Search Results (140)

Triple-negative breast cancer (TNBC) is a highly aggressive subtype known for its rapid metastatic potential. Despite its severity, treatment options for TNBC remain limited. Olaparib, an FDA-approved PARP inhibitor, has been used to treat germline BRCA-mutated TNBC in both metastatic and high-risk early-stage settings. However, acquired resistance to PARP inhibitors and their limited applicability in non-BRCA TNBCs are now two major growing clinical problems. Activation of the IL-6/STAT3 signaling cascade has been implicated in therapeutic resistance. In this study, we evaluated the combined effects of the PARP inhibitor olaparib and the STAT3 inhibitor LLL12B in human TNBC cell lines with both BRCA mutations and wild-type BRCA status. Our results demonstrate that the PARP inhibitor olaparib can induce increased interleukin-6 (IL-6) in TNBC cells, with ELISA showing a 2- to 39-fold increase across five cell lines. MTT assays revealed that knocking down or inhibiting STAT3, a key downstream effector of the IL-6/GP130 pathway, sensitizes TNBC cells to olaparib. Treatment with either olaparib or LLL12B alone reduced TNBC cell viability, migration, and invasion. Notably, their combined administration produced a markedly enhanced inhibitory effect compared to individual treatments, regardless of BRCA mutation status. These findings highlight the potential of dual PARP and STAT3 inhibition as a novel targeted therapeutic strategy for both BRCA-mutant and BRCA-proficient TNBC. Full article

Fanconi anemia (FA) is a DNA repair deficiency disorder associated with genomic and chromosomal instability and a high cancer risk. In a small percentage of cases, FA is caused by biallelic pathogenic variants (PVs) in the BRCA2/FANCD1 gene, defining the FA-D1 subtype. Experimental and epidemiologic data indicate that the complete absence of BRCA2 is incompatible with viability. Therefore, cells from individuals affected with FA caused by biallelic BRCA2 PVs must have a residual BRCA2 function. This activity may be maintained through hypomorphic missense mutations, translation termination–reinitiation associated with a translational stop mutation, or other non-canonical or uncommon translation initiation and elongation events. In some cases, however, residual BRCA2 function is provided by alternatively or aberrantly spliced BRCA2 transcripts. Here, we review and debate aspects of the contribution of splicing in the 5′ segment to BRCA2 functions in the context of PVs affecting this largely intrinsically disordered protein region, with a focus on recent findings in individuals with FA-D1. In this Perspective, we also discuss some of the broader biological implications and open questions that arise from considering 5′-terminal BRCA2 splicing in light of old and new findings from FA-D1 patients and beyond. Full article

PARP inhibitors (PARPi), alone or in combination with androgen receptor signaling inhibitors (ARSi), have shown clinical benefit in metastatic castration-resistant prostate cancer (mCRPC), particularly in tumors with homologous recombination repair (HRR) gene alterations. Recent data from the TALAPRO-2 trial complete the current evidence on PARPi–ARSi combination strategies in this setting. Background/Objectives: To evaluate the efficacy and safety of PARPi-based therapies—monotherapy and combination with ARSi—in patients with mCRPC, focusing on molecular subgroups defined by DNA repair alterations. Methods: We conducted a systematic review and meta-analysis of phase III randomized controlled trials (RCTs) assessing PARPi as monotherapy or in combination with ARSi. Searches were performed in PubMed, EMBASE, the Cochrane Library, and oncology conference proceedings up to February 2025. Outcomes included radiographic progression-free survival (rPFS), overall survival (OS), second progression-free survival (PFS2), and grade ≥3 adverse events (AEs). Data were pooled using a random-effects model, with subgroup analyses by DNA repair status. Results: Five RCTs (n = 2921) were I confirmincluded: three on combination therapy (n = 2271) and two on monotherapy (n = 650). Combination therapy improved rPFS in the ITT (HR = 0.64; 95% CI: 0.56–0.74), HRRm (HR = 0.55; 95% CI: 0.44–0.68), and BRCAm (HR = 0.33; 95% CI: 0.18–0.58) subgroups. OS was also improved in the ITT (HR = 0.80; 95% CI: 0.70–0.92), HRRm (HR = 0.68; 95% CI: 0.55–0.83), and BRCAm (HR = 0.54; 95% CI: 0.34–0.85) groups. No benefit was observed in non-HRRm patients. PFS2 favored combination therapy (HR = 0.77; 95% CI: 0.64–0.91). Grade ≥3 AEs were more frequent (RR = 1.44; 95% CI: 1.20–1.73). Monotherapy improved rPFS in ITT (HR = 0.46; 95% CI: 0.20–0.81) and BRCAm (HR = 0.33; 95% CI: 0.15–0.75); OS benefit was seen only in BRCAm (HR = 0.73; 95% CI: 0.57–0.95). Conclusions: PARPi therapies improve outcomes mainly in HRR- and BRCA-mutated mCRPC. Molecular selection is key to optimizing benefit and minimizing toxicity. Further research on the activity of PARPi combinations in non-HRR mutated mCRPC is needed to better understand the underlying mechanisms of efficacy. Full article

