BRCA1 Mutation Research Articles

Identification of BRCA1 Exon15 Mutations in Bangladeshi Ovarian Cancer Patients

After cervical and uterine cancer, ovarian cancer is the third most frequent gynecological malignancy worldwide. BRCA1 mutations are the common predisposing factors for ovarian cancer development. Among the South Asian countries, most of studies are focused on Chinese, Indian, Pakistani populations. This study aims to identify BRCA1 exon15 mutations in a Bangladeshi ovarian cancer and benign gynecological disease patient population. This cross-sectional, comparative study was carried out in the Genetic Research Laboratory, Department of Anatomy, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, from March 2020 to July 2021. The mean age at diagnosis of ovarian cancer patients was found 44.9 years and benign gynecological diseases patients was found 35.6 years. Among them, about 40% patients were multiparous and 26.7% had family history of cancer. Upon Sanger sequencing of the targeted region (BRCA1 exon15) of the extracted DNA of thirty (30) ovarian cancer and fifteen (15) benign gynecological diseases patients, a mutation in one ovarian cancer patient was identified. The one mutation in ovarian cancer patient, C.4684C>T (P.Pro1562Ser) where ‘C’ was substituted by ‘T’. This mutation was missense, and it was previously reported in ClinGen Allele Registry. Only 3.33% patient, within the age group of 18-50 years, were found to have mutations in their blood. Among this small samples size, one mutation in blood samples of ovarian cancer patients were identified. Mugda Med Coll J. 2024; 7(2): 82-88

Genomic Characterization of Chordoma: Insights from the AACR Project GENIE Database

Background: Chordoma is a rare primary tumor originating from embryonic notochord remnants, with limited systemic therapeutic options due to a poor understanding of its genomic landscape. This study aims to characterize the genetic alterations in chordoma using a large national patient-level genomic repository, the AACR Project GENIE, to identify potential therapeutic targets and improve disease modeling. Methods: A retrospective analysis of chordoma samples was conducted using the AACR Project GENIE database. Targeted sequencing data were analyzed for recurrent somatic mutations, tumor mutational burden, and chromosomal copy number variations, with significance set at p < 0.05. Results: Frequent mutations were observed in genes associated with SWI/SNF complex affecting chromatin remodeling (SETD2, PBRM1, ARID1A). Mutations were also common among the TERT promoter regions, and cell cycle regulation (CDKN2A). Significant co-occurrences were identified among PBRM1, BRCA2, and KMT2D mutations. CDKN2A/B deletions were enriched in metastatic tumors, and pediatric cases demonstrated distinct mutation profiles compared to adults. Conclusions: This study provides a genomic profile of chordoma, identifying key mutations and potential therapeutic targets. These findings highlight the roles of chromatin remodeling and cell cycle pathways in chordoma biology, offering insights for future precision medicine approaches and therapeutic interventions.

Large scale population screening for BRCA1 and BRCA2 Ashkenazi founder mutations: perspectives of professionals providing oncogenetic consultations

Introduction: In March 2020, a nationwide population carrier screening for BRCA1/2 pathogenic variants among Ashkenazi Jewish women was initiated in Israel. We aimed to assess views regarding the program among professionals who provide oncogenetic counseling for detected carriers. Methods: An online survey was distributed to clinical geneticists and genetic counselors. Results: The participants’ impression was that most carriers did not comprehend the implications of a positive result when deciding to take the test. Some carriers, in retrospect, regretted taking it. Some had a known mutation carrier in the family, and some had a family history that justified a broader test (and so should not have been tested through the screening program). Eight survey participants (29%) reported they were initially against the screening program, but half of them are currently in favor of it. Most participants are unsatisfied with the way the screening is conducted and suggested various improvements. Emotional distress of carriers, as assessed by participants, was higher for those detected by the screening program, compared to those tested after oncogenetic counseling. No association was found between the age, profession and prior experience of participants and their responses. Conclusions: While the general attitude towards the screening program is positive, most professionals feel the need to improve the current screening program by defining exclusion criteria, providing comprehensive pretest information and adding other BRCA1/2 founder mutations, as well as expanding the screening to include ethnicities other than Ashkenazi Jews.

Susceptibility of Brca1(L63X/+) rat to ovarian reserve dissipation by chemotherapeutic agents to breast cancer.

BRCA1 is one of the causative genes for hereditary breast and ovarian cancer syndrome with a high risk of early-onset breast cancer. Whereas olaparib (OLA), an inhibitor of poly-ADP-ribose polymerase, has been applied as adjuvant therapy to those cancer patients, its effect on ovarian reproductive function remains unelucidated. Recently, a rat model (MUT; Brca1(L63X/+) mutation) mimicking a human BRCA1 pathogenic variant has been established. Using this model, we evaluated the effects of OLA on ovarian reproductive function in comparison with the wild-type (WT) rats. MUT showed a significantly reduced number of primordial follicles and subfertility in accordance with aging. Oxidative stress was significantly elevated in the young MUT granulosa cells (GCs) accompanied by increased mTOR but decreased PTEN signals. OLA administration in MUT further decreased primordial follicles, with gene set enrichment analysis, indicating upregulated DNA repair pathways. Furthermore, a combination of OLA and cyclophosphamide (CPA) induced empty primordial follicles, recognized as CPA-induced severe ovarian toxicity. Whereas OLA + CPA caused greater reduction in primordial follicles both in MUT and WT in comparison with CPA alone, MUT ovaries were more susceptible to oxidative stress, potentially depleting primordial follicles via activation of GCs and inducing oocyte death due to accumulated DNA damage by OLA treatment. Our findings in this preclinical model underscore the importance of evaluating ovarian reserve prior to chemotherapy by performing reproductive consultation with female patients with BRCA1 pathogenic variants.

