Mutations In BRCA1 Genes Research Articles

Clinical Outcomes of Poly(ADP–Ribose) Polymerase Inhibitors as Maintenance Therapy in Patients with Ovarian Cancer in the Southeastern Region of Korea

Purpose: In this study, we aimed to retrospectively investigate the real-world clinical efficacy and adverse events of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors in real-world clinical practice among patients with newly diagnosed epithelial ovarian cancer. Methods: We retrospectively reviewed the medical records from hospitals. Patients with epithelial ovarian cancer treated with olaparib or niraparib as frontline maintenance treatment between 1 January 2014 and 31 December 2022 were included. Progression-free survival (PFS) was analyzed using the Kaplan–Meier method, and adverse events associated with PARP inhibitor treatment were investigated. Results: Ninety-six patients treated with PARP inhibitors were identified. The median follow-up period was 21.8 months (95% confidence interval [CI] 19.4–24.0). Twenty (20.1%) patients experienced disease progression, and two patients died. The median PFS was 45.3 months (95% CI 39.4–NA). BRCA1 or BRCA2 gene mutations and primary cytoreductive surgery were associated with better PFS. Adverse events of any grade occurred in 74 (77.1%) patients. Nineteen (19.8%) patients experienced PARP inhibitor therapy interruptions, and 35 (36.5%) patients experienced dose reductions. Only three patients discontinued the drug due to adverse events. Conclusions: In a real-world setting, PARP inhibitors showed efficacy comparable to that reported in published randomized controlled trials and had acceptable safety profiles.

An interpretable deep learning model for detecting BRCA pathogenic variants of breast cancer from hematoxylin and eosin-stained pathological images

Background Determining the status of breast cancer susceptibility genes (BRCA) is crucial for guiding breast cancer treatment. Nevertheless, the need for BRCA genetic testing among breast cancer patients remains unmet due to high costs and limited resources. This study aimed to develop a Bi-directional Self-Attention Multiple Instance Learning (BiAMIL) algorithm to detect BRCA status from hematoxylin and eosin (H&E) pathological images. Methods A total of 319 histopathological slides from 254 breast cancer patients were included, comprising two dependent cohorts. Following image pre-processing, 633,484 tumor tiles from the training dataset were employed to train the self-developed deep-learning model. The performance of the network was evaluated in the internal and external test sets. Results BiAMIL achieved AUC values of 0.819 (95% CI [0.673–0.965]) in the internal test set, and 0.817 (95% CI [0.712–0.923]) in the external test set. To explore the relationship between BRCA status and interpretable morphological features in pathological images, we utilized Class Activation Mapping (CAM) technique and cluster analysis to investigate the connections between BRCA gene mutation status and tissue and cell features. Significantly, we observed that tumor-infiltrating lymphocytes and the morphological characteristics of tumor cells appeared to be potential features associated with BRCA status. Conclusions An interpretable deep neural network model based on the attention mechanism was developed to predict the BRCA status in breast cancer. Keywords: Breast cancer, BRCA, deep learning, self-attention, interpretability.

Differential methylation of circulating free DNA assessed through cfMeDiP as a new tool for breast cancer diagnosis and detection of BRCA1/2 mutation

BackgroundRecent studies have highlighted the importance of the cell-free DNA (cfDNA) methylation profile in detecting breast cancer (BC) and its different subtypes. We investigated whether plasma cfDNA methylation, using cell-free Methylated DNA Immunoprecipitation and High-Throughput Sequencing (cfMeDIP-seq), may be informative in characterizing breast cancer in patients with BRCA1/2 germline mutations for early cancer detection and response to therapy.MethodsWe enrolled 23 BC patients with germline mutation of BRCA1 and BRCA2 genes, 19 healthy controls without BRCA1/2 mutation, and two healthy individuals who carried BRCA1/2 mutations. Blood samples were collected for all study subjects at the diagnosis, and plasma was isolated by centrifugation. Cell-free DNA was extracted from 1 mL of plasma, and cfMeDIP-seq was performed for each sample. Shallow whole genome sequencing was performed on the immuno-precipitated samples. Then, the differentially methylated 300-bp regions (DMRs) between 25 BRCA germline mutation carriers and 19 non-carriers were identified. DMRs were compared with tumor-specific regions from public datasets to perform an unbiased analysis. Finally, two statistical classifiers were trained based on the GLMnet and random forest model to evaluate if the identified DMRs could discriminate BRCA-positive from healthy samples.ResultsWe identified 7,095 hypermethylated and 212 hypomethylated regions in 25 BRCA germline mutation carriers compared to 19 controls. These regions discriminate tumors from healthy samples with high accuracy and sensitivity. We show that the circulating tumor DNA of BRCA1/2 mutant breast cancers is characterized by the hypomethylation of genes involved in DNA repair and cell cycle. We uncovered the TFs associated with these DRMs and identified that proteins of the Erythroblast Transformation Specific (ETS) family are particularly active in the hypermethylated regions. Finally, we assessed that these regions could discriminate between BRCA positives from healthy samples with an AUC of 0.95, a sensitivity of 88%, and a specificity of 94.74%.ConclusionsOur study emphasizes the importance of tumor cell-derived DNA methylation in BC, reporting a different methylation profile between patients carrying mutations in BRCA1, BRCA2, and wild-type controls. Our minimally invasive approach could allow early cancer diagnosis, assessment of minimal residual disease, and monitoring of response to therapy.