Background/Objectives: To correlate blood lead (Pb) levels with cancer risk in a prospective cohort of healthy women with non-occupational exposure to lead. We hypothesize that blood Pb levels can predict the risk of cancer in healthy women. Methods: The study was performed with women registered at the Hereditary Cancer Centre, Szczecin, aged 40 years and above between September 2010 and March 2024. A total of 2927 unaffected women were included in the study. Exclusion criteria were BRCA1 gene mutation, women with diagnosed cancer, and women with occupational exposures to Pb. All patients were asked about their occupational exposure and tested for the three Polish BRCA1 founder mutations (c.5266dupC/5382insC; c.181T > G/300T > G; c.4035delA/4153delA). Inductively coupled plasma mass spectrometry was used to measure blood Pb levels. The study was blinded to all scientists involved, and all samples were assayed in the absence of any knowledge about the clinical status of each participant. Results: There were 239 incident cancers diagnosed in the cohort after an average follow-up of 6 years. Compared to women with the lowest blood Pb concentration, women with higher blood Pb levels had a significantly increased risk of developing any cancer (HR = 1.46; (95% CI: 1.006–2.13; p = 0.046)). The association was stronger for women below the age of 50 years at study entry (HR = 2.59; (95% CI: 1.37–4.89; p = 0.003)). For women over 50 years of age, the results were statistically insignificant. Conclusions: This study suggests that blood Pb levels have the potential to be used as a marker of cancer risk in women under 50 years of age who have no known occupational exposure to this heavy metal. Further investigations using additional groups of women from Poland and other countries are needed for validate these findings. Full article

Global epidemiological reports indicate a steady increase in the tendency to develop ovarian cancer. The symptoms of ovarian cancer are non-specific, and there is no effective screening tool. Most often, surgery, chemotherapy, and radiotherapy, alone or in combination, are used to treat ovarian cancer. We have a better understanding of the biology of ovarian cancer, the genetic basis of hereditary ovarian cancer, the stage of the disease, and the role of cytoreductive surgery and more effective chemotherapy, which translates into an increase in the percentage of patients who survive 5 years after diagnosis. A growing body of evidence points to the role of genetic factors in the development of cancer. It is known that mutations in the BRCA1 gene are responsible for an increased risk of developing ovarian cancer. The role of other genetic disorders, such as polymorphic variants, in increasing the risk of developing cancer is still being investigated. Ovarian cancer is a hormone-dependent cancer and its steroid hormones are estrogens. Estrogens affect cells through the estrogen receptors ERα and ERβ. An imbalance between ERα and ERβ receptor expression may, therefore, be a key step in estrogen-dependent carcinogenesis. In 60% of cancer cases, significantly elevated levels of ERα receptors are detected. The ERα receptor is encoded by the ESR1 gene, so its polymorphisms can be considered molecular markers of ovarian cancer. This article discusses the epidemiology, pathogenesis, risk factors, genetic testing, treatment, and diagnosis of ovarian cancer, as well as providing an overview of standard treatment approaches and new, targeted biologic therapies. Full article

