Research on the function of HGH1 in breast cancer remains lacking.

TCGAand GEO (GSE45827) datasets investigated discrepancies in HGH1 expression in BC. An aggregate of 106 clinical samples were gathered through immunohistochemistry, KM curves were drawn for prognostic analysis, and the function of HGH1 of BC was predicted. Finally, the effects of HGH1 knockdown on MDA-MB-231 and MCF-7 BC cells were verified via CCK8, invasion, wound healing and colony formation assays.

HGH1 is highly expressed in BC and is linked to unfavorable prognosis. HGH1 overexpression is connected to keratinization and the cell cycle and is closely related to ER and PR expression and tumor stage in BC patients. Knocking down HGH1 in BC cells inhibited the viability, invasion and migration.

Knockdown of HGH1 in breast cancer cell lines can inhibit the viability, invasion and migration of tumor cells.

Approximately 1 in 10 women diagnosed with breast cancer before the age of 35 carry germline BRCA pathogenic/likely pathogenic variants. Poly (ADP-ribose) polymerase (PARP) inhibitors have been recently approved in the treatment of both early and advanced breast cancer. However, there are no published cases of exposure to PARP inhibitors during pregnancy. Treatment with PARP inhibitors during pregnancy is currently contraindicated and can potentially harm fertility in young women with breast cancer. We here summarize all clinical and preclinical data on the effect of PARP inhibitors on pregnancy, fertility and breast-feeding to provide guidance on their optimal use in women of childbearing potential.

Homologous recombination repair (HRR) is crucial for maintaining genomic stability by repairing DNA damage. Despite its importance, HRR's role in cancer progression is not fully elucidated. Here, this work shows that nuclear-localized branched-chain α-ketoacid dehydrogenase kinase (BCKDK) acts as a modulator of HRR, promoting cell resistance against DNA damage-inducing therapy in breast cancer. Mechanistically, this work demonstrates that BCKDK is localized in the nucleus and phosphorylates RNF8 at Ser157, preventing the ubiquitin-mediated degradation of RAD51, thereby facilitating HRR-mediated DNA repair under replication stress. Notably, aberrant expression of the BCKDK/p-RNF8/RAD51 axis correlates with breast cancer progression and poor patient survival. Furthermore, this work identifies a small molecule inhibitor of BCKDK, GSK180736A, that disrupts its HRR function and exhibits strong tumor suppression when combined with DNA damage-inducing drugs. Collectively, this study reveals a new role of BCKDK in regulating HRR, independent of its metabolic function, presenting it as a potential therapeutic target and predictive biomarker in breast cancer.

Since the introduction of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) as the first-line treatment for metastatic hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative (HR+/HER2-) breast cancer, there has been a significant expansion in the number of therapeutic options for subsequent lines of therapy. Many new agents are being studied, with potential for future regulatory approval. The increased number of therapeutic options raises questions about the optimal selection and sequencing of therapies for individual patients. These advances represent an important clinical challenge in this rapidly evolving field, given the introduction of new therapies targeting various pathways (alone or in combination) and new therapeutic classes being studied.

Recently approved targeted therapies have demonstrated improvements in progression free survival (PFS) for patients whose cancer harbors mutations in the PI3K/AKT pathway, ESR1, BRCA1/2, and/or PALB2. Data to support continuation of CDK4/6 inhibition after progression on a prior CDK4/6i remains mixed, though some studies suggest a subset of patients may benefit from this approach. Several agents with unique mechanisms of action have shown promise in data from early phase trials, and have the potential to enter the treatment lexicon in the coming years. Examples include CDK2- and CDK4-selective inhibitors, complete estrogen receptor antagonists (CERANs), proteolysis targeting chimeras (PROTACs), and next-generation PI3K pathway inhibitors. In this narrative review, we summarize the current and upcoming treatments for metastatic HR+/HER2- breast cancer after progression on a CDK4/6i plus ET, with a focus on the following: an overview of first-line regimens of CDK4/6i plus ET and observed mechanisms of resistance; currently approved second-line therapy options; and upcoming options currently under exploration in clinical trials. We focus primarily on new therapy classes that may offer therapeutic options beyond currently available treatments.

Homologous recombination deficiency (HRD) is a key biomarker associated with increased sensitivity to PARP inhibitors (PARPi) in advanced epithelial ovarian cancer. Accurate identification of HRD status is essential for selecting patients most likely to benefit from these therapies. Current diagnostic approaches combine sequencing to detect mutations in homologous recombination repair genes-particularly BRCA1 and BRCA2-with genome-wide analysis of structural genomic alterations indicative of HRD. This review briefly outlines the biological basis of HRD and its clinical significance and then focuses on currently available assays for HRD assessment. We compare their molecular strategies, including the use of targeted gene panels and genomic instability metrics such as loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions. The review also highlights the strengths and limitations of each platform and discusses their role in guiding clinical decision-making. Challenges related to dynamic tumor evolution and the interpretation of HRD status in recurrent disease settings are also addressed.

Background: Niraparib is an oral poly (adenosine diphosphate-ribose) polymerase inhibitor with promising activity for patients with advanced breast cancer harboring germline BRCA1/2 mutations. Methods: LUZERN (NCT04240106) was a multicenter, open-label, Simon's two-stage, phase II clinical trial evaluating the efficacy and safety of niraparib with aromatase inhibitors (AIs) for patients with HR-positive/HER2-negative advanced breast cancer with either a germline BRCA1/2 mutation (cohort A) or germline BRCA1/2 wild-type and homologous recombination deficiency (exploratory cohort B). Eligible patients received ≤1 line of chemotherapy and 1-2 prior lines of endocrine therapy for advanced disease with secondary resistance to the last AI-based regimen. Patients received niraparib (300 mg or 200 mg) plus an AI. The primary endpoint was the clinical benefit rate (CBR) in cohort A. Results: Between June 2020 and November 2022, 14 patients were enrolled in cohort A (n = 6 for stage I, n = 8 for stage II) and no patients were enrolled in cohort B. One patient was excluded from the efficacy analysis due to no prior AI treatment. Nearly all patients (92.9%) previously received a cyclin-dependent kinase 4/6 inhibitor, but no patients had received prior platinum-based chemotherapy. Median follow-up was 16.7 months (range: 13.2-18.2). The CBR was 46.2% (95% CI: 19.2-74.9), meeting the primary endpoint. Median progression-free survival was 5.5 months (95% CI: 1.9-8.5), and median overall survival was 18.1 months (95% CI: 9.7-NE). The safety profile was consistent with the known toxicity of both drugs. Conclusions: Niraparib combined with an AI has encouraging antitumor activity and a manageable safety profile in patients with AI-resistant HR-positive/HER2-negative advanced breast cancer with germline BRCA1/2 mutations.

