Partner And Localizer Of BRCA2 Research Articles

Challenges in the management of operable triple-negative breast cancer in a survivor of the B-cell acute lymphoblastic leukemia: a case report

BackgroundOperable triple-negative breast cancer (TNBC) is an unfavorable subtype of breast cancer, which usually requires an aggressive perioperative systemic treatment. When TNBC presents as a second primary cancer after cured acute leukemia, its management might be challenging.Case presentationWe present a case report of a young postmenopausal woman with an operable TNBC who had a history of the B-cell acute lymphoblastic leukemia (B-ALL) and graft versus host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). A history of previous treatment with anthracyclines and radiotherapy and GVHD limited the use of doxorubicin for treatment of her TNBC. Due to the history of GVHD, perioperative treatment with pembrolizumab was omitted. Genetic testing was challenging due to the possible contamination of her tissues with the donor’s cells after allo-SCT. In samples of our patient’s buccal swab, peripheral blood, and tumor tissue, a pathogenic variant in the partner and localizer of BRCA2 (PALB2) gene was found. With neoadjuvant chemotherapy which included carboplatin, a pathologic complete response was achieved. Although our patient has a low risk for recurrence of TNBC, her risk for the development of new primary cancers remains substantial.ConclusionThis case highlights challenges in the systemic treatment, genetic testing, and follow-up of patients with operable TNBC and other solid cancers who have a history of acute leukemia.

Quantitative Assessment of PALB2 and BRIP1 Genes Expression in the Breast Cancer Cell Line under the Influence of Tamoxifen

Background:Breast cancer is considered one of the leading causes of mortality in the world. Cancer incidence and consequently, drug consumption can strongly influence gene expressions at the transcriptome level. Therefore, the assessment of the candidate biomarkers’ gene expression can accelerate the diagnosis process and increase the chance of treatment and remission. In this regard, the quantitative assessment of Partner and localizer of BRCA2 (PALB2) and BRCA1 Interacting Helicase 1 (BRIP1) genes expression in the breast cancer cell line under the treatment of Tamoxifen (TAM) was executed in this study. Materials and Methods :MCF7 cells were cultured as TAM-treated and control groups. RNA extraction and cDNA synthesis were performed based on the instructions of provided kits. qPCR Hi-ROX Master Mix kit was applied to the Quantitative Real-Time Polymerase Chain Reaction (Q-PCR). The outputs of Q-PCR were analyzed by REST statistical software. Results:Outcomes derived from data analysis of BRIP1 gene expression did not show any significant difference between the gene expression of control and TAM-treated groups. The expression of PALB2 was significantly higher in the TAM-treated group compared to the control group (P<0.05). Conclusion:Our findings showed a significant alteration between PALB2 gene expression in the TAM-treated breast cancer cell line and the control cell line. The quantitative assessment of mentioned genes as possible markers could be considered a non-invasive method for breast cancer in the processes of prognostic evaluations, screening, and treatment monitoring.

Evolutionary Origin of Human PALB2 Germline Pathogenic Variants.

PALB2 (Partner and localizer of BRCA2) is crucial for repairing DNA double-stranded breaks (DSBs) through homologous recombination (HR). Germline pathogenic variation in PALB2 disrupts DNA damage repair and increases the risk of Fanconi Anemia, breast cancer, and ovarian cancer. Determination of the evolutionary origin of human PALB2 variants will promote a deeper understanding of the biological basis of PALB2 germline variation and its roles in human diseases. We tested the evolution origin for 1444 human PALB2 germline variants, including 484 pathogenic and 960 benign variants. We performed a phylogenic analysis by tracing the variants in 100 vertebrates. However, we found no evidence to show that cross-species conservation was the origin of PALB2 germline pathogenic variants, but it is indeed a rich source for PALB2 germline benign variants. We performed a paleoanthropological analysis by tracing the variants in over 5000 ancient humans. We identified 50 pathogenic in 71 ancient humans dated from 32,895 to 689 before the present, of which 90.1% were dated within the recent 10,000 years. PALB2 benign variants were also highly shared with ancient humans. Data from our study reveal that human PALB2 pathogenic variants mostly arose in recent human history.

Molecular basis and therapeutic targets in prostate cancer: A comprehensive review.