Phase II study of niraparib and dostarlimab for the treatment of germline or somatic homologous recombination repair mutated (HRD) metastatic pancreatic cancer.

727 Background: PARP inhibition (PARPi) is a standard maintenance therapy for patients (pts) with germline BRCA1/2 mutations in pancreatic cancer. Combination of PARPi therapy and immunotherapy has potential to increase efficacy and may offer benefit beyond germline BRCA1/2 . Methods: We performed a multisite single-arm phase 2 study using the highly potent PARPi niraparib with anti-PD1 drug dostarlimab in pts with germline or somatic HRD mutations in BRCA1/2, PALB2, RAD51C/D, or BARD1 . Pts were required to have metastasis, progressed on ≥1 regimen, and prior platinum-exposure unless refused/intolerant. Pts were treated with niraparib 200 mg orally once daily continuously. Dostarlimab 500 mg was administered IV every 3 weeks for 4 cycles, then 1000 mg IV every 6 weeks. The primary endpoint was disease control rate (DCR) at 12 weeks (DCR12) using iRECIST criteria. At least 8 pts with DCR12 in the first 19 eligible pts (41%) would be considered promising for further trials. Results: 22 pts were enrolled from Dec 2020 to Oct 2023. Two pts withdrew prior to receiving therapy, and 2 were later found to be ineligible, leaving 18 eligible pts for final analyses. Median age was 63.0 yrs, 39% male, 94% non-Hispanic white, 1 black (6%). 17 pts were platinum exposed, 7 were platinum-refractory, and 5 had previously progressed on PARPi maintenance. Mutation distribution was: BRCA2 13/18 (72%), BRCA1 4/18 (22%), BARD1 2/18 (11%). One pt had both BRCA1 (somatic) and BRCA2 (germline) mutations. Germline mutations were identified in 14/18 (78%). DCR12 was achieved in 5/18 (27.8%), so the primary endpoint (>41%) was not met. Pts received a median 2 cycles (range 1-8) of niraparib + dostarlimab. No clinical factors were significantly associated with improved DCR12 (all p > 0.05) in subgroup analyses, but we did observe the following statistically nonsignificant associations. Pts who were platinum-refractory had a lower DCR12 compared to those not (14.3% vs. 36.4%). Counterintuitively, PARPi exposed/refractory pts had a higher DCR12 than non-exposed/non-refractory (50 vs 17% exposed/nonexposed and 40% vs 23% refractory/nonrefractory). Pts with germline mutations had a higher DCR12 compared to those without (38.5% vs. 0%). Non- BRCA2 mutations had a higher DCR12 than those with BRCA2 mutations (50% vs.17%), with highest DCR12 rates among BRCA1 patients (67%). Tolerability was in line with similar combinations, with 60% non-hematologic Gr3 or higher, including fatigue (15%), AST increase (10%), nausea/vomiting (10%), sepsis (10%). Two grade 5 events were not attributed to treatment. Conclusions: PARPi plus anti-PD1 checkpoint inhibition was not sufficiently active as later line therapy in metastatic pancreatic cancer for the majority of patients with HRD mutations. Additional molecular analyses to elucidate predictive markers of sensitivity/resistance are ongoing. Clinical trial information: NCT04493060 .

Niraparib in patients with BRCA -mutated unresectable or recurrent biliary tract, pancreatic and other gastrointestinal cancers: An investigator-initiated phase 2 trial (NIR-B trial).