Skin metastasis of BRCA mutated prostate cancer: A case report and a brief review of literature.

Metastatic castration-resistant prostate cancer has a poor prognosis especially when harboring DNA damage repair gene mutations, nevertheless, in the case of pathogenic BRCA gene mutations, PARPi demonstrated a survival benefit and is a validated treatment. Nowadays, there is no data regarding unusual metastases after these drugs. Cutaneous metastases appear rarely in prostate cancer and were associated with a worse prognosis. Moreover, there are no consolidated data concerning skin tropism of prostate cancer cells, neither in the case of BRCA-associated cancers. Here, we report the case of a patient with a long history of BRCA1-mutated metastatic castration-resistant prostate cancer who developed a skin lesion on the scalp while on his fifth line of systemic therapy with olaparib. After a complete radical surgical excision, the pathology report showed prostate cancer localization. A diagnosis of skin metastasis from prostate cancer was reported. The patient then continued olaparib therapy; after 7 months from excision, he experienced further bone and biochemical progression but not cutaneous progression. A literature review of all reported cases of cutaneous metastasis in prostate cancer was conducted to shed light on the incidence, clinical presentation, diagnosis, treatment, and prognosis of this entity. We also reviewed published cases of skin metastasis in BRCA-associated cancers with an effort to correlate skin involvement with PARPi treatment, BRCAness status, and prognosis.

6847 Poorly Differentiated Thyroid Cancer: A Rare Entity

Abstract Disclosure: S. Fatima: None. S. Ward: None. A. Champion: None. Introduction: Poorly differentiated thyroid carcinoma (PDTC) is a rare thyroid carcinoma originating from follicular epithelial cells. Regarding the degree of differentiation, PDTC ranks between differentiated thyroid cancer and anaplastic thyroid cancer. We hereby present a rare case of PDTC. Case: 29-year-old female with a history of metastatic papillary thyroid cancer (PTC) presented to the emergency department with shortness of breath. She initially noticed a left thyroid mass in 2021. CT neck in 1/2022 showed a 7 cm left thyroid mass with substernal extension, small right thyroid mass with tracheal compression, left bulky cystic nodal masses extending anterior and posterior to carotid and internal jugular vein. PET scan in 3/2022 showed left 7.6 cm thyroid mass SUV 12.1 with tracheal compression, left level II-IV adenopathy with level IV nodal masses 5.1 cm SUV 4.5. Ultrasound-guided FNA in 4/2022 showed PTC in left 8.7cm thyroid nodule; right 2.8 cm nodule showed Atypia of Undetermined Significance; Left 5.5 cm neck level III lymph node (LN) showed PTC metastasis; right 5.1 cm neck level III LN showed PTC metastasis (+ thyroglobulin and TTF-1). CT chest in 11/2022 showed additional involvement of manubrium. Repeat core needle biopsy of left thyroid mass showed left invasive thyroid carcinoma. She was started on neoadjuvant Lenvatinib in 1/2023. Follow-up CT neck in 5/2023 showed a reduction in the size of the left thyroid mass to 5.5cm x 5.8cm x 6.5cm. At this time, she had symptoms of dysphagia, orthopnea, weight loss of about 60 lbs and neck pain. In 11/2023 at time of current presentation she underwent total thyroidectomy, bilateral modified radical neck dissection and manubriectomy. Surgical pathology showed PDTC in left thyroid mass, PTC in right thyroid mass with metastatic PDTC in left proximal sternocleidomastoid, manubrium and LN involvement in neck and mediastinum. OmniSeq Insight testing showed APC and BRCA1 gene mutations, negative BRAF V600E, RET fusion, RET mutation, NTRK1/2/3 fusion and PD L1 immunohistochemistry score is <1%. The patient is planned to receive [1]3[1]I ablation therapy. Conclusion: PDTC accounts for 3–5% of all thyroid carcinomas. The 5, 10-, and 15-year survival rates of patients are 50–85%, 34–50%, and 0%, respectively. RAS gene alterations are found in 25–35%, BRAF mutation in 15–27%, TERT promoter mutation in 40% and mutant TP53 in 16–28% of PDTCs. TERT promoter gene and TP53 mutation usually indicate an aggressive phenotype and a dismal prognosis. Surgery, [1]3[1]I therapy, and external beam radiotherapy constitute the mainstay of traditional treatment for patients with advanced disease; however, treatment is challenging. Tyrosine kinase inhibitors i.e, sorafenib and lenvatinib, have been used in cases of progressive, recurrent, or metastatic disease not responsive to [1]3[1]I therapy. Immunotherapy may be an option in PD-L1-positive tumors. Presentation: 6/1/2024