Brain metastases (BrM) arising from breast cancer (BC) are an increasing consequence of advanced disease, with up to half of patients with metastatic HER2 + or triple negative BC experiencing central nervous system (CNS) recurrence. The genomic alterations driving CNS recurrence, along with contributions of the immune microenvironment, particularly by intrinsic subtype, remain unclear.

We characterized the genomic and immune landscape of BCBrM from a cohort of 42 patients by sequencing whole-exome DNA (WES) and total RNA libraries from frozen and FFPE BrM and FFPE extracranial tumors (ECT). Analyses included PAM50 intrinsic subtypes, somatic mutations, copy number variations (CNV), pathway alterations, immune cell type deconvolution, and associations with clinical outcomes RESULTS: Intrinsic subtype calls were concordant for the majority of BrM-ECT pairs (60%). Across all BrM and ECT samples, the most common somatic gene mutation was TP53 (64%, 30/47). For patients with matched FFPE BrM-FFPE ECT, alterations tended to be conserved across tissue type, although differential somatic mutations and CNV in specific genes were observed. Several genomic pathways were differentially expressed between patient-matched BrM-ECT; MYC targets, DNA damage repair, cholesterol homeostasis, and oxidative phosphorylation were higher in BrM, while immune-related pathways were lower in BrM. Deconvolution of immune populations between BrM-ECT demonstrated activated dendritic cell populations were higher in BrM compared to ECT. Increased expression of several oncogenic preselected pathways in BrM were associated with inferior survival, including DNA damage repair, inflammatory response, and oxidative phosphorylation CONCLUSIONS: Collectively, this study illustrates that while some genomic alterations are shared between BrM and ECT, there are also unique aspects of BrM including somatic mutations, CNV, pathway alterations, and immune landscape. A deeper understanding of differences inherent to BrM will contribute to the development of BrM-tailored therapeutic strategies. Additional analyses are warranted in larger cohorts, particularly with additional matched BrM-ECT.

Breast cancer is one of the most prevalent malignant tumors worldwide, and triple-negative breast cancer (TNBC) presents a major therapeutic challenge due to the lack of effective targeted treatment options. Poly (ADP-ribose) polymerase (PARP) plays a critical role in DNA damage repair, and its inhibitors have shown significant therapeutic efficacy in patients with TNBC exhibiting breast cancer susceptibility gene (BRCA) mutations. The present review aimed to analyze the molecular mechanisms of cell death induced by DNA damage related to PAR and PARP, thoroughly exploring the role of PARP in regulatory pathways. Additionally, it intended to highlight clinical trials and therapeutic outcomes of PARP inhibitors currently used in TNBC treatment. In particular, the current review delves into the mechanisms of drug resistance, such as BRCA mutation reversion and PARP protein trapping, and examines potential strategies to overcome PARP inhibitor resistance in the future. Ultimately, the present study aims to offer novel perspectives and research directions for further optimizing the application of PARP inhibitors in TNBC therapy.

Despite the advances in cancer prevention, early detection, and treatments, all of which have led to improved cancer survival, globally, there is an increased incidence in cancer-related deaths. Although each patient and each tumor is wholly unique, the tipping point to incurable disease is common across all patients: the dual capacity for cancers to metastasize and resist systemic treatment. The discovery of genetic mutations and epigenetic variation that emerges during cancer progression highlights that evolutionary and ecology principles can be used to understand how cancer evolves to a lethal phenotype. By applying such an eco-evolutionary framework, the authors reinterpret our understanding of the metastatic process as one of an ecologic invasion and define the eco-evolutionary paths of evolving therapy resistance. With this understanding, the authors draw from successful strategies optimized in evolutionary ecology to define strategic interventions with the goal of altering the evolutionary trajectory of lethal cancer. Ultimately, studying, understanding, and treating cancer using evolutionary ecology principles provides an opportunity to improve the lives of patients with cancer.

Poly (ADP-ribose) polymerases (PARPs) are enzymes essential for detecting and repairing DNA damage through poly-ADP-ribosylation. In cancer, cells with deficiencies in homologous recombination repair mechanisms often become more dependent on PARP-mediated repair mechanisms to effectively repair dsDNA breaks. As such, PARP inhibitors (PARPis) were introduced into clinical practice, serving as a key targeted therapy option through synthetic lethality in the treatment of cancers with homologous recombination repair deficiency (HRD). Though PARPis are currently approved in the adjuvant setting for several cancer types such as ovarian, breast, prostate and pancreatic cancer, their potential role in the neoadjuvant setting remains under investigation. This review outlines the rationale for using PARPi in the neoadjuvant setting and evaluates findings from early and ongoing clinical trials.

Our analysis indicates that numerous studies have explored PARPi as a neoadjuvant treatment for HRD-related cancers. The majority of neoadjuvant PARPi trials have been performed in breast and ovarian cancer, while phase II/III evidence supporting efficacy in prostate and pancreatic cancers remains limited. Studies are investigating PARPi in the neoadjuvant setting of HRD-related cancers. Future research should prioritize combination strategies with immune checkpoint inhibitors and expand outcome measures to include patient satisfaction and quality-of-life metrics.

Precision oncology is making remarkable advancements in optimizing patient care by personalizing treatments. To date, the US Food and Drug Administration (FDA) has approved poly(ADP-ribose) polymerase inhibitors (PARPi) olaparib (Lynparza, AstraZeneca and Merck) and talazoparib (Talzenna, Pfizer Oncology Together™) for germline or somatic BRCA1/2-mutated metastatic breast cancer (BC) patients, and PI3K inhibitor alpelisib (Piqray, Novartis) plus fulvestrant for patients with hormone receptor-positive human epidermal growth factor receptor 2-negative (HR+HER2-) PIK3CA-mutated advanced BC. In addition, the FDA approved capivasertib (Trucap, AstraZeneca) for HR+HER2- locally advanced or metastatic BC patients with one or more AKT1, PIK3CA, or PTEN alterations. Finally, the FDA recently approved elacestrant (Orserdu, Stemline Therapeutics, Inc.) for postmenopausal patients with ER+ HER2- ESR1-mutated advanced or metastatic BC with disease progression following at least one line of endocrine therapy.

