• Epithelial ovarian cancer
• Immune activation
• Olaparib
• PARP inhibitor
• Tremelimumab

• Humans
• Female
• Phthalazines/administration & dosage
• Phthalazines/adverse effects
• Middle Aged
• Carcinoma, Ovarian Epithelial/drug therapy
• Carcinoma, Ovarian Epithelial/immunology
• Piperazines/administration & dosage
• Piperazines/adverse effects
• Neoplasm Recurrence, Local/drug therapy
• Neoplasm Recurrence, Local/immunology
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Aged
• Adult
• Antibodies, Monoclonal, Humanized/administration & dosage
• Antibodies, Monoclonal, Humanized/adverse effects
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/immunology
• Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage
• Poly(ADP-ribose) Polymerase Inhibitors/adverse effects

• P30 CA006973 NCI NIH HHS

• cancer therapy
• molecular medicine
• gynaecological cancer

• Humans
• Female
• Endometrial Neoplasms/drug therapy
• Endometrial Neoplasms/pathology
• Phthalazines/administration & dosage
• Phthalazines/adverse effects
• Piperazines/administration & dosage
• Piperazines/adverse effects
• Metformin/administration & dosage
• Metformin/therapeutic use
• Metformin/adverse effects
• Middle Aged
• Cyclophosphamide/administration & dosage
• Cyclophosphamide/adverse effects
• Cyclophosphamide/therapeutic use
• Aged
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/administration & dosage
• Neoplasm Recurrence, Local/drug therapy
• Adult
• Administration, Metronomic
• Aged, 80 and over
• Progression-Free Survival
• Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage
• Poly(ADP-ribose) Polymerase Inhibitors/adverse effects
• Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use

• CLIP2 Institut National Du Cancer (French National Cancer Institute)
• Investigator sponsored study AstraZeneca

• NGS
• Ovarian cancer
• biomarker
• expression
• pathogenic mutations

• 3-aminobenzamide
• Chronic myeloid leukemia
• Immunogenic cell death
• Indolequinone
• NAD
• Necrosis
• OXPHOS
• PARP1

• PARP inhibitors
• antiangiogenic agents
• bevacizumab
• combination therapy
• meta-analysis
• olaparib
• ovarian cancer

• Clinical trial
• DNA damage repair
• Homologous recombination repair
• Pharmacology
• Poly-ADP-ribosylation
• Targeted agent

• Adult
• Female
• Humans
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• BRCA1 Protein/genetics
• BRCA2 Protein/genetics
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Leukocytes, Mononuclear
• Phthalazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases/genetics

• HHSN261201500003C NCI NIH HHS
• HHSN261201500003I NCI NIH HHS
• UM1 CA186712 NCI NIH HHS
• National Cancer Institute

DNA ligases are crucial for DNA repair and cell replication since they catalyze the final steps in which DNA breaks are joined. DNA Ligase III (LIG3) exerts a pivotal role in Alternative-Non-Homologous End Joining Repair (Alt-NHEJ), an error-prone DNA repair pathway often up-regulated in genomically unstable cancer, such as Multiple Myeloma (MM). Based on the three-dimensional (3D) LIG3 structure, we performed a computational screening to identify LIG3-targeting natural compounds as potential candidates to counteract Alt-NHEJ activity in MM.

Virtual screening was conducted by interrogating the Phenol Explorer database. Validation of binding to LIG3 recombinant protein was performed by Saturation Transfer Difference (STD)—nuclear magnetic resonance (NMR) experiments. Cell viability was analyzed by Cell Titer-Glo assay; apoptosis was evaluated by flow cytometric analysis following Annexin V-7AAD staining. Alt-NHEJ repair modulation was evaluated using plasmid re-joining assay and Cytoscan HD. DNA Damage Response protein levels were analyzed by Western blot of whole and fractionated protein extracts and immunofluorescence analysis. The mitochondrial DNA (mtDNA) copy number was determined by qPCR. In vivo activity was evaluated in NOD-SCID mice subcutaneously engrafted with MM cells.