P85-7 PARP inhibitors and chemotherapy in breast cancer patients with BRCA-1 or BRCA-2 gene mutations: a systematic review

P85-7 PARP inhibitors and chemotherapy in breast cancer patients with BRCA-1 or BRCA-2 gene mutations: a systematic review

Exploring Molecular Drivers of PARPi Resistance in BRCA1-Deficient Ovarian Cancer: The Role of LY6E and Immunomodulation.

Approximately 50% of patients diagnosed with ovarian cancer harbor tumors with mutations in BRCA1, BRCA2, or other genes involved in homologous recombination repair (HR). The presence of homologous recombination deficiency (HRD) is an approved biomarker for poly-ADP-ribose polymerase inhibitors (PARPis) as a maintenance treatment following a positive response to initial platinum-based chemotherapy. Despite this treatment option, the development of resistance to PARPis is common among recurrent disease patients, leading to a poor prognosis. In this study, we conducted a comprehensive analysis using publicly available datasets to elucidate the molecular mechanisms driving PARPi resistance in BRCA1-deficient ovarian cancer. Our findings reveal a central role for the interferon (IFN) pathway in mediating resistance in the context of BRCA1 deficiency. Through integrative bioinformatics approaches, we identified LY6E, an interferon-stimulated gene, as a key mediator of PARPi resistance, with its expression linked to an immunosuppressive tumor microenvironment (TME) encouraging tumor progression and invasion. LY6E amplification correlates with poor prognosis and increased expression of immune-related gene signatures, which is predictive of immunotherapy response. Interestingly, LY6E expression upon PARPi treatment resistance was found to be dependent on BRCA1 status. Gene expression analysis in the Orien/cBioPortal database revealed an association between LY6E and genes involved in DNA repair, such as Rad21 and PUF60, emphasizing the interplay between DNA repair pathways and immune modulation. Moreover, PUF60, Rad21, and LY6E are located on chromosome 8q24, a locus often amplified and associated with the progression of ovarian cancer. Overall, our study provides novel insights into the molecular determinants of PARPi resistance and highlights LY6E as a promising prognostic biomarker in the management of HRD ovarian cancer. Future studies are needed to fully elucidate the molecular mechanisms underlying the role of LY6E in PARPi resistance.

Enhancing Breast Cancer Risk Prediction with Machine Learning: Integrating BMI, Smoking Habits, Hormonal Dynamics, and BRCA Gene Mutations—A Game-Changer Compared to Traditional Statistical Models?

Enhancing Breast Cancer Risk Prediction with Machine Learning: Integrating BMI, Smoking Habits, Hormonal Dynamics, and BRCA Gene Mutations—A Game-Changer Compared to Traditional Statistical Models?

Mutational landscape of BRCA gene mutations in Indian breast cancer patients: retrospective insights from a diagnostic lab