This study presents a single institutional retrospective review of genomic reports of patients with BC. Analysis of genomic reports of 1361 BC sequencing reports was performed for 1010 patients with BC from 2013 to 2023 (23% of patients had multiple reports). Eligible patients had at least one primary or metastatic tumor. Multiple sequencing platforms were used for FFPE specimens including Tempus xT targeted next-generation sequencing (NGS), Foundation One Medicine, HopeSeq, Ashion Analytics GEM ExTra, and Exact Sciences Oncomap. Liquid biopsies were performed by Guardant, Tempus, and Foundation One Medicine. Chart reviews were performed to collect patient characteristics. BRCA1/2-mutated, metastatic BC patients who initiated treatment with olaparib or talazoparib, and PIK3CA-mutated, HR+ metastatic BC patients who initiated treatment with alpelisib were reported. In addition, patients with ESR1 or AKT1/PIK3CA/PTEN mutations were identified. Clinical outcomes, including progression-free survival (PFS) and overall survival (OS) were analyzed for BRCA1/2 and PIK3CA-mutated patients who received PARPi or alpelisib. Survival curves were generated using the Kaplan Meier method.

A cohort of 1010 BC patients with 1361 genomic reports was identified. A total of 935/1361 (69%) specimens were formalin-fixed paraffin-embedded (FFPE) tumor biopsies and 426/1361 (31%) were liquid biopsies. Receptor status included 65% HR+HER2-, 8% HR+HER2+, 4% HR-HER2+, and 23% TNBC. Racial and ethnic distribution of these patients included 50% non-Hispanic White, 26% Hispanic, 17% Asian, 6% African American, 1% other (Native Hawaiian or Other Pacific Islander, American Indian or Alaska Native, or unknown). Sequencing platforms included 30% Tempus xT, 31% Foundation One, 10% HopeSeq, 20% GEM ExTra, and 9% Exact Sciences. Liquid biopsies included 79% Guardant, 20% Tempus, and 1% Foundation One. Of 1010 patients, the most common mutations were TP53 (44%), PIK3CA (38%), ESR1 (14%), PTEN (12%), CCND1 (11%), FGFR1 (10%), CDH1 (10%), ERBB2 (9%), MYC (9%), FGF3 (8%), GATA3 (8%), FGF19 (8%), FGF4 (7%), ARID1A (6%), RB1 (5%), BRCA2 (5%), MAP3K1 (4%), AKT1 (4%), NF1 (4%), MLL3 (4%), ZNF703 (4%), CDKN2A (4%), BRCA1 (4%), MCL1 (3%), ATM (3%), PALB2 (1%), and CHEK2 (1%). The majority of reports with tumor mutation burden (TMB) results (97%) had low or intermediate TMB. A total of 784 actionable mutations in 1010 patients were reported, including 381/1010 (38%) PIK3CA; 144/1010 (14%) ESR1; 122/1010 (12%) PTEN; 48/1010 (5%) BRCA2; 36/1010 (4%) BRCA1; 41/1010 (4%) AKT1; and 12/1010 (1%) PALB2. Of the 96/1010 (10%) patients with BRCA1, BRCA2, or PALB2 mutations not including variants of uncertain significance (VUS), 33/96 (34.4%) received olaparib and 3/96 (3%) received talazoparib in the metastatic setting, and 28 were eligible for response (one had toxicity, two were lost to follow-up, and two went to hospice). Median PFS was 9.0 months and median OS was 21.8 months for patients receiving PARPi. Of the 381/1010 (38%) patients with PIK3CA mutations, 84/381 (22%) received alpelisib and 41 were eligible for response (22 had toxicity, 13 were discontinued, six were lost to follow-up, and two went to hospice). Median PFS was 7.9 months and median OS was 31.2 months for patients receiving alpelisib. A total of 544/1010 (54%) patients had AKT1, PIK3CA, or PTEN mutations which are now FDA approved for capivasertib in HR+HER2- metastatic BC patients. In addition, 144/1010 (14%) patients had ESR1 mutations which are FDA approved for elacestrant in HR+HER2- metastatic BC patients.

In this study, a total of 784 clinically actionable mutations were reported for 1010 patients with genomic sequencing. Of these, 96/1010 (10%) patients had at least one actionable mutation in homologous recombination repair genes (BRCA1, BRCA2, PALB2) and 36/96 (37.5%) patients received PARP inhibitors (33 olaparib and three talazoparib). In addition, 381/1010 (38%) patients had at least one clinically actionable PIK3CA mutation, and 84/381 (22%) received alpelisib. Additionally, 544/1010 (54%) of patients had either AKT1 (41/1010), PIK3CA (381/1010), or PTEN (122/1010) alterations that were FDA approved in November 2023 for capivasertib in the treatment of HR+HER2- metastatic BC (MBC) patients. Furthermore, 144/1010 (14%) patients in this study had at least one ESR1 mutation, a clinically actionable mutation that was FDA approved in January 2023 for elacestrant in the treatment of ER+HER2- MBC patients (44% detected by liquid biopsy). Future studies are needed to determine the efficacy of elacestrant and capivasertib for patients with these mutations, and to tailor strategies for optimal patient quality of life and cancer outcome.

Simultaneous inhibition of poly(ADP-ribose) polymerase (PARP) and nicotinamide phosphoribosyltransferase (NAMPT) has been shown to be synergistically effective against breast cancer susceptibility (BRCA) wild-type triple-negative breast cancer (TNBC) through synthetic lethality, which may be explored to broaden the clinical utility of PARP inhibitors. Herein, we report the discovery of dual PARP/NAMPT inhibitors through a pharmacophore linking approach. The lead compound 13j with potent inhibitory activity against both PARP1 and NAMPT (IC50 = 0.8 and 18 nM, respectively) effectively inhibited the proliferation of TNBC MDA-MB-231 cells with wild-type BRCA at submicromolar level. Mechanically, 13j disrupted the homologous recombination repair (HRR) pathway, caused the accumulation of DNA double-strand breaks (DSBs) and ultimately induced apoptotic cell death. In addition, this compound exhibited potent inhibitory potency on the migration of MDA-MB-231 cells. This study demonstrates that compound 13j is a promising lead compound for the development of better PARP/NAMPT inhibitors to treat TNBC with wild-type BRCA.

Background: The treatment landscape in HR+/HER2- metastatic breast cancer (mBC) is continuously evolving, with evidence on new agents and combinations published almost every year. Despite updated therapeutic guidelines, second-line (2L) selection may be challenging due to clinical factors, biomarker status, and available agents. Methods: A two-round Delphi consensus was organized in July 2024, gathering input from 10 experts in research, diagnosis, and treatment of HR+/HER2- mBC on optimal 2L and beyond choice, considering the available biomarkers and results from published clinical trials. Consensus was defined as 70% agreement or disagreement. Results: The experts considered initially a list of 39 statements, structured into the following four sections: biomarker testing; selection of 2L treatment at progression of disease on first line endocrine therapy (ET) + CDK4/6i at ≥6 months after initiation of ET for mBC; selection of 2L treatment at disease progression on ET + CDK4/6i, at <6 months after initiation of ET for mBC, whilst on ET; and selection of post-2L treatment options. After a discussion, the experts decided to remove four statements, refine ten, and include three new ones. The final list consisted of 38 statements, and consensus was achieved in 37. Conclusions: The panel recommends next-generation sequencing as the method of choice for genomic characterization at disease progression on first line. The optimal agent or treatment class is indicated depending on the presence of specific mutations; however, the panel admits that the strategy is different in clinical practice, where novel therapies might not be available or reimbursed.