Prostate cancer is one of the most significant causes of morbidity and mortality in male patients. The incidence increases with age, and it is higher among African Americans. The occurrence of prostate cancer is associated with many risk factors, including genetic and hereditary predisposition. The most common genetic syndromes associated with prostate cancer risk are BRCA-associated hereditary breast and ovarian cancer (HBOC) and Lynch syndrome. Local-regional therapy, i.e., surgery is beneficial in early-stage prostate cancer management. Advanced and metastatic prostate cancers require systemic therapies, including hormonal inhibition, chemotherapy, and targeted agents. Most prostate cancers can be treated by targeting the androgen-receptor pathway and decreasing androgen production or binding to androgen receptors (AR). Castration-resistant prostate cancer (CRPC) usually involves the PI3K/AKT/mTOR pathway and requires targeted therapy. Specific molecular therapy can target mutated cell lines in which DNA defect repair is altered, caused by mutations ofBRCA2, partner and localizer of BRCA2 (PALB2), and phosphatase and tensin homolog (PTEN) or the transmembrane protease serine 2-ERG (TMPRSS2-ERG)fusion. Most benefits were demonstrated incyclin dependent-kinase 12 (CDK12)mutated cell lines when treated with anti-programmed cell death protein 1 (PD1) therapy. Therapies targetingp53and AKT are the subject of ongoing clinical trials. Many genetic defects are listed as diagnostic, prognostic, and clinically actionable markers in prostate cancer. Androgen receptor splice variant 7 (AR-V7) is an important oncogenic driver and an early diagnostic and prognostic marker, as well as a therapeutic target in hormone-resistant CRPC. This review summarizes the pathophysiological mechanisms and available targeted therapies for prostate cancer.

Spectrum of High-Risk Mutations among Breast Cancer Patients Referred for Multigene Panel Testing in a Romanian Population

(1) Background: Multigene panel testing for Hereditary Breast and Ovarian Cancer (HBOC) using next generation sequencing (NGS) is becoming a standard in medical care. There are insufficient genetic studies reported on breast cancer (BC) patients from Romania and most of them are focused only on BRCA 1/2 genes (Breast cancer 1/2). (2) Methods: NGS was performed in 255 consecutive cases of BC referred for management in our clinic between 2015-2019. (3) Results: From the 171 mutations identified, 85 were in the high-penetrance BC susceptibility genes category, 72 were pathogenic genes, and 13 genes were in the (variants of uncertain significance) VUS genes category. Almost half of the mutations were in the BRCA 1 gene. The most frequent BRCA1 variant was c.3607C>T (14 cases), followed by c.5266dupC (11 cases). Regarding BRCA-2 mutations we identified c.9371A>T (nine cases), followed by c.8755-1G>A in three cases, and we diagnosed VUS mutations in three cases. We also identified six pathogenic variants in the PALB2 gene and two pathogenic variants in (tumor protein P 53) TP53. (4) Conclusions: The majority of pathogenic mutations in the Romanian population with BC were in the BRCA 1/ 2 genes, followed by PALB2 (partner and localizer of BRCA2) and TP53, while in the CDH1 (cadherin 1) and STK11 (Serine/Threonine-Protein Kinase) genes we only identified VUS mutations.

Diagnosis, Management, and Surveillance for Patients With PALB2, CHEK2, and ATM Gene Mutations

BackgroundThis study aims to capture clinical and surgical practice patterns of patients with deleterious mutations in partner and localizer of BRCA2 (PALB2), checkpoint kinase 2 (CHEK2) and ataxia telangiesctasia mutated (ATM) genes. Materials and MethodsThis study is a retrospective chart review of patients with PALB2, CHEK2 or ATM mutations. Patient demographics, testing indications, management decisions, and surveillance strategies were recorded. ResultsSixty-two patients were found to have deleterious mutations: 14 (23%) with a PALB2 mutation, 30 (48%) with a CHEK2 mutation, and 18 (29%) patients with an ATM mutation.Thirty-one (50%) patients have a history of breast cancer. Twenty-three patients were diagnosed and treated prior to genetic testing while 8 patients learned of their mutation status and breast cancer diagnosis simultaneously. Of these 8 patients, 4 sought treatment at our institution, 3 underwent bilateral mastectomy, and 1 patient opted for lumpectomy and surveillance.Thirty-one patients had no history of breast cancer. After genetic diagnosis, 3 of the 9 patients who continued clinical follow-up proceeded with bilateral prophylactic mastectomy within 2 years. Clinical surveillance continued for 23 months on average. ConclusionMost patients who learned of their genetic and breast cancer diagnoses simultaneously underwent bilateral mastectomy, whereas only a third of patients without cancer opted for bilateral prophylactic mastectomy.