BackgroundPresence of Germline mutations in the BRCA1 and BRCA2 genes is the most significant epidemiological factor for breast cancer (BC), where germline BRCA1 (gBRCA 1) mutation increases the risk for BC by 59–87% and gBRCA 2 mutation increases the risk by 38–80%. In this retrospective study, we have analyzed NGS-based genetic data for samples received at our laboratory for genetic testing over a three-year period to understand the prevalence and pattern if any of BRCA1 and BRCA2 mutations in Indian breast cancer patients.ResultsBRCA gene sequencing using NGS was performed in 395 consecutive cases of BC referred for testing to our lab between 2021 and 2023. Genetic analysis of mutations BRCA 1 and BRCA 2 genes resulted in 115 (29%) positive patients. Out of 115 patients, 79 reported BRCA1 mutations, whereas 36 had BRCA2 mutations. Exon 10 (57.3%) of BRCA1 and exon 11 (52%) of BRCA2 were the most mutated exons observed in this study. The c.1961delA (26.4%) variant, followed by the c.68_69delAG (22.7%) variant in BRCA1, and the c.6373delA (20.5%) variant in BRCA2, were the most common mutations found in our study. Our data shows positive correlation of younger age group (20–45 years) with BRCA positive status (Chi-square p value = 0.001).ConclusionBRCA mutation prevalence was 29.1% in our data which is higher than Western countries. Based on our findings BRCA screening looks imperative for women with BC especially younger women (< 50 years), as family history based BRCA testing would miss out many BRCA positive candidates which could benefit from PARP therapy options.

Unusual Pattern of Spread of High-Grade Serous Fallopian Tubal Carcinoma in a Woman with BRCA1 Gene Mutation

A 40-year-old woman presented with chronic watery vaginal discharge for one-month and right pelvic pain radiating to the right flank for 2 weeks. Physical and pelvic examination revealed a right pelvic mass. Computerized tomography and magnetic resonance of whole abdomen revealed a 6-cm of heterogeneous mass at the right adnexa and a larger mass of 8-cm with internal cystic portions compressing on the inferior vena cava. Her serum cancer antigen (CA) 125 elevated to 540 U/ml. Surgical intervention revealed a right fallopian tube mass with an intact serosal surface, several enlarged pelvic and para-aortic nodes, and a bulky precaval node. No gross peritoneal nor other organ invasion was found. Complete surgical staging was performed by gynecologic oncologists and a surgeon, resulting in optimal surgery. Pathology revealed high-grade serous carcinoma of the right fallopian tube with metastasis to all resected nodes and a positive peritoneal cytology. Subsequent blood testing showed BReast CAncer (BRCA) 1 gene mutation. Adjuvant therapy with paclitaxel/carboplatin/bevacizumab was given for six cycles. Maintenance therapy with bevacizumab/olaparib, and periodic surveillance for other cancers, including breast magnetic resonance imaging were planned. This case presented an unusual pattern fallopian tubal cancer spread to a large precaval lymph node which was bulkier than the primary tumor. A thorough pre-operative evaluation and a surgical team specialized in cancer surgery are crucial for successful surgical management. Appropriate adjuvant treatment and follow-up for a woman with BRCA mutation were also to be emphasized.

Genetic Testing Among Breast Cancer Patients in the Eastern Region of Saudi Arabia: Single-Center Experience

BackgroundGenetic testing for persons with a heightened likelihood of harboring a germline mutation permits early identification and appropriate management. This study aimed to identify the proportion of breast cancer (BC) patients who were offered genetic testing and the prevalence of BRCA mutations among them. Additionally, we assessed the demographic and clinical features of BC patients in the Eastern Region of Saudi Arabia.Materials and MethodsData from 2535 patients with BC were retrieved from the registry between 2017 and 2021. The data were analyzed and presented using univariate and bivariate statistics. Odds ratios and 95% confidence intervals using logistic regression analysis were computed to identify the predictors of BRCA testing.ResultsPatients with BC ranged in age from 18 to 103 years, and the mean age was 49.60 ± 12.14 years. BC was detected in men in 29 (1.1%) cases. Among diagnosed patients with BC, a total of 96 (3.7%) patients underwent testing for BRCA gene mutations. Of them, 36 (37.5%) patients had a BRCA gene mutation. The likelihood of undergoing BRCA testing was higher for those who were diagnosed with the condition before the age of 50, patients who were referred from private institutions, and patients with a history of previously diagnosed cancer. The likelihood of conducting BRCA testing was significantly lower among those with distant metastases.ConclusionThe proportion of BRCA testing among BC patients was found to be relatively low. The development of a cost-effective, locally developed risk assessment tool that incorporates genetic counseling and testing for those with a familial predisposition to BC is imperative.