Triple-negative breast cancer (TNBC) is an aggressive malignancy characterized by limited therapeutic options and poor prognosis. Despite advancements in precision oncology, conventional chemotherapy remains the cornerstone of TNBC treatment, often accompanied by debilitating side effects and suboptimal outcomes. This review presents a comprehensive analysis of clinical trials on targeted therapies, aiming to establish a novel, evidence-based treatment strategy exclusively leveraging molecularly targeted agents. By integrating patient-specific genetic profiles with therapeutic responses observed across various clinical trial phases, this approach seeks to optimize efficacy while minimizing toxicity. The proposed targeted therapy combinations hold significant potential to revolutionize TNBC treatment, offering a paradigm shift toward precision medicine and improved patient outcomes.

BRCA-related hormone receptor (HR)-negative breast cancers (BC) are reported to have aggressive tumor biology but also exhibit chemosensitivity. However, the impact of BRCA1/2 pathogenetic variants (PV) on BC outcomes remains unclear. This study compares survival outcomes for HR-negative BC between BRCA carriers and noncarriers.

From 489 female BRCA-carriers prospectively registered in western Sweden (1996-2017), those with primary HR-negative BC who underwent breast surgery until 2019 were included in the BRCA cohort. For each BRCA-carrier, three BRCA-noncarriers with HR-negative BC were matched based on age, time of diagnosis, and follow-up duration. Overall survival (OS) was analyzed using Kaplan‑Meier estimates and Cox proportional hazard ratios after adjustment for stage, chemotherapy, and surgical technique. A sensitivity analysis was performed to investigate the effect of HER2 status on HR-negative BC diagnosed after 2007.

Among the 106 BRCA carriers, 101 (95%) had a BRCA1 and 5 (5%) a BRCA2 PV. Most of the BRCA-carriers (89/106, 84%) were diagnosed with BC prior to genetic screening. Surgical techniques were similar between BRCA-carriers (n = 106) and noncarriers (n = 318). Chemotherapy was more common among BRCA-carriers (87% vs. 72%, p < 0.001). No significant difference in OS was found between BRCA-carriers and noncarriers among patients with HR-negative BC (adjusted HR: 0.81 [95% confidence interval [CI]: 0.43-1.53], p = 0.51) or considering HER2 status (adjusted HR 0.95 [95% CI: 0.43-2.07], p = 0.89).

This study suggests that BRCA1/2 pathogenic variants do not independently impact survival outcomes in HR-negative BC. However, a moderate association between BRCA status and OS cannot be ruled out.

Triple-negative breast cancer (TNBC) is an aggressive sub-type of breast cancer that is associated with higher rates of recurrent disease. Chemotherapy with an anthracycline is an integral part of curative therapy but resistance remains a clinical problem. Cellular senescence is a terminal cell fate that has been observed in models of doxorubicin resistance. Identifying novel combinations with doxorubicin to eliminate senescent cells and promote apoptosis may lead to improved clinical outcomes. The purpose of this study was to investigate the combination of doxorubicin with the pro-apoptotic BCL-2 inhibitor venetoclax in TNBC cell lines and to assess the role of p53 in cellular senescence and apoptosis.

TNBC cell lines with wild-type (WT), mutated or knocked-down (KD) p53 were treated with doxorubicin, venetoclax or the combination in vitro and evaluated for impacts on viability, proliferation, apoptosis, and senescence. Down-stream markers of apoptosis were also assessed to evaluate cellular mechanistic changes. An in vivo TNBC MDA-MB-231 murine model was used to assess tumor growth, cellular proliferation, and senescence changes following treatment with doxorubicin, venetoclax or combination.

Venetoclax with doxorubicin had synergistic antiproliferative activity against TNBC cell lines and increased apoptosis. The addition of venetoclax to doxorubicin reduced senescent cells in a p53-independent manner. In vivo, the addition of venetoclax to doxorubicin improved tumor growth inhibition and reduced senescent cells.

The combination of doxorubicin with venetoclax is promising for the treatment of p53-WT and mutated TNBC and this work supports further investigation.

Breast and prostate cancer are among the most commonly diagnosed cancers worldwide. Recent advances in tumor sequencing and gene studies have led to a paradigm shift from treatment centered on the type of tumor to therapy more focused on specific immune phenotype markers and molecular alterations. In this review, we discuss the utility and function of talazoparib concerning prostate cancer treatment and summarize recent and planned clinical trials on talazoparib. We searched medical databases for articles relating to the use of talazoparib in prostate cancer from inception. Poly ADP ribose polymerase (PARP) is a family of 17 necessary DNA repair enzymes responsible for base excision repair, single-strand break repair, and double-strand break repair. PARP inhibitors are a class of oral targeted therapies that compete for the NAD + binding site on PARP molecules. Talazoparib, a potent PARP inhibitor, has emerged as a significant therapeutic option in the treatment of metastatic castration-resistant prostate cancer (mCRPC), particularly for patients with specific genetic alterations. Its role as a PARP inhibitor makes it a targeted therapy, focusing on cancer cells with DNA repair deficiencies. Talazoparib's role as a biomarker-directed therapy in advanced prostate cancer has been increasingly recognized. The TALAPRO-1 demonstrated durable antitumor activity in mCRPC patients. TALAPRO-2 is a notable clinical trial, specifically examining the effectiveness of Talazoparib when used in combination therapies. Current investigations demonstrate a significant improvement in survival outcomes for the patients of mCRPC, making Talazoparib a promising intervention.

Germline (likely) pathogenic variants (PVs) are identified in 5%-10% of patients with breast cancer (BC) and play a critical role in guiding clinical management, including the use of targeted therapies such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi). High-risk genes such as BRCA1, BRCA2, and PALB2, and moderate-risk genes such as CHEK2 and ATM, influence BC risk and treatment decisions. This study evaluates the prevalence and clinical impact of PVs in a large consecutive cohort.

A retrospective analysis was conducted on 912 individuals with BC who underwent germline testing at the Hospital Clinic of Barcelona from 2016 to 2023. Genetic testing for 14 BC and Lynch syndrome genes was carried out using the TruSight Hereditary Cancer Panel. Statistical analyses were carried out to assess associations between germline results and clinical characteristics, including eligibility for PARPi therapy.