Abstract 2420: The effects of structural changes in PALB2 (partner and localizer of BRCA2) ability to bind DNA

Abstract 2420: The effects of structural changes in PALB2 (partner and localizer of BRCA2) ability to bind DNA

Aspirin for the primary prevention of breast cancer: an unforeseen advantage

Aspirin for the primary prevention of breast cancer: an unforeseen advantage

A phase II study of talazoparib monotherapy in patients with wild-type BRCA1 and BRCA2 with a mutation in other homologous recombination genes

Talazoparib, a PARP inhibitor, is active in germline BRCA1 and BRCA2 (gBRCA1/2)-mutant advanced breast cancer, but its activity beyond gBRCA1/2 is poorly understood. We conducted Talazoparib Beyond BRCA (NCT02401347), an open-label phase II trial, to evaluate talazoparib in patients with pretreated advanced HER2-negative breast cancer (n = 13) or other solid tumors (n = 7) with mutations in homologous recombination (HR) pathway genes other than BRCA1 and BRCA2. In patients with breast cancer, four patients had a Response Evaluation Criteria in Solid Tumors (RECIST) partial response (overall response rate, 31%), and three additional patients had stable disease of ≥6 months (clinical benefit rate, 54%). All patients with germline mutations in PALB2(gPALB2; encoding partner and localizer of BRCA2) had treatment-associated tumor regression. Tumor or plasma circulating tumor DNA (ctDNA) HR deficiency (HRD) scores were correlated with treatment outcomes and were increased in all gPALB2 tumors. In addition, a gPALB2-associated mutational signature was associated with tumor response. Thus, talazoparib has been demonstrated to have efficacy in patients with advanced breast cancer who have gPALB2 mutations, showing activity in the context of HR pathway gene mutations beyond gBRCA1/2.

1707P The landscape of PALB2 alteration in Chinese solid tumor patients

Partner and localizer of BRCA2 (PALB2) is a nuclear protein that localizes to sites of DNA double-strand breaks and interacts with BRCA1 and BRCA2 to promote DNA repair. The differences in mutation profiles of PALB2 gene in pan-cancer can help understand pathogenesis, prognosis, and identify targets for therapy. Using commercial NGS assays, we retrospectively analyzed genomic DNA alterations in normal-paired samples from 3880 patients with malignancies between 2019 to 2021, and alterations including single base substitution, short and long insertion/deletions, copy number variations, gene fusions and rearrangements. PALB2 gene was altered in 2.0% (78 of 3880) of all solid tumors, comparable to 1.5% (158 of 10336) of PALB2 alterations in the MSK-IMPACT Clinical Sequencing Cohort (MSKCC, Nat Med 2017). The frequency of PALB2 variations was assessed in multiple cancer types, including bladder cancer 6.1% (2/33), thyroid cancer 4.9% (2/41), colorectal cancer 4.0% (19/478), prostatic cancer 3.8% (1/26), small cell lung cancer 3.4% (1/29), pancreatic cancer 2.5% (4/160), gastrointestinal stromal tumor 2.3% (1/44), liver cancer 2.2% (5/230), biliary tract tumor 2.1% (3/141) and non-small cell lung cancer 2.0% (28/1402). A total 93 genetic alterations were identified in 78 patients, including 58 missense mutations (63%), 18 nonsense (12%), 12 frameshift (10%), 3 splicing (8%), 5 copy number loss (5%), 1 in-frame insertion (2%), 1 in-frame deletion (2%). Among these patients, 14 had pathogenic or likely pathogenic germline PALB2 heterozygous mutations, including prostatic cancer 3.8% (1/26), biliary tract tumor 2.1% (3/141), pancreas tic cancer 1.3% (2/160), colorectal cancer 0.8% (4/478), liver cancer 0.4% (1/230) and non-small cell lung cancer 0.2% (3/1821). Furthermore, in our cohort, PALB2 mutation carriers also owned other actionable, the most frequent one was TP53 (65%), followed by LRP1B (28%), KRAS (27%) and PIK3CA (24%). PALB2 deleterious mutations are highly diverse and present at low to moderate frequencies across many cancers. PALB2 alterations warrant further investigation as predictive biomarkers of response to PARP inhibitors or platinum-based therapy.