Here, we provide evidence that a natural flavonoid Rhamnetin (RHM), selected by a computational approach, counteracts LIG3 activity and killed Alt-NHEJ-dependent MM cells. Indeed, Nuclear Magnetic Resonance (NMR) showed binding of RHM to LIG3 protein and functional experiments revealed that RHM interferes with LIG3-driven nuclear and mitochondrial DNA repair, leading to significant anti-MM activity in vitro and in vivo.

Taken together, our findings provide proof of concept that RHM targets LIG3 addiction in MM and may represent therefore a novel promising anti-tumor natural agent to be investigated in an early clinical setting.

The online version contains supplementary material available at 10.1186/s12967-022-03705-z.

• DNA Ligase III
• DNA repair
• Flavonoid
• Genomic Instability
• LIG3
• Multiple myeloma
• Natural compounds
• Polyphenols
• Rhamnetin

Background: PARP inhibitors have shown significant improvement in progression-free survival, but their costs cast a considerable financial burden. In line with value-based oncology, it is important to evaluate whether drug prices justify the outcomes.

Objectives: The aim of the study was to systematically evaluate PARP inhibitors on 1) cost-effectiveness against the standard care, 2) impact on cost-effectiveness upon stratification for genetic characteristics, and 3) identify factors determining their cost-effectiveness, in four cancer types.

Methods: We systematically searched PubMed, EMBASE, Web of Science, and Cochrane Library using designated search terms, updated to 31 August 2021. Trial-based or modeling cost-effectiveness analyses of four FDA-approved PARP inhibitors were eligible. Other studies known to authors were included. Reference lists of selected articles were screened. Eligible studies were assessed for methodological and reporting quality before review.

Results: A total of 20 original articles proceeded to final review. PARP inhibitors were not cost-effective as recurrence maintenance in advanced ovarian cancer despite improved performance upon genetic stratification. Cost-effectiveness was achieved when moved to upfront maintenance in a new diagnosis setting. Limited evidence indicated non–cost-effectiveness in metastatic breast cancer, mixed conclusions in metastatic pancreatic cancer, and cost-effectiveness in metastatic prostate cancer. Stratification by genetic testing displayed an effect on cost-effectiveness, given the plummeting ICER values when compared to the “treat-all” strategy. Drug cost was a strong determinant for cost-effectiveness in most models.

Conclusions: In advanced ovarian cancer, drug use should be prioritized for upfront maintenance and for patients with BRCA mutation or BRCAness at recurrence. Additional economic evaluations are anticipated for novel indications.

• DNA damage repair
• PARPi
• cancer treatment
• genetic mutation
• homologous recombination repair

• AD site
• Benzimidazole
• NI site
• PARP-1 inhibitors
• Structure-activity relationship
• enzyme activity.

Medical school education typically consists of two main student bodies: medical students and biomedical graduate students. For both groups, compassion and empathy represent a major component of future professional roles. For medical students, this takes the form of the all-important doctor-patient relationship and adherence to the Hippocratic Oath. For biomedical students, future research and teaching are often driven by the opportunity to contribute to treatments to help pain and suffering for those in need. For both groups, such positive contributions further extend to families, who often suffer emotional distress watching the health struggles of a loved one. Given the key role that compassion and empathy play here, including them as part of student educational development is important. Such focus, however, is limited - especially during the initial academic classroom years - with most time here dedicated to the learning of facts and foundational material. Given its importance in the future professional roles of these students, we posit that more can be done to introduce and reinforce the concept of compassion and empathy during the initial didactic course years. Modest but viable options exist for the introduction of these concepts as a part of basic teaching that will provide additional reinforcement of this all-important sensitivity for others. Here we present a model providing suggestions and recommendations for the integration of compassion and empathy in otherwise basic scientific teaching, and in a way that also includes progressive equality positions on social issues. While the focus here is medical school education since it represents this author’s expertise as well as a field where young trainees graduate to professional careers requiring compassion, it can potentially be applied to many other disciplines.