Fear of cancer recurrence in breast cancer survivors carrying a BRCA1 or 2 genetic mutation : a cross-sectional study

BackgroundFear of cancer recurrence (FCR) affects virtually all patients who have been treated for cancer, to varying degrees. Breast cancer survivors who carry a BRCA1 or BRCA2 gene mutation are at high risk of cancer recurrence. No study has yet assessed FCR specifically in this population.ObjectivesThis cross-sectional study, conducted in women who were treated for breast cancer and carrying a BRCA1/2 mutation, aimed to: (1) assess the mean level of FCR and estimate the proportion of patients with clinical levels of FCR; (2) examine the relationships between FCR and selected psychological variables (e.g., avoidance, intolerance to uncertainty) and quality of life; (3) explore whether FCR levels vary as a function of the past preventive treatment received; and (4) to assess the associations between FCR and the presence of decisional conflict or regret regarding the various preventive options.MethodParticipants were recruited through an e-mail sent to an oncogenetic network mailing list (Réseau ROSE). Participants were asked to complete a battery of questionnaires online assessing FCR and other psychological and quality of life variables.ResultsA total of 89 women completed the survey. Most participants had undergone a preventive mastectomy (62.9%) and a preventive salpingo-oophorectomy (75.3%) at the time of the study. The mean Fear of Cancer Recurrence Inventory-severity score was 16.8, which exceeds the clinical cut-off score of 13, and 70.8% of the participants showed a clinical level of FCR. FCR was significantly associated with higher levels of anxiety and depression, and higher avoidance and intolerance of uncertainty, but not with quality of life. No significant difference was observed on the total FCR score between women who had received preventive surgery (mastectomy and/or salpingo-oophorectomy) and those considering it, and those not considering it. The association was significant between higher FRC scores and greater decisional conflicts and regrets about choosing to undergo preventive surgery.ConclusionThese data suggest that FCR is a significant problem for breast cancer survivors carrying a BRCA1/2 genetic mutation, even after undergoing a prophylactic surgery. This highlights the importance of providing these women with specific psychological intervention focusing on FCR.

BRCA1/2 mutations and outcomes among Middle Eastern patients with early-onset breast cancer in Oman.

High prevalence of early-onset breast cancer (EOBC) has been reported in Middle Eastern populations. For example, in Oman more than 50% of patients with breast cancer (BC) are under age 45 at diagnosis. Causes for this high incidence are unknown. Germline BRCA gene mutations have been associated with EOBC, however, prevalence of these mutations and how they relate to EOBC in Oman has not been assessed. Clinical data were collected for patients with BC treated at Royal Hospital, Oman between 2010 and 2022. Germline BRCA1/2 gene mutations were identified using sequencing and MLPA. Correlation and Kaplan-Meier survival analyses were performed to test relationships among clinico-pathological features, gene mutations, and outcomes. Total of 1336 Middle Eastern patients with BC were included; 611 were aged <45 at diagnosis (45.7%). No significant correlation was found between BRCA1/2 mutation status and EOBC (P = .229), and the majority of EOBC cases had no family history of BC. EOBC tumors did, however, differ in clinicopathological features; EOBCs were significantly larger (P < .0001), of higher grade (P < .0001), and included more HER2-enriched, and triple negative subtypes (P = .018) compared with later onset cases. Accordingly, survival analyses revealed that EOBC had significantly worse disease-free survival (P = .002). BRCA gene variants showed a distinct range of mutations including, in BRCA2, 3 previously unreported mutations and 4 potential founder recurrent mutations. Our findings showed that germline BRCA1/2 mutations were not over-represented in EOBC cases in Oman, and therefore are unlikely to be responsible for high EOBC rates.

Occurrence of contralateral breast cancer in a BRCA-positive breast cancer patient who underwent free TRAM flap reconstruction: a case report

This report presents a case of contralateral breast cancer in a BRCA mutation-positive patient who had previously undergone delayed free transverse rectus abdominis myocutaneous flap reconstruction for unilateral breast cancer. Having used up the available abdominal autologous tissue in the first reconstruction, a direct-to-implant procedure was employed for the reconstruction of the second, contralateral breast. Therefore, one breast was reconstructed using autologous tissue from the abdomen, while the other was asymmetrically reconstructed with an implant. If the risk of contralateral breast cancer had been anticipated initially, we might have opted for implant-based reconstruction from the start to facilitate a more symmetrical outcome in the event of subsequent contralateral reconstruction. This case underscores the importance of reviewing the risk of contralateral breast cancer in patients with unilateral breast cancer who also carry mutations in BRCA and other breast cancer susceptibility genes. Furthermore, it encourages consideration of how mutations in breast cancer susceptibility genes, including BRCA, influence the choice of plastic surgery reconstruction techniques. The findings from genetic testing for breast cancer susceptibility are now crucial to achieving aesthetic completeness in breast reconstruction.