Of the 912 individuals, 129 (14.1%) had a PV, with BRCA2 (31.8%) and BRCA1 (24%) being the most frequently altered genes. Additionally, 16.2% carried variants of uncertain significance, most commonly in ATM and BRCA2 genes. Patients with PV were younger compared with PV-negative individuals (median age: 43.5 versus 48.2 years, P = 0.006), more likely to have bilateral BC (13.3% versus 5.8%, P = 0.002), and more frequently diagnosed with triple-negative BC (TNBC; 28.7% versus 20.8%, P = 0.046). Of those with PVs, 39.1% completed a bilateral mastectomy, 36.7% had a risk-reducing salpingo-oophorectomy, and 22.7% had both surgeries. PV detection was associated with higher stages at diagnosis (stage IV: 13.0% versus 5.9%, P < 0.001). In the metastatic cohort, 12.9% received PARPi therapy, with 80.7% harboring BRCA1/2 PVs. In early BC, 13.1% met the criteria for adjuvant PARPi.

The identification of germline PVs significantly influences surgical decisions and systemic therapies. Genetic testing for patients with BC optimizes care, particularly in selecting candidates for PARPi in both early and advanced BC, improving management and prevention strategies.

Despite the impressive improvements achieved by endocrine therapy and CDK4/6 inhibitors (CDK4/6i) and the forthcoming availability of alternative endocrine manipulations and targeted therapies, hormone-receptor positive/HER2 negative (HR+/HER2-) advanced breast cancer (ABC) is almost inevitably destined to become endocrine- refractory. At this time chemotherapy has been recently challenged and partly replaced by new targeted options as antibody-drug conjugated (ADCs). Trastuzumab-deruxtecan has been proven meaningfully superior to chemotherapy either in 1st and later lines after progression to CDK4/6i in HER2-low ABC and results with other ADCs as Sacituzumab Govitecan and Datopotamab-deruxtecan are promising, but the definition of cross-resistance between these drugs sharing either antibody or payload is crucial before implementing them in a useful sequence. While PARP inhibitors are the standard 2nd line in patients with gBRCA mutation, it is not still known whether patients with mutations of PALB2 or of other homologous recombinant defect (HRD)-related genes will benefit of the same treatment. On the other hand, the results obtained with immune checkpoint inhibitors (ICIs) in HR+ /HER2-ABC contrarily to the early setting are disappointing up to now, but investigations of ICIs in combination with other targeted drugs which may increase immune response and the search for better markers of activity are under way. Moreover the anticipation in upfront treatment of ADCs or PARPi in patients with features of putative endocrine resistance and/or of less sensitiviy to CDK4/6i and the choice of therapy in patients recurring during or soon after adjuvant CDK4/6i and olaparib represent further challenges for the future.

The combination of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is the standard first-line treatment for hormone receptor-positive (HR + ) and HER2-negative metastatic breast cancer (mBC). Despite their efficacy, resistance inevitably develops, necessitating alternative therapeutic strategies post-progression. This review explores current and emerging treatment options following progression on CDK4/6i, focusing on endocrine therapies, targeted therapies, combination approaches, and the continued use of CDK4/6i. Endocrine therapies, including fulvestrant and novel oral selective estrogen receptor degraders (SERDs) like elacestrant, show promise, especially in patients with ESR1 mutations. Targeted therapies such as PI3K/AKT/mTOR inhibitors, exemplified by alpelisib and capivasertib, offer potential by addressing downstream signaling pathways involved in resistance. Additionally, FGFR inhibitors like erdafitinib are under investigation for their role in overcoming specific resistance mechanisms. Combination strategies involving CDK4/6 inhibitors with immune checkpoint inhibitors or other targeted agents are also being explored, with early trials suggesting possible synergistic effects, although further validation is required. Continuation of CDK4/6 inhibitors beyond progression has shown potential benefits in selected patients, but the data are heterogeneous, and further studies are needed to clarify their role. While chemotherapy remains a standard option for patients who progress on these treatments, the goal is to delay its use through the effective utilization of endocrine and targeted therapies. Understanding resistance mechanisms and tailoring treatment to individual patient profiles is crucial for optimizing outcomes. Ongoing clinical trials are expected to provide deeper insights, guiding the development of more effective post-progression therapeutic strategies. This evolving landscape highlights the need for continuous research and individualized patient care to improve survival and quality of life in HR + mBC patients.

This study evaluates real-world outcomes, toxicities, and prescribing patterns of PARP inhibitors (PARPis) for the treatment of metastatic breast cancer (MBC).

Electronic health records of 62 MBC patients treated with olaparib (n = 48) or talazoparib (n = 14) at Mayo Clinic System between 2017 and 2022 were analyzed. Time-to-treatment-failure (TTF) was assessed utilizing the Kaplan-Meier method. Predictors of TTF were identified in a multivariate Cox-proportional hazard regression model adjusting for relevant tumor and demographic characteristics.

Among 62 patients who received PARPis for MBC, 55 had germline (g) pathogenic variants (PVs) (gBRCA1 = 24, gBRCA2 = 26, and gPALB2 = 4) and 8 patients had somatic (s) PVs (sBRCA1 = 4, sBRCA2 = 2, sATM = 1, sCDKN2A = 1). Median TTF in the gBRCA1, gBRCA2, and gPALB2 PV carriers were 7, 8, and 9 months, respectively (P = .37). Complete or partial responses were observed among 51.8% of patients with gBRCA or gPALB2 PVs. In multivariate analysis, HER2 positivity (hazard ratio, HR: 4.9, P = .007) and somatic PVs in homologous recombination repair (HRR) genes other than BRCA (sATM or sCDKN2A) (HR: 11.7, P = .01) were associated with a shorter TTF. No significant difference in TTF was observed by the type of PARPi, estrogen and progesterone receptor status, age, or number of prior therapies. Eight (16.7%) patients receiving olaparib and seven (50%) receiving talazoparib required dose reductions due to toxicities.

In real-world practice, PARPis are well-tolerated with promising TTF in gBRCA1/2 and gPALB2 carriers. Further studies will delineate the clinical efficacy of PARPis in other MBC subsets, such as sBRCA mutations, HER2-positive disease, and CNS metastasis.

Globally, breast cancer is both the most common cancer and the most common cause of death related to cancer among women. It is estimated that over 2 million women were diagnosed with breast cancer in 2022 worldwide, while almost 400,000 were diagnosed in the EU. Breast cancer has different histopathological subtypes that require different therapeutic approaches. Triple-negative breast cancer (TNBC) is a type that is considered more aggressive; it occurs in about 10 to 20% of all breast cancer cases. Approximately 40% of women initially diagnosed with TNBC will develop metastases. The objective of this study is to present current clinical trials focused on new treatment of advanced and metastatic TNBC. The study was conducted by searching the clinicaltrials.gov database. Due to the scope of this paper, primary endpoints in the included studies were objective response rate, treatment-emergent adverse events or serious adverse events, progression-free survival, and probability of pathologic complete response. Some of the selected studies were phase I or II RCTs; therefore, we should carefully examine their future results and implications for clinical guidelines.