• PARP inhibitor
• combination therapy
• efficacy
• meta-analysis
• monotherapy
• safety

• Colorectal cancer
• Poly adenosine diphosphate-ribose
• Poly adenosine diphosphate-ribose polymerase-1
• Poly-adenosine diphosphate ribosylation

• Colorectal cancer
• Poly adenosine diphosphate-ribose
• Poly adenosine diphosphate-ribose polymerase-1
• Poly-adenosine diphosphate ribosylation

Cancer onset and progression lead to a high rate of DNA damage, due to replicative and metabolic stress. To survive in this dangerous condition, cancer cells switch the DNA repair machinery from faithful systems to error-prone pathways, strongly increasing the mutational rate that, in turn, supports the disease progression and drug resistance. Although DNA repair de-regulation boosts genomic instability, it represents, at the same time, a critical cancer vulnerability that can be exploited for synthetic lethality-based therapeutic intervention. We here discuss the role of the error-prone DNA repair, named Alternative Non-Homologous End Joining (Alt-NHEJ), as inducer of genomic instability and as a potential therapeutic target. We portray different strategies to drug Alt-NHEJ and discuss future challenges for selecting patients who could benefit from Alt-NHEJ inhibition, with the aim of precision oncology.

Error-prone DNA repair pathways promote genomic instability which leads to the onset of cancer hallmarks by progressive genetic aberrations in tumor cells. The molecular mechanisms which foster this process remain mostly undefined, and breakthrough advancements are eagerly awaited. In this context, the alternative non-homologous end joining (Alt-NHEJ) pathway is considered a leading actor. Indeed, there is experimental evidence that up-regulation of major Alt-NHEJ components, such as LIG3, PolQ, and PARP1, occurs in different tumors, where they are often associated with disease progression and drug resistance. Moreover, the Alt-NHEJ addiction of cancer cells provides a promising target to be exploited by synthetic lethality approaches for the use of DNA damage response (DDR) inhibitors and even as a sensitizer to checkpoint-inhibitors immunotherapy by increasing the mutational load. In this review, we discuss recent findings highlighting the role of Alt-NHEJ as a promoter of genomic instability and, therefore, as new cancer’s Achilles’ heel to be therapeutically exploited in precision oncology.

• DNA damage
• LIG3
• PARP1
• PolQ
• alternative non-homologous end joining pathway (Alt-NHEJ)
• error-prone DNA repair
• genomic instability
• synthetic lethality

Purpose: The effectiveness of poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib for metastatic castration-resistant prostate cancer (MCRPC) with multiple loss-of-function alterations in genes that are involved in DNA repair has been demonstrated. We aimed to evaluate the cost-effectiveness of genomic test-directed olaparib on MCRPC from the US payer perspective.

Methods: A partitioned survival model was adopted to project the disease course of MCRPC had at least one gene alteration in BRCA1, BRCA2 and ATM (Scenario A) and has alterations in any of all 15 prespecified genes (Scenario B) after next-generation sequencing test. The efficacy and toxicity data were gathered from the PROfound trial. Clinical probabilities related to survival were estimated from the reported survival probabilities in each PROfound group. Cost and health preference data were derived from the literature. The incremental cost-effectiveness ratio (ICER) was measured. Subgroup analysis and sensitivity analysis were performed for exploring the model uncertainties.

Results: Olaparib yielded an additional 0.063 and 0.068 of quality-adjusted life year (QALY) with the augmented cost of $7,382 and saved the cost of $ 1,980 compared to standard care in scenario A and B, respectively, which yielded an ICER of $116,903/QALY and a cost-saving option. The lower weekly cost related to olaparib treatment led to the dominant findings in scenario B. The varied results between scenario A and B could be partly explained by different the number need to screen for identifying eligible patients who could be administered with olaparib, which sharply augmented the costs of the olaparib arm in scenario A. Subgroup analysis and sensitivity analysis revealed the results were generally robust in both of two scenarios.