Disease-related protein co-expression networks are associated with the prognosis of resectable node-positive pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a multifactorial disease, the molecular profile of which remains unclear. This study aimed at unveiling the disease-related protein networks associated with different outcomes of resectable, node-positive PDAC cases. We assessed laser-microdissected cancerous cells from PDAC tissues of a poor outcome group (POG; n = 4) and a better outcome group (BOG; n = 4). Noncancerous pancreatic duct tissues (n = 5) were used as the reference. We identified four representative network modules by applying a weighted network correlation analysis to the obtained quantitative PDAC proteome datasets. Two network modules that were significant for POG were associated with the heat shock response to hypoxia-related stress; in the latter, a large involvement of the non-canonical Hedgehog pathway (regulated by GLI1), the internal ribosome entry site-mediated cap-independent translation, the inositol requiring enzyme 1-alpha (IRE1α)/X-box binding protein 1 pathway of the unfolding protein response (UPR), and the aerobic glycolysis was observed. By contrast, the BOG characteristic module was involved in the inactivation of the UPR pathway via the synoviolin 1-dependent proteasomal degradation of IRE1α, the activation of SOX2, and the loss of PALB2 (partner and localizer of BRCA2) function, all potentially suppressing malignant tumor development. Our findings might facilitate future therapeutic strategies for PDAC.

Partner and localizer of BRCA2 (PALB2) pathogenic variants and ovarian cancer: A systematic review and meta-analysis.

e17597 Background: Approximately 20% of ovarian cancers are due to an underlying germline pathogenic variant. While several genes have been well-established in the development of hereditary ovarian cancer (e.g. BRCA1/2, RAD51C, RAD51D, BRIP1, mismatch repair genes), there are other genes for which the cancer risk is less certain and management recommendations remain controversial, including partner and localizer of BRCA 2 (PALB2). We sought to evaluate the association between PALB2 germline pathogenic mutations and ovarian cancer in the first meta-analysis on this topic. Methods: We conducted a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO no.: CRD42021281325). We searched key electronic databases to identify studies evaluating multigene panel testing in patients with ovarian cancer. Eligible trials were subjected to meta-analysis. Results: Thirty-seven studies met inclusion criteria. We found 55,137 cases of ovarian cancer with information available on germline PALB2 pathogenic variant status. Reported histological subtypes included serous adenocarcinoma (74.8%), endometroid (6.5%), clear cell (2.1%), mucinous (3.1%), and other (13.5%). Most ovarian cancers were stages III (73.5%) and IV (22.3%), followed by II (6.0%), and I (4.1%). Among ovarian cancer cases with PALB2 sequencing data available, 0.4% demonstrated a germline pathogenic variant in the PALB2 gene and the pooled odds ratio (OR) for having a PALB2 mutation was 2.31 (95% CI 0.89- 5.98). Among 94 patients with a germline PALB2 pathogenic variant, the pooled odds ratio (OR) for developing ovarian cancer was 2.85 (95% CI 1.58-5.15) relative to 33,855 patients without PALB2 mutations. Conclusions: Our meta-analysis demonstrates that the pooled OR for developing ovarian cancer with an underlying PALB2 germline pathogenic variant was 2.85 (95% CI 1.58-5.15). While this risk is lower than many of the well-established hereditary ovarian cancer genes, it does exceed the baseline population risk of 1-2%. Whether this meets the threshold to consider risk-reducing salpingo-oophorectomy is up for debate. Large population-based studies and evaluation of the combination of PALB2 mutations and cancer family history are needed to improve management recommendations for patients harboring pathogenic mutations in this gene.

Disrupted BRCA1-PALB2 interaction induces tumor immunosuppression and T-lymphocyte infiltration in HCC through cGAS-STING pathway.