Multigene sequencing technologies provide a foundation for targeted therapy and precision oncology by identifying actionable alterations and enabling the development of treatments that substantially improve clinical outcomes. This review emphasizes the importance of having a molecular compass guiding treatment decision-making through the multitude of alterations and genetic mutations, showcasing why NGS plays a pivotal role in modern oncology.

Matched targeted therapies (MTT) given alone or in combination with systemic anti-cancer therapies have delivered proven survival benefit for many people with newly diagnosed cancer. However, there is little evidence of their effectiveness in the recurrent or late-stage setting. With this uncertainty, alongside the perception that late-stage cancers are too genetically heterogenous or too mutationally diverse to benefit from matched targeted therapies, next-generation sequencing (NGS) of tumours in people with refractory cancer remains a low priority. As a result, next-generation sequencing testing of recurrent or late-stage disease is discouraged. We lack evidence to support the utility of next generation sequencing in guiding matched targeted therapies in this setting.

To evaluate the benefits and harms of matched targeted therapies in people with advanced cancers in randomised controlled trials.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organisation International Clinical Trials Registry Platform (WHO-ICTRP) search portal up to 30th October 2024. We also screened reference lists of included studies and also the publications that cited these studies.

We included randomised controlled trials (RCTs) that had enroled participants with advanced/refractory solid or haematological cancers who had progressed through at least one line of standard anti-cancer systemic therapy. To be eligible, all participants should have received matched targeted therapy based on next-generation sequencing carried out on their tumour (tumour tissue, blood or bone marrow).

We systematically searched medical databases (e.g. MEDLINE, Embase) and trial registers for randomised controlled trials (RCTs). Outcomes of interest were progression-free survival (PFS), overall survival (OS), overall response rates (ORR), serious (grade 3 or 4) adverse events (AEs) and quality of life (QOL). We used a random-effects model to pool outcomes across studies and compared predefined subgroups using interaction tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment of certainty was used to evaluate the quality of evidence.

We identified a total of 37 studies, out of which 35 studies (including 9819 participants) were included in the meta-analysis. All included studies compared a matched targeted therapy intervention to standard-of-care treatment, non-matched targeted therapies or no treatment (best supportive care): Matched targeted therapy versus standard-of-care treatment Matched targeted therapy (MTT) compared with standard systematic therapy probably reduces the risk of disease progression by 34% (hazard ratio (HR) = 0.66, 95% confidence interval (CI) 0.59 to 0.74; 14 studies, 3848 participants; moderate-certainty evidence). However, MTT might have little to no difference in risk of death (HR = 0.85, 95% CI 0.75 to 0.97; 14 studies, 3848 participants; low-certainty evidence) and may increase overall response rates (low-certainty evidence). There was no clear evidence of a difference in severe (grade 3/4) adverse events between matched targeted therapy and standard-of-care treatment (low-certainty evidence). There was limited evidence of a difference in quality of life between groups (very low-certainty of evidence). Matched targeted therapy in combination with standard-of-care treatment versus standard-of-care treatment alone Matched targeted therapy in combination with standard-of-care treatment compared with standard-of-care treatment alone probably reduces the risk of disease progression by 39% (HR = 0.61, 95% CI 0.53-0.70, 14 studies, 2,637 participants; moderate-certainty evidence) and risk of death by 21% (HR = 0.79, 95% CI 0.70 to 0.89; 11 studies, 2575 participants, moderate-certainty evidence). The combination of MTT and standard-of-care treatment may also increase overall response rates (low-certainty evidence). There was limited evidence of a difference in the incidence of severe adverse events (very low-certainty evidence) and quality of life between the groups (very low-certainty of evidence). Matched targeted therapy versus non-matched targeted therapy Matched targeted therapy compared with non-matched targeted therapy probably reduces the risk of disease progression by 24% (HR = 0.76, 95% CI 0.64 to 0.89; 3 studies, 1568 participants; moderate-certainty evidence) and may reduce the risk of death by 25% (HR = 0.75, 95% CI 0.65 to 0.86, 1307 participants; low-certainty evidence). There was little to no effect on overall response rates between MTT and non-MTT. There was no clear evidence of a difference in overall response rates (low-certainty evidence) and severe adverse events between MTT and non-MTT (low-certainty evidence). None of the studies comparing MTT and non-MTT reported quality of life. Matched targeted therapy versus best supportive care Matched targeted therapy compared with the best supportive care (BSC) i.e. no active treatment probably reduces the risk of disease progression by 63% (HR 0.37, 95% CI 0.28 to 0.50; 4 studies, 858 participants; moderate-certainty evidence). There was no clear evidence of a difference in overall survival between groups (HR = 0.88, 95% CI 0.73 to 1.06, 3 studies, 783 participants; low-certainty evidence). There was no clear evidence of a difference in overall response rates (very low-certainty of evidence) and incidence of severe adverse events (very low-certainty of evidence) between the groups. Quality of life was reported in a single study but did not provide composite scores. Risk of bias The overall risk of bias was judged low for eight studies, unclear for two studies, and the remaining 27 studies were high risk.

Matched targeted therapies guided by next-generation sequencing in people with advanced cancer prolongs the time before cancer progresses compared to standard therapies. However, there is limited evidence to suggest that it prolongs overall survival, improves the quality of life or increases adverse events. Importantly, this review supports equitable access to next-generation sequencing technology for all people with advanced cancer and offers them the opportunity to access genotype-matched targeted therapies.

Annexin A3 has been demonstrated to be a key pathogenic protein in the occurrence and development of triple-negative breast cancer (TNBC); its overexpression in TNBC cells can promote the proliferation, migration, and drug resistance of TNBC. Previously, we reported the first ANXA3 degrader, (R)-SL18, with potent anti-TNBC effects, albeit with moderate ANXA3 binding affinity leading to off-target effects and relatively poor degradation selectivity of family proteins. To obtain molecules with stronger binding with ANXA3 and lower toxicity, we performed further structural optimization of (R)-SL18 to explore structure-activity relationships for a series of 1,4-benzodiazepines. Among them, compound 18a5 exhibited a 14-fold increase in ANXA3 binding activity, along with better cancer cell inhibition and functional activity. In particular, 18a5 showed more desirable ANXA3 selective degradation than (R)-SL18 and displayed excellent inhibitory effect in a TNBC tumor xenograft model (TGI = 96%). Collectively, 18a5 proved to be a promising lead compound to treat TNBC through the degradation of ANXA3.