Conclusion: The genomic test-directed olaparib is a preferred option compared with standard care strategy for men with MCRPC who had any of all 15 prespecified genes.

• cost-effectiveness
• metastatic castration-resistant prostate cancer (mCRPC)
• next-generation sequencing
• olaparib
• partitioned survival model

PTEN is an important tumor suppressor that is frequently mutated in malignancy. PTEN mutational loss has been associated with reduced RAD51 expression and homologous recombination deficiency (HRD), however; recent studies have failed to recapitulate these findings. Here, we show that RAD51 expression, foci formation and homologous recombination repair activity are unaltered in normal and tumorigenic PTEN-deficient cells and patient samples. Furthermore, we show that PTEN-deficient tumor cell lines do not synergize with the clinical PARP inhibitor olaparib, underscoring a need to discontinue its use in treating patients with PTEN-deficient tumors that do not otherwise exhibit HRD.

PTEN mutation occurs in a variety of aggressive cancers and is associated with poor patient outcomes. Recent studies have linked mutational loss of PTEN to reduced RAD51 expression and function, a key factor involved in the homologous recombination (HR) pathway. However, these studies remain controversial, as they fail to establish a definitive causal link to RAD51 expression that is PTEN-dependent, while other studies have not been able to recapitulate the relationship between the PTEN expression and the RAD51/HR function. Resolution of this apparent conundrum is essential due to the clinically-significant implication that PTEN-deficient tumors may be sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) commonly used in the clinical management of BRCA-mutated and other HR-deficient (HRD) tumors. Methods: Primary Pten-deficient (and corresponding wild-type) mouse embryonic fibroblasts (MEFs) and astrocytes and PTEN-null human tumor cell lines and primary cells were assessed for RAD51 expression (via the Western blot analysis) and DNA damage repair analyses (via alkali comet and γH2AX foci assays). RAD51 foci analysis was used to measure HR-dependent DNA repair. Xrcc2-deficient MEFs served as an HR-deficient control, while the stable knockdown of RAD51 (shRAD51) served to control for the relative RAD51/HR-mediated repair and the phospho-53BP1 foci analysis served to confirm and measure non-homologous end joining (NHEJ) activity in PTEN-deficient and shRAD51-expressing (HRD) lines. Cell proliferation studies were used to measure any potential added sensitivity of PTEN-null cells to the clinically-relevant PARPi, olaparib. RAD51 levels and DNA damage response signaling were assessed in PTEN-mutant brain tumor initiating cells (BTICs) derived from primary and recurrent glioblastoma multiforme (GBM) patients, while expression of RAD51 and its paralogs were examined as a function of the PTEN status in the RNA expression datasets isolated from primary GBM tumor specimens and BTICs. Results: Pten knockout primary murine cells display unaltered RAD51 expression, endogenous and DNA strand break-induced RAD51 foci and robust DNA repair activity. Defective HR was only observed in the cells lacking Xrcc2. Likewise, human glioblastoma multiforme (GBM) cell lines with known PTEN deficiency (U87, PTEN-mutated; U251 and U373, PTEN-null) show apparent expression of RAD51 and display efficient DNA repair activity. Only GBM cells stably expressing shRNAs against RAD51 (shRAD51) display dysfunctional DNA repair activity and reduced proliferative capacity, which is exacerbated by PARPi treatment. Furthermore, GBM patient-derived BTICs displayed robust RAD51 expression and intact DNA damage response signaling in spite of PTEN-inactivating mutations. RNA expression analysis of primary GBM tissue specimens and BTICs demonstrate stable levels of RAD51 and its paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and DMC1), regardless of the PTEN mutational status. Conclusions: Our findings demonstrate definitively that PTEN loss does not alter the RAD51 expression, its paralogs, or the HR activity. Furthermore, deficiency in PTEN alone is not sufficient to impart enhanced sensitivity to PARPi associated with HRD. This study is the first to unequivocally demonstrate that PTEN deficiency is not linked to the RAD51 expression or the HR activity amongst primary neural and non-neural Pten-null cells, PTEN-deficient tumor cell lines, and primary PTEN-mutant GBM patient-derived tissue specimens and BTICs.