MRNA-specific readthrough of nonsense codons by antisense oligonucleotides (R-ASOs).

Nonsense mutations account for >10% of human genetic disorders, including cystic fibrosis, Alagille syndrome, and Duchenne muscular dystrophy. A nonsense mutation results in the expression of a truncated protein, and therapeutic strategies aim to restore full-length protein expression. Most strategies under development, including small-molecule aminoglycosides, suppressor tRNAs, or the targeted degradation of termination factors, lack mRNA target selectivity and may poorly differentiate between nonsense and normal stop codons, resulting in off-target translation errors. Here, we demonstrate that antisense oligonucleotides can stimulate readthrough of disease-causing nonsense codons, resulting in high yields of full-length protein in mammalian cellular lysate. Readthrough efficiency depends on the sequence context near the stop codon and on the precise targeting position of an oligonucleotide, whose interaction with mRNA inhibits peptide release to promote readthrough. Readthrough-inducing antisense oligonucleotides (R-ASOs) enhance the potency of non-specific readthrough agents, including aminoglycoside G418 and suppressor tRNA, enabling a path toward target-specific readthrough of nonsense mutations in CFTR, JAG1, DMD, BRCA1 and other mutant genes. Finally, through systematic chemical engineering, we identify heavily modified fully functional R-ASO variants, enabling future therapeutic development.

Prevalence of homologous recombination biomarkers in multiple tumor types: an observational study.

Aim: To determine the prevalence of deleterious mutations in BRCA1 and BRCA2 and in 13 genes involved in homologous recombination repair (HRR), the prevalence of genomic loss of heterozygosity and the allelic and hereditary status of BRCA1, BRCA2 and other HRR gene mutations in multiple solid tumor types. Patients & methods: This was a retrospective observational study of patients with an advanced/metastatic diagnosis in one of 15 solid tumor types, who were identified in a real-world clinico-genomic database. Results: Tumor tissue samples from 9457 patients were analyzed, among which 4.7% had known or suspected deleterious BRCA1/2 mutations. The prevalence (range) of mutations in HRR genes was 13.6% (2.4%-26.0%) and genomic loss of heterozygosity ≥16% was 20.6% (2.6-34.4%) across all tumor types. Conclusion: The prevalence of mutations varied significantly depending on the type of tumor.

Overcoming Chemoresistance in Cancer: The Promise of Crizotinib.

Chemoresistance is a major obstacle in cancer treatment, often leading to disease progression and poor outcomes. It arises through various mechanisms such as genetic mutations, drug efflux pumps, enhanced DNA repair, and changes in the tumor microenvironment. These processes allow cancer cells to survive despite chemotherapy, underscoring the need for new strategies to overcome resistance and improve treatment efficacy. Crizotinib, a first-generation multi-target kinase inhibitor, is approved by the FDA for the treatment of ALK-positive or ROS1-positive non-small cell lung cancer (NSCLC), refractory inflammatory (ALK)-positive myofibroblastic tumors (IMTs) and relapsed/refractory ALK-positive anaplastic large cell lymphoma (ALCL). Crizotinib exists in two enantiomeric forms: (R)-crizotinib and its mirror image, (S)-crizotinib. It is assumed that the R-isomer is responsible for the carrying out various processes reviewed here The S-isomer, on the other hand, shows a strong inhibition of MTH1, an enzyme important for DNA repair mechanisms. Studies have shown that crizotinib is an effective multi-kinase inhibitor targeting various kinases such as c-Met, native/T315I Bcr/Abl, and JAK2. Its mechanism of action involves the competitive inhibition of ATP binding and allosteric inhibition, particularly at Bcr/Abl. Crizotinib showed synergistic effects when combined with the poly ADP ribose polymerase inhibitor (PARP), especially in ovarian cancer harboring BRCA gene mutations. In addition, crizotinib targets a critical vulnerability in many p53-mutated cancers. Unlike its wild-type counterpart, the p53 mutant promotes cancer cell survival. Crizotinib can cause the degradation of the p53 mutant, sensitizing these cancer cells to DNA-damaging substances and triggering apoptosis. Interestingly, other reports demonstrated that crizotinib exhibits anti-bacterial activity, targeting Gram-positive bacteria. Also, it is active against drug-resistant strains. In summary, crizotinib exerts anti-tumor effects through several mechanisms, including the inhibition of kinases and the restoration of drug sensitivity. The potential of crizotinib in combination therapies is emphasized, particularly in cancers with a high prevalence of the p53 mutant, such as triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC).