PARP inhibitors are a class of agents that have shown significant preclinical activity in models defective in homologous recombination (HR). The identification of synthetic lethality between HR defects and PARP inhibition led to several clinical trials in tumors with known HR defects (initially mutations in BRCA1/2 genes and subsequently in other genes involved in HR). These studies demonstrated significant responses in breast and ovarian cancers, which are known to have a significant proportion of patients with HR defects. Since the approval of the first PARP inhibitor (PARPi), olaparib, several other inhibitors have been developed, expanding the armamentarium available to clinicians in this setting. The positive results obtained in breast and ovarian cancer have expanded the use of PARPi in other solid tumors with HR defects, including prostate and pancreatic cancer in which these defects have been identified. The clinical trials have demonstrated responses to PARPi which are now also available for the subset of patients with prostate and pancreatic cancer with HR defects. This review summarizes the results obtained in solid tumors with PARPi and their potential use when combined with other agents, including immune checkpoint inhibitors that are likely to further increase the survival of these patients which still needs a dramatic improvement.

Mutations in the tumor suppressor genes BRCA1 and BRCA2 are associated with the triple-negative breast cancer phenotype, particularly aggressive and hard-to-treat tumors lacking estrogen, progesterone, and human epidermal growth factor receptor 2. This research aimed to understand the metabolic and genetic links behind BRCA1 and BRCA2 mutations and investigate their relationship with effective therapies. Using the Cytoscape software, two networks were generated through a bibliographic analysis of articles retrieved from the PubMed-NCBI database. We identified 98 genes deregulated by BRCA mutations, and 24 were modulated by therapies. In particular, BIRC5, SIRT1, MYC, EZH2, and CSN2 are influenced by BRCA1, while BCL2, BAX, and BRIP1 are influenced by BRCA2 mutation. Moreover, the study evaluated the efficacy of several promising therapies, targeting only BRCA1/BRCA2-mutated cells. In this context, CDDO-Imidazolide was shown to increase ROS levels and induce DNA damage. Similarly, resveratrol decreased the expression of the anti-apoptotic gene BIRC5 while it increased SIRT1 both in vitro and in vivo. Other specific drugs were found to induce apoptosis selectively in BRCA-mutated cells or block cell growth when the mutation occurs, i.e., 3-deazaneplanocin A, genistein or daidzein, and PARP inhibitors. Finally, over-representation analysis on the genes highlights ferroptosis and proteoglycan pathways as potential drug targets for more effective treatments.

Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors, such as olaparib, talazoparib, rucaparib, and niraparib, comprise a therapeutic class that targets PARP proteins involved in DNA repair. Cancer cells with homologous recombination repair defects, particularly BRCA alterations, display enhanced sensitivity to these agents because of synthetic lethality induced by PARP inhibitors. These agents have significantly improved survival outcomes across various malignancies, initially gaining regulatory approval in ovarian cancer and subsequently in breast, pancreatic, and prostate cancers in different indications. This review offers a comprehensive clinical overview of PARP inhibitor approvals, emphasizing their efficacy across different cancers based on landmark phase 3 clinical trials.

Endocrine therapy (ET) combined with cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) agents is the standard first-line treatment for patients with hormone receptor-positive, ERBB2 (formerly HER2 or HER2/neu)-negative metastatic breast cancer. However, optimal therapy after tumor progression to ET plus CDK4/6i remains unclear.

To evaluate progression-free survival (PFS) and overall survival (OS) in the clinical practice setting in patients with hormone receptor-positive, ERBB2-negative metastatic breast cancer following progression with ET plus CDK4/6i.

The multicenter retrospective cohort study included 506 patients diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer between April 22, 2015, and January 31, 2023, and who received ET-based or chemotherapy (CT)-based treatment following progression during ET plus CDK4/6i. Outcomes were analyzed based on treatment type, clinicopathologic features, and the duration of prior CDK4/6i therapy.

The primary end point was PFS in the clinical practice setting, defined as the time between the initiation of the first systemic treatment on tumor progression to ET plus CDK4/6i treatment and the detection of disease progression or patient death from any cause. The secondary end point was OS in the clinical practice setting, defined as the time interval between tumor progression during ET plus CDK4/6i treatment and patient death from any cause.

In 506 women (median age at diagnosis, 52.4 [IQR, 44.6-62.8] years) diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer progressing during ET plus CDK4/6i, independent factors associated with poorer PFS outcomes were visceral metastases (hazard ratio [HR], 1.45; 95% CI, 1.17-1.80; P = .008) and de novo metastatic disease (HR, 1.25; 95% CI, 1.01-1.54; P = .04). A longer duration of CDK4/6i therapy (OS HR, 0.55; 95% CI, 0.41-0.73; P < .001) and an older age (PFS HR, 0.99; 95% CI 0.98-1.00; P = .03) were associated with better outcomes. Compared with oral CT, both intravenous CT- and ET-based treatments were associated with shorter PFS (intravenous CT: hazard ratio [HR], 1.45; 95% CI, 1.11-1.89; P = .006; everolimus plus exemestane: HR, 1.38; 95% CI, 1.06-1.78; P = .02; ET only: HR, 1.38; 95% CI, 1.05-1.89; P = .02). A duration of CDK4/6i treatment exceeding 12 months was associated with longer OS (HR, 0.55; 95% CI, 0.41-0.73; P < .001). Among patients with visceral metastases, intravenous CT was associated with shorter OS compared with oral CT (HR, 1.52; 95% CI, 1.03-2.24; P = .04).

In this cohort study, the duration of tumor control achieved with CDK4/6i-based therapy and the presence of visceral metastases emerged as key factors that may affect treatment decision. Oral CT may offer potential benefits for specific patient subgroups.

Immunohistochemical (IHC) tissue profiling is a standard practice in the management of metastatic breast cancer (mBC), that enables the identification of distinct biological phenotypes based on hormone receptors' expression. Luminal-like tumors primarily benefit from a first line treatment strategy combining endocrine therapy and cyclin-dependent kinase 4/6 inhibitors. However, IHC analyses necessitate invasive procedures and may encounter technical and interpretational challenges. In the current era of precision medicine, liquid biopsy holds potential to provide clinicians with additional insights into disease biology, including mechanisms underlying endocrine resistance and disease progression. Several liquid-based biomarkers are entering clinical practice and hold prognostic and predictive values in Luminal-like mBC, while many others are currently being investigated. The present work aims to summarize the current evidence regarding the clinical meanings of hormone receptors and their downstream molecular pathways, alongside their implications for therapeutic decision-making in Luminal-like mBC.