Background: Defective DNA repair systems result in the accumulation of mutations, loss of genomic integrity, and eventually cancer. Following initial malignant transformation due to specific DNA damage and defective DNA repair, cancer cells become reliant upon other DNA repair pathways for their survival. The co-occurrence of specific repair deficiencies brings catastrophic outcomes such as cell death for cancer cells and thus holds promise as a potential therapeutic strategy. Exploring the co-occurrence and mutual exclusivity of mutational signatures provides valuable knowledge regarding combinations of defective repair pathways that are cooperative and confer selective advantage to cancer cells and those that are detrimental and cannot be tolerated by them. Methods: Taking advantage of mutational signature profiling, we analyzed whole-genome sequences of 1014 breast cancers to reveal the underlying mutational processes and their interrelationships. Results: We found an inverse relationship between deficiencies of homologous recombination (HRd) and non-homologous end joining (NHEJd) with reactive oxygen species (ROS). Moreover, HRd and NHEJd co-occurred with APOBEC but were mutually exclusive with mismatch repair deficiency (MMRd) and ROS. Our analysis revealed that SBS8 and SBS39 signatures of currently unknown etiology correlate with NHEJd. ID1 and ID2 signatures co-occur with ROS and have mutual exclusivity with HRd, SBS8, SBS39 and NHEJd. The ID4 signature, with currently unknown etiology, has mutual exclusivity with HRd and NHEJd and co-occurred with ROS. On the other hand, the ID15 signature, with currently unknown etiology, co-occurred with SBS8, SBS39, HRd, NHEJd and DBS2, while having an inverse relationship with MMRd and ROS. Comparing the mutational signatures of HRd and non-HRd TNBC genomes reveals the unique presence of ROS signatures in non-HRd tumors and the lack of ROS signature in HRd tumors. Conclusion: Taken together, these analyses indicate the possible application of mutation signatures and their interactions in advancing patient stratification and suggest appropriate therapies targeting the make-up of individual tumors’ mutational processes. Ultimately, this information provides the opportunity to discover promising synthetic lethal candidates targeting DNA repair systems. Full article

Transcribed conserved non-coding elements (TCNEs), which are non-coding genomic elements that can regulate vital gene expression, play an unclear role in the development of severe diseases mainly associated with carcinogenesis. Currently, there are no mature tools for the identification of TCNEs. To compensate for the lack of a systematic interpretation of the functional characterization and regulatory mechanisms of TCNE spatiotemporal activities, we developed a flexible pipeline, called captureTCNE, to depict the landscape of TCNEs and applied it to our breast cancer cohort (SEU-BRCA). Meanwhile, we investigated the genome-wide characteristics of TCNEs and unraveled that TCNEs harbor enhancer-like chromatin signatures as well as participate in the transcriptional machinery to regulate essential genes or architect biological regulatory networks of breast cancer. Specifically, the TCNE transcripts could recruit RBPs, such as ENOX1 and PTBP1, which are involved in gene expression regulation, to participate in the formation of regulatory networks and the association with altered splicing patterns. In particular, the presence of a non-classical secondary structure, called RNA G-quadruplex, on TCNE transcripts contributed to the recruitment of RBPs associated with subtype-specific transcriptional processes related to the estrogen response in breast cancer. Ultimately, we also analyzed the mutational signatures of variant-containing TCNEs and discerned twenty-one genes as essential components of the regulatory mechanism of TCNEs in breast cancer. Our study provides an effective TCNE identification pipeline and insights into the regulatory mechanisms of TCNEs in breast cancer, contributing to further knowledge of TCNEs and the emergence of innovative therapeutic strategies for breast cancer. Full article