BRCA1 (BRCA1 DNA repair associated) and PALB2 (partner and localizer of BRCA2) interact with each other to promote homologous recombination and DNA double-strand breaks repair. The disruption of this interaction has been reported to play a role in tumorigenesis. However, its precise function in HCC remains poorly understood. We demonstrated that mice with disrupted BRCA1-PALB2 interaction were more susceptible to HCC than wild-type mice. HCC tumors arising from these mice showed plenty of T-lymphocyte infiltration and a better response to programmed cell death 1 (PD-1) antibody treatment. Mechanistically, disruption of the BRCA1-PALB2 interaction causes persistent high level of DNA damage in HCC cells, leading to activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in both malignant hepatocytes and M1 macrophages in the tumor microenvironment. The activated cGAS-STING pathway induces programmed cell death 1 ligand 1 expression via the STING-interferon regulatory factor 3 (IRF3)-signal transducer and activator of transcription 1 pathway, causing immunosuppression to facilitate tumorigenesis and tumor progression. Meanwhile, M1 macrophages with an activated cGAS-STING pathway could recruit T lymphocytes through the STING-IRF3 pathway, leading to T-lymphocyte infiltration in tumors. After normalizing immune responses by PD-1 antibody treatment, the infiltrating T lymphocytes attack tumor cells rapidly and effectively. This study reveals that persistent DNA damage caused by a defective BRCA pathway induces tumor immunosuppression and T-lymphocyte infiltration in HCC through the cGAS-STING pathway, providing insight into tumor immune microenvironment remodeling that may help improve HCC response to PD-1 antibody treatment.

Advancements in the Treatment of Triple-Negative Breast Cancer: A Narrative Review of the Literature.

Triple-negative breast cancers (TNBCs) are aggressive tumors that are more common in young women, African American populations, and those with hereditary mutations. These tumors are notable for their high recurrence rate and predilection for chemoresistance. The goal of this narrative review is to describe the current treatment options for patients diagnosed with TNBC and to review the studies that have put forward these recommendations. We searched PubMed and Cochrane databases for free full-text, English-language studies published within the last several years pertaining to the search items “triple negative breast cancer” and “treatment”. We included clinical trials and retrospective reviews that had clear designs and assessed their findings against a gold standard or placebo and included evidence of overall response and/or survival outcomes. Patients with early-stage (I-III) TNBC still benefit from treatment with chemotherapeutic regimens involving anthracyclines, taxanes, and antimetabolites. Platinum-based therapies have been shown to improve the overall pathologic complete response (pCR), but there is conflicting evidence with regard to their contribution to disease-free survival (DFS) and overall survival (OS), even with the addition of a poly (ADP-ribose) polymerase (PARP) inhibitor. Patients with residual disease after neoadjuvant chemotherapy and surgical intervention have shown a significant improvement in OS when treated with adjuvant capecitabine. The high mutation burden in metastatic TNBC (mTNBC) allows for targeted therapies and immune checkpoint inhibitors. mTNBCs that express programmed death ligand-1 (PD-L1) receptors may achieve improved response and survival if their regimen includes a monoclonal antibody. Antibody-drug conjugates (ADCs) can deliver high doses of chemotherapy and significantly impact survival in mTNBC regardless of the level of biomarkers expressed by the tumor cells. PARP inhibitors significantly improve survival in newly diagnosed, treatment-naive mTNBC, but have shown mixed results in patients with a history of previous therapy. PARP inhibitors may also target patients with somatic breast cancer (BRCA) and partner and localizer of BRCA-2 (PALB2) mutations, which would allow for more options in this subset of patients. While other rare targets have shown mixed results, the future of treatment may lie in anti-androgen therapy or the development of cancer vaccinations that may increase the immunogenicity of the tumor environment.The management of TNBC includes treatment with multimodal chemotherapy, immune checkpoint inhibitors, and ADCs. The optimal approach depends on a multitude of factors, which include the stage of the tumor, its unique mutational burden, comorbid conditions, and the functional status of the patient. Physicians should be familiar with the advantages and disadvantages of each therapy in order to appropriately counsel and guide their patients.

Coiled-Coil Domain: Uncoiling Tumor Suppression by BRCA1.

The coiled-coil domain of BRCA1 is essential for its interaction with partner and localizer of BRCA2 (PALB2). In mice, loss of this interaction is known to result in Fanconi anemia-associated phenotypes. In a study published in this issue of Cancer Research, Pulver and colleagues from the Jonkers lab have generated a mouse model with a leucine to proline change in codon 1363 in the coiled-coil domain of BRCA1 (Brca1LP ), which disrupts its binding with PALB2. Unlike the previously reported viable coiled-coil defective mice, homozygous Brca1LP/LP mutant mice die during embryogenesis. The authors examined the role of the BRCA1/PALB2 interaction on mammary tumorigenesis and reported increased incidence of mammary tumors that are carcinosarcomas or sarcomatoids, unlike the adenocarcinomas that are characteristic mammary tumor types associated with loss of Brca1 and Trp53 in mice. The findings reveal the relevance of the coiled-coil domain in mammary tumor suppression by BRCA1.See related article by Pulver et al., p. 6171.