O-061 Ovarian cancer and fertility - current understanding

Abstract Introduction Ovarian cancer is a significant health concern worldwide and is the leading cause of death from gynecologic malignancies. While fertility preservation is essential for many young women diagnosed with cancer, concerns have been raised regarding the potential impact of fertility treatments on the risk of ovarian cancer development. 1. Ovarian Cancer Risk Factors Ovarian cancer is a multifactorial disease with various risk factors contributing to its development. A woman has a risk of 1 in 78 of having ovarian cancer in her life time, risk factors include: • Age: Ovarian cancer risk increases with age, with the highest incidence observed in women over 50 years old. About 12.1% of Ovarian Cancer patients are younger than 44 years old. • Family History: Women with a family history of ovarian or breast cancer, especially first-degree relatives, have an increased risk. • BRCA Mutations: Inherited mutations in BRCA1 and BRCA2 genes significantly elevate the risk of ovarian cancer. • Reproductive Factors: Factors such as nulliparity, early menarche, late menopause, and infertility have been associated with an increased risk of ovarian cancer. 2. Fertility Treatments and Ovarian Cancer Risk Understanding the mechanisms underlying ovarian cancer development is crucial for assessing the potential impact of fertility treatments : • Ovulation Hypothesis: The repeated ovulation theory suggests that each ovulatory cycle increases the risk of DNA damage to ovarian epithelial cells, potentially leading to cancer development. The use of fertility drugs to stimulate ovulation, such as clomiphene citrate and gonadotropins, has been studied , the early studies suggested a potential increased risk, more recent evidence has been conflicting, with some studies reporting no association. • In Vitro Fertilization (IVF): Several large-scale studies have investigated the relationship between IVF and ovarian cancer risk found no significant increase in ovarian cancer risk . • Hormonal Influence: Fertility drugs alter hormonal levels, particularly estrogen and progesterone, which may influence ovarian cancer risk. • Selection Bias: Some studies have suggested that the ovarian cancer risk may be confounded by underlying infertility factors rather than the treatments themselves. 3. Clinical Implications and Recommendations • Individual Risk Assessment: Clinicians should assess each patient's individual risk factors for ovarian cancer, including age, family history, and reproductive history, before initiating fertility treatments. • Informed Consent: Patients should be provided with comprehensive information regarding the potential risks and benefits of fertility treatments • Regular Surveillance: Women undergoing fertility treatments should receive regular gynecologic screenings and follow-up care to monitor for any signs or symptoms of ovarian cancer. • Shared Decision Making: Shared decision making between patients and healthcare providers is essential to ensure that treatment decisions align with patients' preferences and values. 4. Fertility Preservation Options • Most therapeutic options for Ovarian Cancer cause infertility, either by premature ovarian failure caused by cytotoxic agents in chemotherapy or surgical approaches that include unilateral or bilateral oophorectomy • In ovarian cancer patients, Oocyte cryopreservation is still the best option and the only one established along with embryo cryopreservation. Fertility preservation surgery can be suggested depending on histology, stage of disease and pre-existing ovarian reserve. • Ovarian tissue cryopreservation will not be an option as long as the risk of reseeding cancer cells is not fully eliminated. 5. Future Directions Advancements in molecular biology and genetics may shed light on the underlying mechanisms of ovarian cancer development and its potential association with fertility treatments. The artificial ovary and in vitro maturation of oocytes is a very attractive option in these patients, but further milestones have to be achieved

P-376 Letrozole to minimise exposure to elevated serum estradiol during superovulation for breast cancer patients prior to chemotherapy. Real world experience from a statewide oncofertility service