Background and Objectives: Despite the well-established role of the BRCA and mismatch repair (MMR) genes in DNA damage repair pathways, a substantial proportion of familial cancer cases still lack pathogenic variants in those genes. Next Generation Sequencing (NGS) panels have emerged as a powerful tool to identify hereditary cancer at-risk individuals and subsequently provide them with accurate management. Materials and Methods: Families harbouring PVs in RAD50, RAD51C, RAD51D, and BRIP1 were identified by analysing a cancer-predisposing genes panel using Ion S5 system technology. A retrospective cohort of 155 families tested only for the BRCAs of MMR genes were reanalysed, prompted by an increase in familial cases or new cancer diagnoses among index cases. Results: We identified 40 families through molecular reanalysis (33 with Hereditary Breast and Ovarian Cancer (HBOC) and 7 with Lynch Syndrome (LS)), with positive test results among 155 families lacking BRCA or MMR mutations. The most frequently mutated genes after ATM and CHEK2 were BRIP1, RAD51D, and RAD51C with 16, 13, and 9 positive families, respectively. The phenotype–genotype correlations not only revealed ovarian and HER-negative breast cancer predispositions but also other cancer types, particularly lung and gastric, and individuals with a second or third distinct cancer episode. Conclusions: Broader ranges of malignancies, including gastric, lung, and bladder, have been identified among BRIP1, RAD51D, and RAD51C positive families. The results generated using NGS provide a comprehensive genetic landscape in each patient that could explain the diversity of phenotypes shown in PV families that, combined with non-genetic factors, might enable accurate surveillance and personalized treatments. NGS reanalysis doubled our diagnostic yield and was a good strategy to identify hereditary cancer families that would otherwise be overlooked. Full article

Patients with a BRCA1 germline mutation often represent a challenge for medical healthcare, since they develop malignancies that tend to be more aggressive and which need to be addressed in multidisciplinary teams with more individualized therapies. We report a case of a 37-year-old woman with a BRCA1 mutation who was diagnosed and treated for high-grade papillary serous carcinoma of the fallopian tube. Eight years later, her regular check-up imaging revealed a latero-aortic lymphadenopathy and a right breast tumor. She underwent a fine needle breast biopsy which was positive for invasive non-specific type carcinoma with negative estrogen, progesterone and Her2 receptors in immunohistochemistry tests. The patient underwent debulking surgery for metastatic lymphadenopathy, followed by chemotherapy with Carboplatin and Paclitaxel, and a modified right mastectomy with axillary lymphadenectomy. She subsequently initiated therapy with the PARP inhibitor Olaparib. No evidence of tumor recurrence was detected during the six-month postoperative follow-up period. The primary goal of this paper is to emphasize the complexity and challenges of managing patients with BRCA1 mutations who develop synchronous malignancies. This case report aims to highlight the increasing role of precision medicine and the importance of personalized, multidisciplinary therapeutic strategies, which include surgery, chemotherapy, and targeted therapies. Full article

Background: Pancreatic cancer (PC) is among the deadliest types of cancer globally. While early detection helps avert adverse outcomes, screening is only recommended for individuals at high risk, specifically those with familial and/or genetic predispositions. The objectives of this study are to systematically review primary studies on the cost-effectiveness of PC screening and to identify the critical factors that influence cost-effectiveness. Methods: This systematic review was performed using PRISMA guidelines. Economic evaluation studies on PC screening were identified from searches on the SCOPUS and PubMed databases. The quality of reporting of the selected articles was assessed according to CHEERS 2022. Using predefined inclusion and exclusion criteria, two reviewers conducted the title–abstract review, full-text review, and data extraction to select relevant articles. The authors’ consensus was used to settle disagreements. The primary outcome was the incremental cost-effectiveness ratio, measured by cost per quality-adjusted life year and cost per life year saved. Results: Nine studies were selected for the final review. Most studies demonstrated that one-time screening for PC among high-risk individuals was cost-effective compared with no screening, while others found annual screening to also be cost-effective. High-risk was generally defined as having a >5% lifetime risk of PC and included individuals with either familial pancreatic cancer (FPC) or genetic susceptibility syndromes such as Peutz–Jeghers Syndrome, hereditary pancreatitis, hereditary non-polypoid colorectal cancer syndrome, familial adenomatous polyposis, and BRCA2 mutations. Individuals with new-onset diabetes (NOD) were also considered high-risk. Screening using mainly endoscopic ultrasound was cost-effective among FPC individuals and those with genetic syndromes. Risk-based screening was also cost-effective among patients with NOD. Conclusion: Screening for PC is cost-effective among selected high-risk individuals. However, cost-effectiveness depends on epidemiological factors, cost, the diagnostic performance of screening tools, and the overall design of studies. Full article

