐line therapy in HR+ patients with endocrine therapy–refractory disease (Fig. ) .…”

Section: The Evolving Treatment Landscapementioning

confidence: 99%

Hormone Receptor–Positive/Human Epidermal Growth Receptor 2–Negative Metastatic Breast Cancer in Young Women: Emerging Data in the Era of Molecularly Targeted Agents

et al. 2020

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“…In BRCA mutated cancer cells, inhibiting PARP leads to preferential use of other nonconservative error‐prone DNA repair mechanisms, resulting in an accumulation of DNA alterations, and ultimately cell death 146 . Loss of function of the BRCA genes, clinically mostly caused by a germline BRCA mutation, is a prerequisite for the effectiveness of PARP inhibitors 147 . While the majority of BRCA1 ‐related, and to a lesser extent BRCA2‐ related, breast cancers are triple‐negative, 148 PARP inhibition is effective for breast cancers with a germline BRCA mutation, irrespective of HR status 149 .…”

Section: Targeted Therapymentioning

confidence: 99%

Marker assessments inER‐positive breast cancers: old markers, new applications?

Tse

2022

Histopathology

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Evaluation of oestrogen receptor (ER) expression by immunostaining is essential in the pathological assessment of breast cancer. Its expression is intercorrelated with clinicopathological features, molecular typing, and treatment selection. The development of novel therapeutic agents related to ER status, the recent ASCO introduction of an ER-low positive category of breast cancers, and the ever-increasing plethora of diagnostic and theragnostic markers call for a timely update. In this article we aim to review the clinicopathological features of ER-positive breast cancers, with an emphasis on ER-low positive breast cancers, and a focus on updating the (i) assessment, reporting and interpretation of ER immunohistochemical (IHC) staining, (ii) correlations of ER status with other diagnostic and theragnostic markers, and (iii) implications for treatment selection and response. In the face of the developments in IHC and molecular techniques and targeted therapy, ER immunostaining is still expected to remain as the core component of prognostic and theragnostic assessment of breast cancers.

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“…DNA repair inhibitors for oncotherapy fall into several classes, which include poly ( ADP ) ribose polymerase ( PARP ) inhibitors, nucleotide excision repair (NER) inhibitors, DNA-PK inhibitors, MRN , ATM , ATR , CHK1 / 2 inhibitors, RAD51 inhibitors, and base excision repair (BER) inhibitors. PARP inhibitors have demonstrated great promise in the treatment of patients with deficiencies in homologous recombination (HR) DNA repairs, such as those with loss of BRCA1 or BRCA2 function [11,15,16,17,18,19,20]. Nucleotide excision repair inhibitors target more than thirty protein-protein interactions and removes DNA adducts caused by platinum-based chemotherapy [21,22,23,24,25].…”

Section: Introductionmentioning

confidence: 99%

Small Molecule Docking of DNA Repair Proteins Associated with Cancer Survival Following PCNA Metagene Adjustment: A Potential Novel Class of Repair Inhibitors

Peterson

2019

Molecules

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Natural and synthetic small molecules from the NCI Developmental Therapeutics Program (DTP) were employed in molecular dynamics-based docking with DNA repair proteins whose RNA-Seq based expression was associated with overall cancer survival (OS) after adjustment for the PCNA metagene. The compounds employed were required to elicit a sensitive response (vs. resistance) in more than half of the cell lines tested for each cancer. Methodological approaches included peptide sequence alignments and homology modeling for 3D protein structure determination, ligand preparation, docking, toxicity and ADME prediction. Docking was performed for unique lists of DNA repair proteins which predict OS for AML, cancers of the breast, lung, colon, and ovaries, GBM, melanoma, and renal papillary cancer. Results indicate hundreds of drug-like and lead-like ligands with best-pose binding energies less than −6 kcal/mol. Ligand solubility for the top 20 drug-like hits approached lower bounds, while lipophilicity was acceptable. Most ligands were also blood-brain barrier permeable with high intestinal absorption rates. While the majority of ligands lacked positive prediction for HERG channel blockage and Ames carcinogenicity, there was a considerable variation for predicted fathead minnow, honey bee, and Tetrahymena pyriformis toxicity. The computational results suggest the potential for new targets and mechanisms of repair inhibition and can be directly employed for in vitro and in vivo confirmatory laboratory experiments to identify new targets of therapy for cancer survival.

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PARP Inhibitors in Breast Cancer: Why, How, and When

Cited by 6 publications

References 5 publications

Hormone Receptor–Positive/Human Epidermal Growth Receptor 2–Negative Metastatic Breast Cancer in Young Women: Emerging Data in the Era of Molecularly Targeted Agents

Hormone Receptor–Positive/Human Epidermal Growth Receptor 2–Negative Metastatic Breast Cancer in Young Women: Emerging Data in the Era of Molecularly Targeted Agents

Marker assessments inER‐positive breast cancers: old markers, new applications?

Small Molecule Docking of DNA Repair Proteins Associated with Cancer Survival Following PCNA Metagene Adjustment: A Potential Novel Class of Repair Inhibitors

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