589 Background: It has been reported that there are BRCA1/2 -mutated patients in biliary tract, pancreatic, and other gastrointestinal cancers. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations. Methods: Main eligibility criteria are unresectable, advanced or recurrent biliary tract cancers (BTC; cohort A), pancreatic cancers (PC; cohort B), and other gastrointestinal cancers (cohort C) with BRCA1/2 gene mutations identified by germline test or genomic profiling test with either circulating tumor DNA (ctDNA) or tumor tissue, refractory or intolerant to previous treatments, and adequate organ function. Patients with body weight of 77 kg or more and a platelet count of 150,000 /µL or more receive 300 mg of niraparib, and less than 77 kg or having a platelet count less than 150,000 /µL received 200 mg of niraparib, orally once daily, until disease progression or intolerable adverse events occurred. Primary endpoint was the investigator-assessed objective response rate (ORR) in each cohort with a threshold response rate of 10% and an expected response rate of 35%. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and safety. Furthermore, pre-treatment ctDNA was collected and analyzed by Guardant360. Results: A total of 62 pts, 26 in cohort A, 26 in cohort B, and 10 in cohort C were enrolled between March 2021 and April 2023. Because one patient in cohort C did not receive protocol treatment, 61 pts were identified for primary efficacy and safety analysis. Median number of prior regimens was 1/2/2 (range, 1–2/1–2/1-6). In cohort A/B/C, the confirmed ORR was 15.4/15.4/0% [95% highest posterior density credible interval, 8.4–27.9/8.4–27.9/0.0–25.9]. The DCR, median (m) PFS, mOS were 57.7/53.8/22.2% [95% confidence interval (CI), 36.9–76.6/33.4–73.4/2.8–60.0], 2.7/1.8/1.4 months (95% CI, 1.5–4.1/1.4–9.3/1.0–2.8), 7.8/9.5/7.4 months (95% CI, 5.9–9.8/3.5–NE/2.9–8.6), respectively. In the pts with BRCA mutations by Guardant360 (cohort A/B/C were 18/21/8), ORR was 11.1/19.0/0% (95% CI, 2.0-30.2/6.5–38.3/0.0–28.3). The most common treatment-emergent adverse events were thrombocytopenia (31.1%), anemia (27.9%), neutropenia (14.8%), nausea (36.1%), fatigue (29.5%), anorexia (24.6%). Conclusions: Although niraparib had signs of clinical activity in pts with BRCA -mutated BTC and PC, the primary endpoint was not achieved statistically. No new safety signal was observed. Alternative approaches, such as evaluation in biomarker-selected patients or in combination with other agents, may demonstrate greater clinical activity of niraparib in this setting. Clinical trial information: jRCT2011200023.

Real-world outcomes of PARP inhibitor maintenance in advanced ovarian cancer: a focus on disease patterns and treatment modalities at recurrence.

The utilization of poly-ADP-ribose polymerase (PARP) inhibitors (PARPi) as a first-line maintenance therapy for advanced ovarian cancer has increased significantly, with ∼80% of patients potentially eligible. This expansion has led to a rise in the population experiencing platinum-sensitive recurrence, yet data on first recurrence during PARPi are limited. This real-world study from a high-volume referral center aims to elucidate recurrence rates, disease distribution, and treatment modalities at the time of progression in PARPi-treated patients. We analyzed our prospectively maintained database to identify patients receiving first-line PARPi maintenance from January 2019 to December 2022 at our institution. A total of 373 cases were identified, 51.5% of which had a BRCA mutation. With a median follow-up of 38 months, 44.8% of patients experienced recurrence, with 90.3% having a platinum-free interval exceeding 6 months. Recurrences were oligometastatic in 44.9% of cases, with BRCA mutations strongly predicting this pattern (hazard ratio 3.014, confidence interval 1.486-6.113, P= 0.002). The median progression-free survival was 39 months, significantly longer for BRCA-mutated and homologous recombination deficiency-positive patients. Over one-third of platinum-sensitive recurrent patients were candidates for local treatments, and PARPi administration was prolonged in 53.7%. Despite the notable survival improvement, a significant proportion of the population will experience a platinum-sensitive recurrence on PARPi, for which local treatments are often a viable option. Our study highlights the need for further research to determine whether the ablation of oligometastatic sites has a significant impact on post-recurrence survival and to identify if there are patient categories that would benefit from personalized follow-up due to their susceptibility to oligometastatic recurrences and local treatments.

A global comparative study on real-world clinical and genomic differences in advanced biliary tract cancer.