Cancers that arise from germline mutations of breast cancer associated gene 1 (BRCA1), which is a crucial player in homologous recombination (HR) DNA repair, are vulnerable to DNA-damaging agents such as platinum and PARP inhibitors (PARPis). Increasing evidence suggests that BRCA1 is an essential driver of all phases of the cell cycle, thereby maintaining orderly steps during cell cycle progression. Specifically, loss of BRCA1 activity causes the S-phase, G₂/M, spindle checkpoints, and centrosome duplication to be dysregulated, thereby blocking cell proliferation and inducing apoptosis. In vertebrates, loss of HR genes such as BRCA1 and/or BRCA2 is lethal, since HR is a prerequisite for genome integrity. Thus, cancer cells utilize alternative DNA repair pathways such as non-homologous end joining (NHEJ) to cope with the loss of BRCA1 function. In this review, we attempt to update and discuss how these novel components are crucial for regulating DNA damage repair (DDR) in BRCA1-deficient cancers. Full article

Background: The location of BRCA mutations within functional domains may affect sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy. This study aimed to evaluate the progression-free survival (PFS) benefit from the PARP inhibitor in relation to the location of mutations in BRCA1/BRCA2 in newly diagnosed ovarian cancer. Materials and methods: Patients with advanced stage III-IV epithelial ovarian cancer who had deleterious BRCA1 or BRCA2 were analyzed. PFS and clinical and molecular data were compared between patients who received olaparib or niraparib as frontline maintenance therapy and those who did not. Subgroup analyses were conducted based on the location of BRCA mutations within the functional domain or the ovarian cancer cluster region (OCCR). Results: Of the 380 patients, 242 (63.7%) harbored BRCA1 mutation, 137 (36.1%) harbored BRCA2, and one (0.3%) harbored both BRCA1 and BRCA2. With a median follow-up of 35.8 months, the DNA binding domain in BRCA1 (HR, 0.34; 95% CI, 0.15–0.79; p = 0.01) and BRCA2 (HR, 0.25; 95% CI, 0.08–0.78; p = 0.01) demonstrated particularly significant benefit. In patients who harbored BRCA1 mutation in the C-terminal domain (BRCT), no statistically significant PFS benefit from PARP inhibitor was observed (HR, 0.76; 95% CI, 0.39–1.52; p = 0.44). PFS benefit from PARP inhibitor maintenance was observed in both OCCR (HR, 0.49; 95% CI, 0.32–0.74; p < 0.01) and non-OCCR (HR, 0.51; 95% CI, 0.27–0.63; p < 0.01). Conclusions: Frontline PARP inhibitor maintenance therapy demonstrated a significant PFS benefit in patients with BRCA1/2 mutations, with particularly pronounced benefits for those with mutations located in the DBD of BRCA1 and BRCA2. However, the benefit was less evident for patients with BRCA1 mutations located in the BRCT domain. Full article