This review offers an expert perspective on biomarkers, CDK4/6 inhibitor efficacy, and therapeutic approaches for managing hormone receptor-positive (HR+), human epidermal growth factor receptor-negative (HER2-) advanced breast cancer (ABC), particularly after CDK4/6 inhibitor progression. Key trials have demonstrated that combining CDK4/6 inhibitors with endocrine therapy (ET) significantly improves progression-free survival (PFS), with median durations ranging from 14.8 to 26.7 months, and overall survival (OS), with median durations reaching up to 53.7 months. Actionable biomarkers, such as PIK3CA and ESR1 mutations, have emerged as pivotal tools to guide second-line treatment decisions, enabling the use of targeted therapies like alpelisib and elacestrant and emphasizing the important role of biomarkers in guiding the selection of therapy. This overview aims to provide clinicians with a practical and up-to-date framework to inform treatment decisions and improve patient care in the context of this challenging disease. Additionally, we review emerging biomarkers and novel treatment strategies to address this difficult clinical landscape.

Triple-negative breast cancer (TNBC) is more aggressive when compared with other breast cancer subtypes, and advanced TNBC (aTNBC) has always been a challenge for clinical treatment. In recent years, significant progress has been made in the research of antibody-drug conjugates (ADCs), especially targeting trophoblast cell-surface antigen 2 (TROP2), as an effective regimen to enhance the potential survival benefit and quality of life of relevant patients. The objective of this narrative review is to provide a comprehensive knowledge on latest progress of ADCs in the treatment of aTNBC. Furthermore, the clinical significance and future research directions for ADCs are also discussed.

As of December 2023, literature spanning the past decade was comprehensively searched and analyzed across PubMed, Wanfang Data, ClinicalTrials.gov, and relevant academic conferences, to identify the latest published literature or ongoing trials on ADCs for aTNBC. The selected literature primarily focused on the drug structural profile, pharmacological mechanism, important trials targeting different antigens, and other exploratory investigations.

The advent of precision therapy has been facilitated by the new generation ADCs, which have demonstrated the capacity to prolong survival in patients with refractory aTNBC, and promote the research on molecular biological characteristics of aTNBC. Meanwhile, several clinical issues on treatment are emerging, including a detailed understanding of the clinical profile differences among specific ADCs, identification of the potential indications for ADCs, and management strategies for the adverse effects related to ADCs. Additionally, it is essential to clarify the clinical significance of the expression level of the target antigen for ADCs, to comprehend resistance mechanisms to ADCs, and to determine the optimal sequence of treatments between different ADCs. Furthermore, there is a need to investigate the potential of combination immunotherapy with ADCs. Up to date, the preliminary investigations on the aforementioned issues have been initiated, and further research will facilitate the enhancement of ADCs clinical utilization.

The use of ADCs has been recommended by various clinical guidelines, and significantly altering the landscape of treatment for aTNBC. Nevertheless, further investigation are required to determine the most effective use of ADCs.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that disproportionately affects younger females, non-Hispanic Black women, Hispanic women, and women with the BRCA1 gene mutation. Hereditary genetic testing is particularly important in this population to assess preventative and treatment strategies, however access to genetic testing is variable. A qualitative review was performed to evaluate barriers to genetic testing for patients with TNBC. Mutations common in breast cancer are reviewed along with updated guidelines on management strategies, including the ability to include PARP inhibitors as a treatment strategy. Barriers to genetic testing are multifactorial, with non-Hispanic Black women being tested less often than other groups. The disparity is even further represented by the limited number of non-Hispanic Black patients with TNBC who receive risk-reducing surgery or targeted systemic therapy. Eliminating barriers to genetic testing can allow us to support guideline-directed care for patients with TNBC at higher risk for genetic mutations.

Identifying patients with gBRCAm is crucial to facilitate screening strategies, preventive measures and the usage of targeted therapeutics in their management. This review examines the evidence for the latest predictive and therapeutic approaches in BRCA-associated cancers.

Data supports the use of adjuvant olaparib in patients with gBRCAm high-risk HER2-negative breast cancer. In advanced gBRCAm HER2-negative breast cancer, the PARPis talazoparib and olaparib have demonstrated benefit over standard chemotherapy. In ovarian cancer, olaparib, niraparib or rucaparib can be used as monotherapy in frontline maintenance. Olaparib and bevacizumab as a combination can also be used as frontline maintenance. In the relapsed platinum-sensitive setting, olaparib, niraparib and rucaparib are effective maintenance options in BRCAm patients who are PARPi naive. Both olaparib and rucaparib are effective options in BRCAm metastatic castrate-resistant prostate cancer (mCRPC). Evidence also exists for the benefit of PARPi combinations in mCRPC. In metastatic pancreatic cancer, olaparib can be used in gBRCAm patients who are responding to platinum chemotherapy. However, there may be a development of PARPi resistance. Understanding the pathophysiology that contributes to such resistance may allow the development of novel therapeutics. Combination therapy appears to have promising results in emerging trials. Seeking avenues for subsidised genetic testing can reduce the total costs of cancer management, leading to improve detection rates.

Identifying breast, ovarian, pancreatic and prostate cancer patients with gBRCAm plays a crucial predictive role in selecting those who will benefit significantly from PARPi therapy. The use of PARPi in gBRCAm HBOC-related cancers has resulted in significant survival benefits. Beyond BRCA1/2, HRR gene assessment and the consideration of other cancer predisposition syndromes may allow more patients to be eligible for and benefit from targeted therapies.

The extensive heterogeneity and the limited availability of effective targeted therapies contribute to the challenging prognosis and restricted survival observed in triple-negative breast cancer (TNBC). Recent research indicates the aberrant expression of diverse tyrosine kinases (TKs) within this cancer, contributing significantly to tumor cell proliferation, survival, invasion, and migration. The contemporary paradigm shift towards precision medicine has highlighted TKs and their receptors as promising targets for pharmacotherapy against a range of malignancies, given their pivotal roles in tumor initiation, progression, and advancement. Intensive investigations have focused on various monoclonal antibodies (mAbs) and small molecule inhibitors that specifically target proteins such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR), cellular mesenchymal-epithelial transition factor (c-MET), human epidermal growth factor receptor 2 (HER2), among others, for combating TNBC. These agents have been studied both in monotherapy and in combination with other chemotherapeutic agents. Despite these advances, a substantial terrain of unexplored potential lies within the realm of TK targeted therapeutics, which hold promise in reshaping the therapeutic landscape. This review summarizes the various TK targeted therapeutics that have undergone scrutiny as potential therapeutic interventions for TNBC, dissecting the outcomes and revelations stemming from diverse clinical investigations. A key conclusion from the umbrella clinical trials evidences the necessity for in-depth molecular characterization of TNBCs for the maximum efficiency of TK targeted therapeutics, either as standalone treatments or a combination. Moreover, our observation highlights that the outcomes of TK targeted therapeutics in TNBC are substantially influenced by the diversity of the patient cohort, emphasizing the prioritization of individual patient genetic/molecular profiles for precise TNBC patient stratification for clinical studies.