628 Background: Biliary tract cancers (BTC) are aggressive malignancies with poor survival outcomes and limited treatment options. This study compared the epidemiological and molecular differences of advanced BTC patients through a global collaboration involving the Mayo Clinic and National Cancer Center Hospital East. Methods: We included patients with advanced BTC who underwent comprehensive tumor molecular profiling who received at least 30 days of systemic therapy. Patients were grouped based on specific alterations. Overall survival (OS) was calculated from the start of first-line therapy until death and compared among subgroups using Cox regression models. Results: 332 (36%) out of 932 patients had at least one actionable mutation : somatic BRCA1/2 mutations N=106, FGFR2 fusions N=61, HER2 amplifications N=65, KRAS G12C/D mutations N=46, IDH1 mutations N=38, and TMB >10 mut/Mb N=16. BRCA1/2 -mutated BTC were more commonly found in older Asian males with intrahepatic tumors and often presented with peritoneal and liver metastases upon initial diagnosis. FGFR2 fusions were more prevalent in younger White females with intrahepatic tumors, while HER2 amplifications were mainly seen in Asian females with gallbladder tumors. KRAS mutations were primarily observed in Asian males, and IDH1 mutations were common in White males with intrahepatic tumors, frequently presenting with liver metastasis. Survival outcomes varied significantly based on the alteration type: patients with FGFR2 fusions had the longest median OS (mOS) at 23.3 months (mo) (95%CI 18.4-34.9), followed by those with IDH1 mutations (19.3 mo; 95% CI 17.4-NE) and TMB >10 mut/Mb (17.8 mo; 95% CI 13.6-NE). BRCA mutations had a mOS of 16 mo (95% CI 14.6-19.8), while HER2 amplifications and KRAS mutations had mOS of 15.5 (95% CI 11.9-20.2) and 11.6 mo (95% CI 10.0-20.9), respectively. Conclusions: These findings underscore the heterogeneity in clinical and genomic characteristics among BTC patients, highlighting the importance of tailored therapeutic approaches. Baseline patient characteristics stratified by mutation status. KRAS G12C/D (N=46) BRCA 1/2 (N=106) IDH1 (N=38) HER2 amplification(N=65) FGFR2 fusion(N=61) TMB>10 mut/Mb(N=16) P-value Median Age, year 67 68 64 66 52 73 <0.001 Female, n (%) 19 (41) 34 (32) 18(47) 34 (52) 45(74) 6 (38) <0.001 Race, n (%) <0.001 Asian 31 (67) 97 (92) 13 (34) 51 (79) 10 (16) 6 (38) White 14 (30) 8 (8) 24 (63) 13 (20) 48 (79) 10 (63) Primary tumor location, n (%) <0.001 Intrahepatic 28 (68) 45 (45) 33 (100) 19 (31) 54(95) 10 (67) Extrahepatic 9 (22) 27(27) 0 (0) 10 (16) 2 (4) 4 (27) Gallbladder 4 (10) 28 (28) 0 (0) 32 (53) 1 (2) 1 (7) Sites of Metastasis at diagnosis, n (%) Abdominal Wall / Peritoneal 9 (24) 15 (19) 4(13) 7 (12) 6 (10) 4 (27) 0.309 Bone 33 (92) 70 (90) 26 (87) 2 (3) 9(15) 0 (0) 0.212 Liver 20 (49) 52 (61) 28 (82) 45 (73) 45 (76) 6 (38) 0.001 Lung 26 (70) 65 (82) 22 (69) 36 (58) 27(45) 11 (69) 0.006

Randomized phase II trial of olaparib + pembrolizumab vs olaparib alone as maintenance therapy in patients with metastatic pancreatic cancer with germline BRCA1 or BRCA2 mutations: SWOG S2001 NCT04548752.

TPS793 Background: Olaparib was approved in 2019 as maintenance therapy for gBRCA1/2+ metastatic pancreatic cancer (mPDA) patients (pts). The POLO trial showed an improvement in median progression-free survival (mPFS) with olaparib compared to placebo (7.4 vs 3.8 months) for platinum sensitive gBRCA1/2+ mPDA pts. Preclinical studies have demonstrated that PARP inhibitors modulate the immune microenvironment by increasing genomic instability, PD-L1 expression and activating the immune inflammatory stimulator of interferon genes (STING) pathway. Results of the phase 2 pembrolizumab and olaparib (POLAR) maintenance trial in patients with germline or somatic BRCA1/2 or PALB2 mutations responding to platinum-based chemotherapy for at least 4 months was presented at ESMO 2024. In 33 patients, a 35% overall response rate with 90% disease control rate at 6 months was observed. S2001 is an important randomized study to better define the impact of the combination. Methods: S2001 was developed in collaboration with the Alliance and was activated in SWOG in October 2020. Key eligibility criteria include: mPDA pts with gBRCA1/2 mutations identified with standard of care germline genetic testing and progression-free after receiving at least 4 months of platinum-based chemotherapy (FOLFIRINOX, FOLFOX or gemcitabine/cisplatin +/- nab-paclitaxel). One cycle of gemcitabine and nab-paclitaxel is allowed while waiting for germline testing. Zubrod performance status (PS) 0 or 1 pts are eligible. Pts are stratified according to first line chemotherapy, PS 0 vs 1, and disease status after 1st line treatment. The primary objective of this study is to evaluate the PFS of mPDA pts treated with olaparib + pembrolizumab compared to olaparib alone as maintenance therapy. Based upon the POLO trial, we expect a mPFS of 7 months in the control arm. Targeting a mPFS of 11.7 months in the experimental arm (hazard ratio 0.6) and assuming 15 months follow-up, 80% power and a 1-sided alpha = 0.10, this design requires 78 evaluable pts with a total sample size of 88 pts. Prospective serial blood samples will be collected to bank DNA and RNA for future correlative studies. Support: NIH/NCI grants U10CA180888 and U10CA180819, U10CA180821 and U10CA180868. Clinical trial information: NCT04548752 .

Impact of long-term chemotherapy (CTx) on outcomes in pancreatic ductal adenocarcinoma (PDAC): A real-world UK multi-centre study.