Background: High-grade advanced ovarian, fallopian tube, and primary peritoneal (HGAOC) cancers require both surgical and systemic treatment. The introduction of polyADP-ribose polymerase inhibitors (PARPis) has significantly improved outcomes. This study presents an analysis of HGAOC patients treated at a single center, following updated guidelines. Methods: We observed 437 women newly diagnosed with HGAOC at the Department of Gynecological Oncology between January 2018 and December 2023. Results: Since November 2022, first-line treatment has included bevacizumab and PARPi, regardless of residual disease post-cytoreductive surgery. In both BRCA1/2-mutated and non-mutated groups, PARPi-based regimens increased significantly after May 2021 (p < 0.01). Recurrence number emerged as a strong prognostic factor for survival (p < 0.001), with each recurrence raising mortality risk by 80%. Median survival was 21 months for paclitaxel + platinum derivatives (PC), 27 months for PC + bevacizumab (BEV), and 30 months for PC + BEV + PARPi. Conclusions: The rapid adoption of modern therapies at our center has aligned treatment strategies with HRD status and global standards. However, variations in financial regulations and drug accessibility persist across countries. Despite these challenges, physicians should prioritize the most effective therapies available. Full article

Background/Objectives: Ductal carcinoma in situ (DCIS) is the most common non-invasive form of breast cancer. It is not clear to what extent DCIS is a part of the hereditary breast/ovarian cancer syndrome caused by BRCA1/2 mutations. Therefore, we investigated the association of BRCA1/2 mutations in patients with DCIS and assessed their impact on survival. Methods: We studied 564 Polish women with DCIS for six alleles in BRCA1 (c.181T>G, c.5266dupC, c.4035delA, c.3700_3704del5, c.68_69del and c.5251C>T) and four in BRCA2 (c.658_659del, c.3847_3848del, c.5946del and c.7913_7917del). To investigate the association of BRCA1/2 founder mutations with DCIS risk, we tested 4702 controls as a reference. To analyze survival, mutation carriers were followed for an average of 110 months. Results: A BRCA1 mutation was present in seven (1.24%) cases and in twenty-two (0.47%) controls (OR = 3.27, 95%CI 1.36 to 7.87, p = 0.01). A BRCA2 mutation was present in eight (1.42%) cases versus six (0.13%) controls (OR = 11.3, 95%CI 3.9 to 32.6, p < 0.0001). Three of the fifteen cases with BRCA1/2 mutations developed invasive ipsilateral or contralateral breast cancer, on average 6 years from the diagnosis of DCIS. There were no deaths reported among the 15 mutation carriers with DCIS. Conclusions: DCIS is a part of the hereditary breast/ovarian cancer syndrome caused by BRCA1/2 mutations. Women with DCIS should receive genetic counseling and testing for BRCA1/2 mutations. BRCA1/2 mutations may predispose women to a better DCIS prognosis, but further studies are needed. Full article

Background/Objectives: Mutations in BRCA1 and/or BRCA2 (BRCAm) and other homologous recombination repair genes (HRRm) are associated with several cancers. We evaluated the prevalence and association with overall survival (OS) of somatic BRCAm and HRRm among patients with advanced solid tumors. Methods: We used deidentified data from the AACR GENIE Biopharma Collaborative dataset derived from patients with tumors genotyped using next-generation sequencing between 1 January 2014 and 31 December 2017. Eligible patients were aged ≥18 years diagnosed with non-small-cell lung, colorectal, breast, bladder, prostate, or pancreatic cancer, with documented BRCA/HRR somatic mutation status. The primary analysis was OS (censored at the start of poly[ADP ribose] polymerase inhibitors [PARPi]/immunotherapy) after initiation of second-line therapy since most patients had sequencing after first-line therapy. Results: Among eligible patients, 242/7022 (3.4%) had BRCAm and 477/5474 (8.7%) had HRRm. Adjusted OS HRs (95% CI) for the primary analysis (using the initiation of second-line therapy as index date) were 0.79 (0.61–1.03) with/without BRCAm (n = 116/n = 3394) and 0.83 (0.69–0.99) with/without HRRm (n = 247/n = 2656); in sensitivity analysis of patients with stage IV disease, HRs were 0.97 (0.68–1.38) with/without BRCAm (n = 58/n = 1847) and 0.92 (0.73–1.18) with/without HRRm (n = 132/n = 1488). Conclusions: Overall, BRCAm and HRRm did not show a strong association with OS, with a trend toward longer OS among patients receiving standard second-line therapies excluding PARPi/immunotherapy. Full article