Germline PALB2 Mutation in High-Risk Chinese Breast and/or Ovarian Cancer Patients.

Simple SummaryBreast cancer is the most commonly diagnosed cancer in women globally. BRCA1 and BRCA2 mutations are most prevalent in hereditary breast cancer and are associated with increased risk of breast and ovarian cancer. The PALB2 (partner and localizer of BRCA2) mutation was found to be associated with an increased risk of breast cancer and one of the most common mutations, after BRCA1 and BRCA2, in non-BRCA1/2 breast cancer patients. The prevalence of the PALB2 mutation in breast cancer varies across different ethnic groups; hence, it is of intense interest to evaluate the cancer risk and clinical association of PALB2 mutation in Chinese breast and/or ovarian cancer patients. The prevalence of the PALB2 mutation in breast cancer varies across different ethnic groups; hence, it is of intense interest to evaluate the cancer risk and clinical association of the PALB2 mutation in Chinese breast and/or ovarian cancer patients. We performed sequencing with a 6-gene test panel (BRCA1, BRCA2, TP53, PTEN, PALB2, and CDH1) to identify the prevalence of the PALB2 germline mutation among 2631 patients with breast and/or ovarian cancer. In this cohort, 39 mutations were identified with 24 types of mutation variants, where the majority of the mutations were frame-shift mutations and resulted in early termination. We also identified seven novel PALB2 mutations. Most of the PALB2 mutation carriers had breast cancer (36, 92.3%) and were more likely to have family history of breast cancer (19, 48.7%). The majority of the breast tumors were invasive ductal carcinoma (NOS type) (34, 81.0%) and hormonal positive (ER: 32, 84.2%; PR: 23, 60.5%). Pathogenic mutations of PALB2 were found in 39 probands with a mutation frequency of 1.6% and 1% in breast cancer and ovarian cancer patients, respectively. PALB2 mutation carriers were more likely have hormonal positive tumors and were likely to have familial aggregation of breast cancer.

A phase II clinical trial of talazoparib monotherapy for PALB2 mutation-associated advanced breast cancer.

TPS1109 Background: PALB2 (Partner and Localizer of BRCA2) plays a critical role in the maintenance of genomic integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. Our recently reported phase II clinical trial (Gruber, et al. JCO 2019) showed that talazoparib monotherapy was associated with single agent activity in germline PALB2 (gPALB2) mutation-associated advanced breast cancers. Of 5 patients with a germline PALB2 mutation, all 5 had reduction in target lesions > 20% with 3 of 5 achieving a RECIST 1.1 response. All patients had visceral metastases and were heavily pretreated; one response occurred in a patient with 8 prior lines of therapy for metastatic breast cancer. Clinical activity of the PARP inhibitor olaparib was also demonstrated in breast cancer patients with gPALB2 mutations in the Olaparib Expanded trial (TBCRC 048). Thus, we believe there is significant value in generating additional PARP inhibitor monotherapy data in subjects with advanced PALB2 mutation-associated breast cancer. We propose this phase II trial to better estimate the rate of RECIST 1.1 objective response in this patient population. Methods: This is a single-arm, two-stage, non-randomized study to assess the objective response rate (ORR) of talazoparib monotherapy in patients with PALB2 mutation-associated advanced breast cancer. Eligible subjects will be adults with inoperable locally advanced or metastatic breast cancer with a germline or somatic PALB2 mutation with 0-3 prior therapies for advanced disease. Eligible patients must have a deleterious or suspected deleterious mutation in PALB2 on a CLIA approved commercial germline or next generation sequencing tumor assay. Study treatment is talazoparib 1 mg PO daily. In stage 1, ORR will be assessed after 15 patients; if at least 2 responses are observed then an additional 15 patients will be enrolled; if less than 2 responses are observed the study will be terminated. The primary objective is to evaluate whether talazoparib monotherapy can induce a 30% ORR in subjects with advanced breast cancer associated with a PALB2 mutation. Response will be assessed by RECIST 1.1. Secondary objectives include safety, PFS, clinical benefit rate, and patient-reported quality-of-life. Exploratory endpoints will assess for the presence of PALB2 loss-of-heterozygosity, biallelic mutations, correlation of ctDNA profile with treatment response and the correlation of germline versus somatic mutations with response rate. This trial is currently activated and enrolling at Stanford Cancer Center and it is expected that 4 additional sites will be added. Conclusion: This trial will evaluate gPALB2 as a biomarker for PARP inhibitor monotherapy in advanced or metastatic HER2- breast cancer. Clinical trial information: pending .