687 Background: PDAC is associated with poor outcomes with limited treatment options. Here, we present a multi-institutional review evaluating outcomes following short and long-term CTx with or without treatment breaks in PDAC patients (pts). Methods: All consecutive PDAC pts receiving > 3 CTx cycles between 2019 – 2023 at University College London Hospitals and Oxford University Hospitals were included. Treatment response, survival outcomes and predictors of clinical benefit were evaluated. Wilcoxon test, Kaplan-Meier and multivariate Cox regression models were performed. Results: Of the 213 screened pts, 127 eligible subjects met the study criteria. 1 st , 2 nd and 3 rd line CTx were received by 127, 40 and 2 pts, respectively. 21 pts had resectable disease (9 remained relapse-free after adjuvant CTx and 8 pts alive at post 2 years follow-up surveillance). 106 pts had unresectable or metastatic disease and were selected for final analyses (12% borderline resectable (BR), 19% locally advanced (LA), 9% localised disease who developed metastases and 60% de novo metastatic pts). 7 pts (7%) pts underwent genetic profiling on pt request or previous clinical trial screening; KRAS aberrations (N = 4), actionable PLAB2 / BRCA2 mutations (N = 2). BR and LA pts (N = 33) achieved a median PFS1 (Progression Free Survival while on 1 st line CTx) of 8.28 (95% Confidence Interval (CI), 5.49 – 15.11) and Overall Survival (OS) of 15.15 (95% CI, 9.46 – 26.41) months (mos). De novo metastatic pts (N = 64) attained a PFS1 of 6.64 (95% CI, 5.98 – 8.18) and OS of 9.30 (95% CI, 8.05 – 12.81) mos. Patient-specific factors in both cohorts comprising of age, gender, performance status, smoking history, co-morbidities were not associated with PFS1 and OS. Improved PFS was associated with ≥ 6 cycles of 1 st line CTx (P = < 0.001), median duration of 1 st CTx of ≥ 3.58 mos (P = < 0.001) and best response to 1 st CTx (P = 0.007). A favourable OS was associated with > 1 line of CTx (P = < 0.001), ≥ 6 cycles of 1 st line CTx (P = 0.009), median duration of 1 st CTx of ≥ 3.58 mos (P = < 0.001) and best response to 1 st CTx (P = 0.002). Subjects receiving ≥ 6 cycles of 1 st CTx were younger than pts tolerating fewer cycles (median age 62.41 vs 72.25 years) (P = 0.04). In the localised disease group, improved PFS was associated with ≥ 6 cycles of 1 st line CTx (P = 0.003), median duration of 1 st CTx of ≥ 2.99 mos (P = 0.008) and local treatment after commencing 1 st line CTx (P = < 0.001). These three factors were also associated with OS; P = 0.02, P = 0.02 and P = < 0.001, respectively. Median number and duration of 1 st line CTx interruptions were not associated with PFS1 or OS in both cohorts. Conclusions: Despite challenges associated with long-term CTx, survival outcomes may be better in pts receiving CTx for longer periods and multiple treatment lines. Genetic profiling currently offers limited value but in carefully selected pts, localised treatment options may be associated with improved survival outcomes.

Rucaparib versus chemotherapy for treatment of relapsed ovarian cancer with deleterious BRCA1 or BRCA2 mutation (ARIEL4): final results of an international, open-label, randomised, phase 3 trial

Rucaparib versus chemotherapy for treatment of relapsed ovarian cancer with deleterious BRCA1 or BRCA2 mutation (ARIEL4): final results of an international, open-label, randomised, phase 3 trial

Genetic mutations and cytotoxic chemotherapy response for advanced solid tumors: A detailed analysis using the C-CAT database in Japan.

130 Background: Chemotherapy regimens are selected based on information about the primary organ or its histological type and are administered based on the results of previous clinical trials. Even now, as cancer genomic research has progressed and precision medicine, which optimizes therapeutic interventions based on tumor genome profiling using next-generation sequencing(NGS), has become standard treatment, cytotoxic anticancer drugs still remain key drugs. We examined the real-world database of genomic and clinical information established by the national central datacenter, the Center for Cancer Genomics and Advanced Therapy (C-CAT) to systematically analyze the effects of mutations across multiple cancers and therapies. Methods: This study delineated the association between genetic mutations and the therapeutic efficacy of cytotoxic chemotherapy in advanced solid tumors in a real-world Japanese clinical context. We incorporated data from 15,474 patients enrolled in the C-CAT database between June 2019 and June 2022. We analyzed the overall response and time to next treatment (TNT) for genetic alterations and five categories of cytotoxic anticancer drugs in gastrointestinal cancers. Results: In the C-CAT data, gastrointestinal cancers were frequently registered, with colorectal cancer being the most common, followed by pancreatic cancer, esophageal/gastric cancer, and biliary tract cancer. For platinum-based drugs, in colorectal cancer, the presence of gene X was associated with not only a higher response rate but also a longer TNT (hazard ratio 0.82, p<0.001). In the case of colorectal cancer and pancreatic cancer with KRAS gene mutations, the ORR was low, and the TNT was also short in the case of pancreatic cancer (hazard ratio 1.33, p<0.001). Interestingly, when BRCA2 genes are mutant, TNT tended to be longer in many organs, suggesting that platinum-based drugs are effective across organs in carcinomas with BRCA2 mutations. Additionally, gene X showed differences in efficacy not only for platinum but also for antimetabolites and topoisomerase inhibitors. Moreover, KRAS mutation was observed in almost all pancreatic cancers and was a treatment-resistant mechanism for all platinum drugs and antimetabolites. Conclusions: This study demonstrated that the effects of cytotoxic anticancer drugs differ depending on genetic mutations. When determining chemotherapy regimens, considering not only the organ but also genetic mutations may enable more efficient drug selection.