• DNA damage
• HRD
• PARP inhibitor
• PTEN
• RAD51
• RAD51 foci
• RNA expression
• alkaline comet assay
• base excision repair
• brain tumor initiating cells
• combination therapy
• glioblastoma multiforme
• homologous recombination
• olaparib
• synthetic lethality
• γH2AX foci

• NS-37956 NIH HHS
• 326086 CIHR
• CA-096832 NIH HHS
• CA-21765 NIH HHS
• R01 NS037956 NINDS NIH HHS
• P01 CA096832 NCI NIH HHS

• KRAS
• Pancreatic adenocarcinoma
• SHP2
• Targeted therapy

• Adult
• Aged
• Aged, 80 and over
• Antibodies, Monoclonal/administration & dosage
• Antibodies, Monoclonal/adverse effects
• B7-H1 Antigen/genetics
• Chemokine CXCL10/genetics
• Chemokine CXCL9/genetics
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Immune Checkpoint Inhibitors/administration & dosage
• Immune Checkpoint Inhibitors/adverse effects
• Interferon-gamma/genetics
• Middle Aged
• Neoplasm Recurrence, Local/drug therapy
• Neoplasm Recurrence, Local/genetics
• Neoplasm Recurrence, Local/pathology
• Ovarian Neoplasms/drug therapy
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/immunology
• Ovarian Neoplasms/pathology
• Phthalazines/administration & dosage
• Phthalazines/adverse effects
• Piperazines/administration & dosage
• Piperazines/adverse effects
• Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage
• Poly(ADP-ribose) Polymerase Inhibitors/adverse effects
• Poly(ADP-ribose) Polymerases/genetics
• Progression-Free Survival
• Vascular Endothelial Growth Factor A/genetics

• HHSN261200800001C NCI NIH HHS
• HHSN261200800001E NCI NIH HHS
• P30 CA014236 NCI NIH HHS
• ZIA BC011525 Intramural NIH HHS

• Lung cancer
• homologous recombination deficiency
• immunohistochemistry
• ovarian cancer
• women

Family history of pancreatic cancer (PC) is a risk factor for PC development, and the risk level correlates with the number of affected families. A case of PC with ≥1 PC cases in the first-degree relative is broadly defined as familial pancreatic cancer (FPC) and accounts for 5% to 10% of total PC cases. FPC possesses several epidemiological, genetic and clinicopathological aspects that are distinct from those of conventional PCs. In Western countries, FPC registries have been established since the 1990s, and high-risk individuals are screened to detect early PCs. For the pharmacotherapy of FPC, especially in cases with germline pathogenic BRCA mutations, regimens using platinum and poly (ADP-ribose) polymerase inhibitor have recently been studied for their effectiveness. To date, the concept of FPC has prevailed in Western countries, and it has begun to infiltrate into Eastern countries. As the genetic background and environmental conditions vary in association with ethnicity and living area, we need to establish our own FPC registries and accumulate data in Asian countries.