Assessment of Global DNA Double-Strand End Resection using BrdU-DNA Labeling coupled with Cell Cycle Discrimination Imaging.

The study of the DNA damage response (DDR) is a complex and essential field, which has only become more important due to the use of DDR-targeting drugs for cancer treatment. These targets are poly(ADP-ribose) polymerases (PARPs), which initiate various forms of DNA repair. Inhibiting these enzymes using PARP inhibitors (PARPi) achieves synthetic lethality by conferring a therapeutic vulnerability in homologous recombination (HR)-deficient cells due to mutations in breast cancer type 1 (BRCA1), BRCA2, or partner and localizer of BRCA2 (PALB2). Cells treated with PARPi accumulate DNA double-strand breaks (DSBs). These breaks are processed by the DNA end resection machinery, leading to the formation of single-stranded (ss) DNA and subsequent DNA repair. In a BRCA1-deficient context, reinvigorating DNA resection through mutations in DNA resection inhibitors, such as 53BP1 and DYNLL1, causes PARPi resistance. Therefore, being able to monitor DNA resection in cellulo is critical for a clearer understanding of the DNA repair pathways and the development of new strategies to overcome PARPi resistance. Immunofluorescence (IF)-based techniques allow for monitoring of global DNA resection after DNA damage. This strategy requires long-pulse genomic DNA labeling with 5-bromo-2'-deoxyuridine (BrdU). Following DNA damage and DNA end resection, the resulting single-stranded DNA is specifically detected by an anti-BrdU antibody under native conditions. Moreover, DNA resection can also be studied using cell cycle markers to differentiate between various phases of the cell cycle. Cells in the S/G2 phase allow the study of end resection within HR, whereas G1 cells can be used to study non-homologous end joining (NHEJ). A detailed protocol for this IF method coupled to cell cycle discrimination is described in this paper.

PALB2 upregulation is associated with a poor prognosis in pancreatic ductal adenocarcinoma.

During DNA repair, BRCA1 and BRCA2 interact with the tumor suppressor partner and localizer of BRCA2 (PALB2). PALB2 mutations are associated with an increased risk of breast and ovarian carcinoma, and upregulated PALB2 expression is associated with poor clinical outcomes. The present study investigated the role and prognostic value of PALB2 in pancreatic ductal adenocarcinoma (PDAC). PALB2 expression was inhibited using a small interfering RNA in PDAC cell lines, and the subsequent effects on cell proliferation and migration were investigated. Tissue microarrays from 157 patients undergoing a pancreaticoduodenectomy for PDAC were analyzed via immunohistochemistry, and PALB2 expression was compared with patient outcomes using Kaplan-Meier curves and the multivariate Cox regression model. PALB2-knockdown in PDAC cells had little effect on cell proliferation, but significantly decreased cell migration. Relatively high PALB2 expression was observed in PDAC tissues compared with in peritumoral tissues. Overall survival (OS) was negatively associated with PALB2 expression. TNM stage and PALB2 expression were identified as independent prognostic factors associated with OS via multivariate analysis. Overall, the present study demonstrated that PDAC cell migration was dependent on PALB2, which was further supported by the finding that elevated PALB2 expression in PDAC tissues was associated with poor survival in patients with PDAC. Therefore, PALB2 may serve as a novel prognostic marker in PDAC, which may aid with the development of therapeutic strategies for the disease.

BRCA1 and PALB2 in a Messy Breakup.

Mutations in the BRCA1 gene cause an extremely high lifetime risk of breast and ovarian cancer, but the exact mechanism by which the BRCA1 protein acts to prevent cancer onset remains unclear. In this edition of Cancer Research, Park and colleagues describe a new mouse model featuring a single amino acid substitution in the coiled-coil motif of BRCA1. This change prevents BRCA1 from interacting with PALB2 (partner and localizer of BRCA2), causing rapid cancer onset and a loss of blood cells similar to Fanconi anemia.See related article by Park et al., p. 4172.