Phase II study of olaparib in patients with advanced pancreatic acinar cell carcinoma.

TPS789 Background: Pancreatic Acinar Cell Carcinoma (PACC) is a rare and biologically distinct subtype of pancreatic cancer, representing 0.5-1% of all pancreatic malignancies, with a median overall survival of 15-20 months. Significant serum CA 19-9 elevation is uncommon, while elevation of serum lipase is observed in at least 50% of patients. Most patients present at advanced stages and treatment with combination chemotherapies extrapolated from other GI malignancies leads to low response rates. No clinical treatment trials specific for PACC have ever been reported. PACC tumors from patients show evidence of high chromosomal instability, a hallmark of DNA repair deficiency. ID3 is ubiquitously downregulated and was recently shown to play a significant role in homologous recombination repair (HRR). Recent genomic profiling of larger PACC patient cohorts has revealed a high prevalence of mutations in HRR genes, including BRCA1, BRCA2, and PALB2. Olaparib is a Poly-ADP ribose polymerase (PARP)-1 inhibitor that has been FDA approved for treatment of BRCA-mutant HRR deficient cancers. We hypothesize that PACC will be sensitive to PARP inhibition with olaparib. Methods: This is an open label, single arm, single center, phase II study of olaparib in patients with advanced previously treated PACC. The primary objective of the trial is to evaluate anti-tumor activity of olaparib (objective response rate). Secondary objectives assess the safety (CTCAE v. 5.0) and alternative measures of efficacy such as clinical outcomes and blood biomarkers (disease control rate, median progression-free survival, median overall survival, best response in serum lipase). Key eligibility criteria include histologic diagnosis of PACC, receipt of at least one line of combination chemotherapy, presence of RECIST measurable disease and adequate organ and bone marrow function. A fixed dose of olaparib at 300 mg will be given orally continuously twice daily during a 28-day cycle, for up to 2 years or until disease progression or intolerable toxicities. In person visits to assess toxicity are required every 4 weeks, and response is determined through serial imaging every 8 weeks (CT or MRI). Exploratory objectives include acquisition of tumor tissue for establishment of new PACC preclinical models, assessment of genetic alterations through genetic mapping technique, assessment of HRR-related gene products as a predictive biomarker, assessment of ID3 protein levels, and assessment of treatment response to tumor profile. Up to 13 evaluable participants will be enrolled. Three participants have been enrolled as of Sep 19, 2024. Clinical trial information: NCT05286827 .

Association between ex vivo pharmacotyping of patient-derived tumor organoids and personalized therapeutic options for patients with biliary tract cancer.

618 Background: Biliary tract cancers (BTC), including cholangiocarcinomas and gallbladder adenocarcinomas, present significant therapeutic challenges due to limited treatment options and poor prognoses. We report findings from the CLIA-certified PARIS assay, evaluating drug sensitivities of patient-derived tumor organoids (PDTOs) to a panel of oncology drugs. Methods: PDTOs were successfully cultured from 27 out of 46 live tumor samples obtained from 43 BTC patients. The majority of patients presented with advanced metastatic disease (60% stage IV, 13% stage III, 10% stage II, 4.4% stage I, 10% unknown) and had exhausted standard therapeutic options. Each PDTO culture underwent testing against an average of 50 drugs, encompassing chemotherapeutic agents and targeted therapies. Results: Comparative analysis of PDTO drug sensitivities with patients' prior treatment histories revealed non-responsiveness to >80% of drugs associated with clinical progression, including gemcitabine, cisplatin, and targeted therapies for FGFR translocations. In contrast, 100% (26/26) of the samples demonstrated significant sensitivity to one or more targeted agents, particularly inhibitors of EGFR, MEK, ERK, mTOR, PI3K, MDM2, BCL2, and BET families. Despite these shared sensitivities, each individual PDTO culture exhibited unique responses to targeted therapies, highlighting the genetic and phenotypic diversity between BTC patients. Comparison of ex vivo drug sensitivities with tumor genomic profiles validated oncogenic drivers such as HER2 amplification, KRAS and PIK3CA pathogenic mutations, correlating with sensitivities to EGFR/HER2 inhibitors, MEK inhibitors, and PI3K inhibitors, respectively. While mutations in KRAS , BRAF , BRCA1 , BRCA2 , ERBB2 , ERBB3 , or MET are present in less than 8% of cases, their role as biomarkers in BTCs requires further validation. PDTOs offer a promising tool to expedite this validation process. The PARIS assay results guided treatment decisions for five patients with metastatic disease, two of whom maintained treatment for over 4 weeks. Notably, two patients showed clinical benefit with everolimus (5 weeks) and dasatinib (11 weeks), experiencing symptom relief and reduced ascites. Intriguingly, 5 out of 7 PDTOs with FGFR alterations exhibited exceptional PARIS test responses to dasatinib, suggesting potential efficacy linked to FGFR activation. Conclusions: In conclusion, our study demonstrates that ex vivo drug testing of PDTO cultures can inform treatment selection and potentially accelerate drug approvals for BTC, leveraging therapies approved for other cancers. Early integration of such assays in patient management, possibly at diagnosis, holds promise for improving outcomes in this challenging disease.