• Familial pancreatic cancer
• Genetic
• High risk
• Surveillance
• Treatment

• BRCA mutations
• BRCAness
• DNA damage response
• PARP enzymes
• PARP inhibitors
• breast cancer
• ovarian cancer
• prostate cancer

• Adjuvant treatment
• Checkpoint inhibitors
• Chemotherapy
• Endometrial cancer
• Molecular alterations
• Molecular risk factors
• PARP inhibitors
• Radiotherapy
• Targeted therapies

• Age Factors
• Biomarkers, Tumor/genetics
• Carcinoma, Endometrioid/genetics
• Carcinoma, Endometrioid/metabolism
• Carcinoma, Endometrioid/pathology
• Carcinoma, Endometrioid/therapy
• Chemotherapy, Adjuvant/methods
• Endometrial Neoplasms/genetics
• Endometrial Neoplasms/metabolism
• Endometrial Neoplasms/pathology
• Endometrial Neoplasms/therapy
• Female
• Humans
• Molecular Targeted Therapy/methods
• Mutation
• Prognosis
• Radiotherapy, Adjuvant/methods
• Risk Factors

• Leiden University Medical Center (LUMC)

• BRCA mutation
• ERBB2 mutation
• Microsatellite-instability
• PARP-inhibition
• Small bowel adenocarcinoma

Significant numbers of variants detected in cancer patients are often left labeled only as variants of unknown significance (VUS). In order to expand precision medicine to a wider population, we need to extend our knowledge of pathogenicity and drug response in the context of VUS’s.

In this study, we analyzed variants from AACR Project GENIE Consortium APG (Cancer Discov 7:818-831, 2017) and compared them to the COSMIC database Forbes et al. (Nucleic Acids Res 43:D805-811, 2015) to identify recurrent variants that would merit further study. We filtered out known hotspot variants, inactivating variants in tumor suppressors, and likely benign variants by comparing with COSMIC and ExAC Lee et al. (Science 337:967-971, 2012).

We have identified 45,933 novel variants with unknown significance unique to GENIE. In our analysis, we found on average six variants per patient where two could be considered as pathogenic or likely pathogenic and the majority are VUS’s. More importantly, we have discovered 730 recurrent variants that appear more than 3 times in GENIE but less than 3 in COSMIC. If we combine the recurrences of GENIE and COSMIC for all variants, 2586 are newly identified as occurring more than 3 times than when using COSMIC alone.

Although it would be inappropriate to blindly accept these recurrent variants as pathogenic, they may warrant higher priority than other observed VUS’s. These newly identified recurrent variants might affect the molecular profiles of approximately 1 in 6 patients. Further analysis and characterization of these variants in both research and clinical contexts will improve patient treatments and the development of new therapeutics.

The online version of this article (10.1186/s12885-019-5313-1) contains supplementary material, which is available to authorized users.

• GENIE
• Precision medicine
• Recurrent variants
• Variant disparity
• Variant of unknown significance

Poly (ADP-ribose) polymerase inhibitors (PARPi) have become the first targeted therapies available in the treatment of patients with high-grade serous ovarian cancer (HGSOC). We recently described a significant reduction in PARP1 protein levels in vitro and in vivo in patients treated with standard carboplatinum-paclitaxel chemotherapy, raising the question whether the sequence of treatment used today with chemotherapy followed by PARPi is optimal. In this study, we aim to evaluate if the sequence of PARPi followed by chemotherapy could be more beneficial.

BRCA1-mutated (UWB1.287, SNU-251), epigenetically-silenced (OVCAR8), and wild-type (SKOV3, A2780PAR & A2780CR) ovarian cancer cell lines were exposed to clinically relevant doses of PARPi followed by different doses of standard chemotherapy and compared to the inverse treatment. The therapeutic efficacy was assessed using colony formation assays. Flow cytometry was used to evaluate cell apoptosis rate and the changes in cell cycle. Finally, apoptotic and cell cycle protein expression was immunodetected using western blot.

Exposure to PARPi prior to standard chemotherapy sensitized BRCA1-mutated or epigenetically-silenced BRCA1 cell lines to lower doses of chemotherapy. Similar results were observed in BRCA1 wild-type and cell lines in which BRCA1 functionality was restored. Moreover, this treatment increased the apoptotic rate in these cell lines.

Pre-treatment with PARPi followed by standard chemotherapy in vitro is more efficient in growth inhibition and induction of apoptosis compared to the administration of standard chemotherapy followed by PARPi.