Abstract Study question How effective is co-treatment with letrozole in supressing peak E2 in a real world setting? Summary answer We observed greater than anticipated supra-physiological serum estadiol concentrations in our cohort. What is known already Breast cancer occurs frequently in women of reproductive age, many of whom request oocyte or embryo cryopreservation before chemo/radiotherapy. Oncofertility treatment requires superovulation with resultant elevation of serum estradiol above concentrations seen physiologically. In order to avoid possible stimulation of estrogen receptor positive breast cancers, co-administration of letrozole is frequently recommended. A 67% lower mean serum estradiol in a letrozole treated group compared with an untreated superovulated comparison group has been reported in the literature, suggesting a protective mechanism. Peak E2 concentration across 4 cohorts of patients co-treated with letrozole has been reported to be 103 – 2350 (mean 564). Study design, size, duration We performed a retrospective cohort study of women referred for fertility preservation following diagnosis of breast cancer to the Fertility Research Centre at The Royal Hospital for Women, Sydney between Jan 2020 and Jan 2024. Women were identified from hospital outpatient paper and electronic medical records. 145 new referrals were received by our centre, with 88 patients undergoing 107 cycles. Participants/materials, setting, methods 145 women aged between 19 and 44 with newly diagnosed breast cancer were referred to our Statewide, multidisciplinary, public oncofertility service for consideration of treatment and review at our fertility multidisciplinary team meeting. Our oncofertility database and outpatient clinical records were used to identify new referrals to the service. Electronic and paper medical records including the ART database were used to obtain cycle information, blood results and demographic information Main results and the role of chance Peak estradiol concentrations (pMol/L) 35% of cycles resulted in peak E2 &amp;gt; 2000. 11% of cycles resulted in peak E2 &amp;gt; 4000 and 2% of cycles resulted in peak E2 &amp;gt; 7000. We calculated a mean E2 of 1837. The mean anti-mullerian hormone was 20.3 pMol/L and mean antral follicle count 19.7. The mean BMI was 24.7. The average stimulation length was 13 days (7-16 days) with an average cumulative gonadotrophin dose of 2769 IU. Average number of MII oocytes per cycle was 7.2. 16 % of patients elected to preserve embryos. The fertilisation rate was 50%, with 61% of fertilised eggs resulting in frozen blastocytes. There have been 2 pregnancies and one live birth to date. 32% of cycles had a germline genetic result prior to OPU, with 20% having a positive BRCA gene mutation. Breast cancer hormone status 56% were Estrogen Receptor positive. 38 % were Progesterone Receptor positive, 18% were HER2 positive, 24% were hormone receptor negative Complications 5% of cycles were cancelled prior to OPU, 8% of cycles resulted in no oocyte or embryo available for freezing. 3% of cycles were reviewed for OHSS symptoms with 2 confirmed cases of OHSS secondary to administration of Zoladex &amp;lt;24hrs following OPU. Limitations, reasons for caution This is a retrospective cohort study in a single academic centre. Our current study duration is too short to permit determination of recurrence rates of breast cancer in the letrozole treated cohort. Wider implications of the findings The impact of short, transient elevation of circulating estradiol during superovulation is uncertain, however it is prudent to try to minimise exposure of ER positive breast cancers to estrogen. Alternative strategies for limiting this phenomenon should be explored, more evidence is needed on oncological and fertility outcomes in this population. Trial registration number N/A

Vaginal assisted NOTES hysterectomy in The Netherlands; A prospective cohort study

ObjectivesVaginal assisted Natural Orifice Transluminal Endoscopic Surgery (NOTES) combines the benefits of vaginal and endoscopic surgery. This study presents the results of the first vaginal assisted NOTES hysterectomies (VANH) in The Netherlands. Study designA prospective cohort study was performed in two non-academic teaching hospitals in The Netherlands. Data was collected from patients who underwent a VANH for benign indications between August 2019 and April 2023. Baseline characteristics and data of intra- and postoperative surgical outcomes were recorded and analysed. The VANHs were performed by four experienced vaginal and endoscopic gynaecological surgeons. ResultsA total of 200 patients underwent a VANH. Indications were dysfunctional menstrual bleeding (61 %; n = 122), abnormal cervical cytology (15.5 %; n = 31), abdominal pain (11.5 %; n = 23), post ablation/sterilization pain syndrome (3.5 %; n = 7), uterine fibroids (5.0 %; n = 10), atypical endometrial hyperplasia (2.5 %; n = 5) and Lynch or BRCA gene mutation carriers (1.0 %, n = 2). The mean surgical time was 61.4 min ( ± 22.8 min) with a mean blood loss of 88 mL ( ± 89 mL) and a mean uterine weight of 150 g ( ± 112 g). In 2.0 % (n = 4) of the cases a conversion was necessary. Same day discharge (SDD) was feasible in 80.2 % (n = 105) of the patients planned in day-care. In 2.0 % (n = 4) an intra-operative complication and in 9.0 % (n = 18) a post-operative complication occurred. ConclusionThis study shows vNOTES to be a safe and feasible surgical technique and can be safely implemented with appropriate patient selection and skilled surgeons. It highlights the importance of surgeon awareness of the challenges inherent in the initial stages of the implementation of a new surgical technique when performing their first vNOTES procedures. Additional randomized clinical trials are needed to show superiority of vNOTES compared to traditional surgery.