BRCA1 and BRCA2 mutations testing in prostate cancer: Detection in formalin fixed paraffin embedded (FFPE) and blood samples.

Prostate cancer (PC) represents one of the leading causes of cancer-related morbidity and mortality in men, requiring further understanding to improve diagnosis and treatment. Germline BRCA1/2 mutations, primarily identified in other hereditary cancers, confer an increased risk of developing PC; thus, testing is essential to assess cancer risk, guiding preventive strategies and screening. Recently, somatic BRCA1/2 mutations have emerged as pivotal predictive biomarkers of responsiveness to the poly ADP-ribose polymerase (PARP) inhibitors. This review provides a comprehensive overview of BRCA1/2 mutations testing in PC, focusing on the germline and somatic mutations frequencies and the technical approach for their identification. A revision of the main data reported in the literature regarding BRCA1/2 mutations identification will be presented, highlighting the critical issue for the detection both in formalin fixed paraffin embedded (FFPE) and blood samples.

Patient perspective: Is intensive screening of women at high risk of breast cancer evidence-based medicine or déjà vu?

In 2023, a breast cancer risk assessment and a subsequent positive test for the BRCA-2 genetic mutation brought me to the uncomfortable intersection of a longstanding career as an advocate for high-quality medical evidence to support shared patient-provider decision making and a new role as a high-risk patient. My search for studies of available risk-management options revealed that the most commonly recommended approach for women with a ⩾20% lifetime breast cancer risk, intensive screening including annual mammography and/or magnetic resonance imaging beginning at age 25-40 years, was supported only by cancer-detection statistics, with almost no evidence on patient-centered outcomes-mortality, physical and psychological morbidity, or quality of life-compared with standard screening or a surgical alternative, bilateral risk-reducing mastectomy. In this commentary, I explore parallels between the use of the intensive screening protocol and another longstanding women's health recommendation based on limited evidence, the use of hormone therapy (HT) for postmenopausal chronic disease prevention, which was sharply curtailed after the publication of the groundbreaking Women's Health Initiative trial in 2002. These declines in HT utilization were followed by marked decreases in breast cancer incidence, providing a compelling lesson on the critical importance of a solid evidentiary basis for women's health decisions. Known harms accompanying the benefits of breast screening-overdiagnosis, psychological effects, and mammography-associated radiation-exposure risks-make empirical measurement of patient-centered outcomes essential. Yet, published research on intensive screening of women at high breast cancer risk has largely ignored these outcomes, leaving patients, providers, and guideline developers lacking the evidence needed for best practice. Outcomes research is both feasible and urgently needed to inform care decisions and health policy for this patient population.

Real-World Impact of Olaparib Exposure in Advanced Pancreatic Cancer Patients Harboring Germline BRCA1-2 Pathogenic Variants.

Pancreatic cancer arising in the context of BRCA predisposition may benefit from poly(ADP-ribose) polymerase inhibitors. We analyzed real-world data on the impact of olaparib on survival in metastatic pancreatic cancer patients harboring germline BRCA mutations in Italy, where olaparib is not reimbursed for this indication. Clinico/pathological data of pancreatic cancer patients with documented BRCA1-2 germline pathogenic variants who had received first-line chemotherapy for metastatic disease were collected from 23 Italian oncology departments and the impact of olaparib exposure on overall survival (OS) was analyzed. Of 114, 53 BRCA-mutant pancreatic cancer patients had received olaparib for metastatic disease. OS was significantly longer in patients who were exposed to olaparib (hazard ratio [HR] 0.568, 95% confidence interval [CI] 0.351-0.918, log-rank p = 0.02) in any setting/line of treatment; similar results were obtained for patients who received olaparib as maintenance treatment (in any line of treatment), patients who had stage IV disease at diagnosis, and patients who did not experience progressive disease as their best response to first-line chemotherapy. Exposure to olaparib in the first-line maintenance setting after platinum-based chemotherapy, however, did not significantly impact survival. At multivariate analysis, CA19.9 levels at diagnosis and response to first-line chemotherapy were independently prognostic; however, when response to chemotherapy was excluded, any exposure to olaparib was a significant independent predictor of longer OS, together with CA19.9 levels. The real-world data presented here support the use of olaparib for metastatic disease in germline BRCA-mutant pancreatic cancer patients, as it may significantly prolong survival.

Single agent olaparib in advanced oesophago-gastric cancer: Primary results from the SOlar clinical phase II single arm trial.