The online version of this article (10.1186/s12885-018-5250-4) contains supplementary material, which is available to authorized users.

• BRCA1/2
• Chemoresistance
• DNA repair pathway
• Ovarian Cancer
• PARP inhibitor
• Synthetic lethality

• BRCA1/2 mutations
• BRCAness
• PARP inhibitors
• Poly(ADP-ribose) polymerases
• Triple-negative breast cancer

Adenocarcinomas or combined adeno-neuroendocrine carcinomas (MANEC) of small bowel usually have a dismal prognosis with limited systemic therapy options. This is the first description of a patient showing a germline-related BRCA1 mutated MANEC of his ileum. The tumor presented a susceptibility to a combined chemotherapy and the PARP1-inhibitor olaparib.

A 74-year old male patient presented with a metastasized MANEC of his ileum. Due to clinical symptoms his ileum-tumor and the single brain metastasis were removed. We verified the same pathogenic (class 5) BRCA1 mutation in different tumor locations. There was no known personal history of a previous malignant tumor. Nevertheless we identified his BRCA1 mutation as germline-related. A systemic treatment was started including Gemcitabine followed by selective internal radiotherapy (SIRT) to treat liver metastases and in the further course Capecitabine but this treatment finally failed after 9 months and all liver metastases showed progression. The treatment failure was the reason to induce an individualized therapeutic approach using combined chemotherapy of carboplatin, paclitaxel and the Poly (ADP-ribose) polymerase- (PARP)-inhibitor olaparib analogous to the treatment protocol of Oza et al.

All liver metastases demonstrated with significant tumor regression after 3 months and could be removed. In his most current follow up from December 2017 (25 months after his primary diagnosis) the patient is in a very good general condition without evidence for further metastases.

We present first evidence of a therapy susceptible germline-related BRCA1 mutation in small bowel adeno-neuroendocrine carcinoma (MANEC). Our findings offer a personalized treatment option. The germline background was unexpected in a 74-year old man with no previously known tumor burden. We should be aware of the familiar background in tumors of older patients as well.

• BRCA1 mutation
• Germline-related
• PARP-inhibition
• Personalized treatment
• Small bowel mixed adeno-neuroendocrine carcinoma (MANEC)

• BRCA1 Protein/genetics
• Breast Neoplasms/drug therapy
• Breast Neoplasms/genetics
• Breast Neoplasms/pathology
• Cell Line, Tumor
• Cell Proliferation/genetics
• Cell Proliferation/radiation effects
• Female
• Glioma/drug therapy
• Glioma/genetics
• Glioma/pathology
• Humans
• Poly(ADP-ribose) Polymerase Inhibitors/pharmacology
• Radiation, Ionizing
• Recombinational DNA Repair/genetics
• Recombinational DNA Repair/radiation effects
• Synthetic Lethal Mutations/genetics
• Tumor Suppressor Protein p53/genetics

• R01 CA118158 NCI NIH HHS
• P01 CA097189 NCI NIH HHS
• R01 CA188500 NCI NIH HHS
• K22 CA218459 NCI NIH HHS
• P30 CA016058 NCI NIH HHS
• R01 CA163838 NCI NIH HHS

Poly(ADP-ribose) polymerase inhibitors (PARPIs) kill cancer cells by trapping PARP1 and PARP2. Talazoparib, the most potent PARPI inhibitor (PARPI), exhibits remarkable selectivity among the NCI-60 cancer cell lines beyond BRCA inactivation. Our genomic analyses reveal high correlation between response to talazoparib and Schlafen 11 (SLFN11) expression. Causality was established in four isogenic SLFN11-positive and -negative cell lines and extended to olaparib. Response to the talazoparib-temozolomide combination was also driven by SLFN11 and validated in 36 small cell lung cancer cell lines, and in xenograft models. Resistance in SLFN11-deficient cells was caused neither by impaired drug penetration nor by activation of homologous recombination. Rather, SLFN11 induced irreversible and lethal replication inhibition, which was independent of ATR-mediated S-phase checkpoint. The resistance to PARPIs by SLFN11 inactivation was overcome by ATR inhibition, mechanistically because SLFN11-deficient cells solely rely on ATR activation for their survival under PARPI treatment. Our study reveals that SLFN11 inactivation, which is common (~45%) in cancer cells, is a novel and dominant resistance determinant to PARPIs.

• ATR
• BRCA
• PARP inhibitor
• PARP-trapping
• homologous recombination

• DNA repair
• cancer
• copy number variations
• gene expression
• mutations

• Molecular profiling
• Pancreatic acinar cell carcinoma
• Targeted therapy

• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Carcinoma, Acinar Cell/genetics
• Carcinoma, Acinar Cell/mortality
• Carcinoma, Acinar Cell/pathology
• Carcinoma, Acinar Cell/therapy
• Gene Expression Profiling
• Humans
• Immunohistochemistry
• Mutation
• Pancreas/pathology
• Pancreas/surgery
• Pancreatectomy
• Pancreatic Neoplasms/genetics
• Pancreatic Neoplasms/mortality
• Pancreatic Neoplasms/pathology
• Pancreatic Neoplasms/therapy
• Prognosis
• Signal Transduction/genetics
• Survival Rate
• Exome Sequencing
• Pancreatic Neoplasms

PURPOSE: Phyllodes tumors (PTs) of the breast are rare, accounting for less than 1% of all breast tumors. Among PTs, malignant PTs (MPTs) have malignant characteristics and distant metastases occur in about 20% to 30% of MPTs. However, there is no effective treatment for MPTs with distant metastasis, resulting in an abject prognosis. We performed targeted deep sequencing on PTs to identify the associations between genetic alterations and clinical prognosis. METHODS: We performed targeted deep sequencing to evaluate the genetic characteristics of PTs and analyzed the relationships between clinical and genetic characteristics. RESULTS: A total of 17 PTs were collected between 2001 and 2012. Histologic review was performed by pathologists. The samples included three benign PTs, one borderline PT, and 13 MPTs. The most frequently detected genetic alteration occurred in the TERT promoter region (70.6%), followed by MED12 (64.7%). EGFR amplification and TP53 alteration were detected in four MPTs without genetic alterations in MED12 and TERT promoter regions. Genetic alterations of RARA and ZNF703 were repeatedly found in PTs with local recurrence, and genetic alterations of SETD2, BRCA2, and TSC1 were detected in PTs with distant metastasis. Especially, MPT harboring PTEN and RB1 copy number deletion showed rapid disease progression. CONCLUSIONS: In this study, we provide genetic characterization and potential therapeutic target for this rare, potentially lethal disease. Further large-scale comprehensive genetic study and functional validation are warranted.

• Organ-on-a-chip
• P53 and BRCA1
• Personalized medicine
• Triple negative

• Antineoplastic Agents/pharmacology
• BRCA1 Protein/metabolism
• Cell Culture Techniques/methods
• Cell Line, Tumor
• Cell Survival/drug effects
• Cisplatin/pharmacology
• Collagen
• Drug Combinations
• Extracellular Matrix/metabolism
• Female
• Humans
• Laminin
• Microfluidics/methods
• Mutation
• Outcome Assessment, Health Care/methods
• Paclitaxel/pharmacology
• Phthalazines/pharmacology
• Piperazines/pharmacology
• Prognosis
• Proteoglycans
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/metabolism
• Triple Negative Breast Neoplasms/pathology
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism

• U19 GM061388 NIGMS NIH HHS
• National Institutes of Health
• Mayo Clinic (US)
• Mayo Clinic

• BRCA mutation
• PARP inhibitors
• biomarkers
• drug resistance
• homologous recombination
• synthetic lethality