427 Background: A subset of pts with advanced oesophago-gastric adenocarcinoma (OGA) are characterised by deficient DNA damage repair (DDR) providing a rationale for PARP inhibition (PARPi) in these tumours. Potential activity was observed in the phase 3 gastric cancer trial with Olaparib + paclitaxel, however the efficacy of Olaparib monotherapy and response biomarkers have not been established. Herein we report the primary clinical results from the SOlar trial. Methods: SOlar is a prospective, open label, single arm phase II trial using a Simon’s two stage optimal design, evaluating the efficacy and safety of Olaparib 300mg twice daily in pts with locally advanced/metastatic OGA who had previously progressed on ≥1 line of therapy in the advanced setting. Pts with measurable disease by RECIST v1.1 amenable to mandatory baseline biopsy were included. The primary end point was disease control rate (DCR) at 8 weeks from Olaparib initiation by RECIST v1.1. In this two-stage optimal design, if ≥5/27 pts had disease control in stage 1, a further 27 pts were to be recruited in stage 2. If ≥12/54 evaluable pts achieved disease control, Olaparib would warrant further investigation. Other key endpoints include; overall response rate, progression free survival and overall survival, and translational biomarker analyses (NCT03829345). Results: Between July 2019 - February 2024, 55 pts with locally advanced/metastatic OGA were enrolled. 51 pts received Olaparib and 50 were evaluable for the primary endpoint (5 withdrew). The median age was 61yrs (range: 54-67), 7 (14%) were HER2 -positive and 2 had a known germline BRCA mutation. 19 (38%) pts had received ≥3 lines of therapy and 22 (44%) pts had received prior immunotherapy for OGA. 30 (60%) pts had objective responses to prior platinum chemotherapy (CR + PR). The DCR at 8-weeks was 28% (91% one-sided confidence interval lower bound: 19.4) with 14/50 evaluable pts having stable disease. No objective response was observed. 36/51 (71%) treated pts experienced a treatment-related adverse event (TRAE) of any grade, and 9 (18%) experienced a grade ≥3 TRAE (most common being anaemia, fatigue, vomiting). Two serious adverse events were reported as treatment-related: definitely related grade 1 pneumonitis, and possibly related grade 4 lung infection. Conclusions: In SOlar, Olaparib met its primary endpoint with 28% DCR in this heavily pre-treated group. No new safety concerns were observed. Ongoing translational analyses include; homologous repair deficiency scoring, whole exome sequencing, RNA expression, serial ctDNA, and multiplex immunofluorescent assessment of the tumour micro-environment, with a view to identify a subgroup who might benefit from PARPi to support ongoing PARPi combinatorial studies in advanced OGA. Clinical trial information: NCT03829345 .

Effects of tumor treating fields (TTFields) with FOLFIRINOX on BRCA WT pancreatic cancer cells.

753 Background: Pancreatic cancer remains one of the most aggressive malignancies, frequently diagnosed at the locally advanced or metastatic stage. In the advanced setting, first-line chemotherapy options include gemcitabine with nab-paclitaxel or FOLFIRINOX, a combination regimen of fluorouracil, oxaliplatin, irinotecan and leucovorin. The FOLFIRINOX regimen is however associated with greater toxicity and is hence used only in patients with good performance status. BRCA-mutated tumors seem to be more sensitive to FOLFIRINOX due to the DNA-damaging, platinum-based component of this treatment regimen. Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes crucial for cancer cell viability that have shown efficacy in preclinical pancreatic cancer models; and, in various cancer types, have been shown to reduce expression of proteins from the BRCA-dependent DNA repair pathway. The current study examined the potential use of TTFields for sensitization of BRCA wild-type pancreatic cancer cells to treatment with FOLFIRINOX. Methods: Human pancreatic BRCA wild-type cancer cells BxPC3 and AsPC1 were treated with TTFields (150 kHz; 0.7 and 1 V/cm RMS, respectively), using the inovitro device. FOLFIRINOX was administered to the cells at increasing concentrations, with or without co-treatment with TTFields. After 72h of treatment, cell count, colony formation, and apoptosis were measured. For mechanistical insight, gene and protein expression were evaluated following 24, 48, or 72h of TTFields treatment. Results: TTFields application to the pancreatic cells together with FOLFIRINOX elevated the cytotoxic, clonogenic and apoptotic effects induced by FOLFIRINOX or TTFields alone. RNA sequencing data revealed that TTFields downregulated DNA damage repair, DNA replication, and cell cycle related processes. Specifically, real-time PCR and Western blot analysis demonstrated reduced expression of several central players in the BRCA DNA damage repair pathway. Conclusions: TTFields application together with FOLFIRINOX in pancreatic cancer cells lacking background BRCA mutations exhibits potential improvement relative to FOLFIRINOX alone, that may be rationalized based on downregulation of key DNA repair pathways. Future studies should explore the possibility of reducing FOLFIRINOX treatment dose, potentially alleviating FOLFIRINOX-related toxicity.

Real-world clinical outcomes of locally advanced unresectable and de-novo metastatic pancreatic ductal adenocarcinoma: A multicenter retrospective study from Saudi Arabia.

691 Background: Pancreatic ductal adenocarcinoma (PDAC) has dismal clinical outcomes, even with existing treatment regimens. This study evaluates the clinical characteristics and outcomes of patients with locally advanced unresectable or de-novo metastatic PDAC in Saudi Arabia to provide real-world data that can be compared to international benchmarks. Methods: This is a retrospective, multicenter study. Patients diagnosed with unresectable locally advanced or de-novo metastatic PDAC between January 2015 and November 2023 were included. Data were collected from 10 oncology centers across Saudi Arabia. Patient characteristics, treatment regimens, and clinical outcomes, including progression-free survival (PFS) and overall survival (OS), were analyzed using univariate and multivariate analyses. Results: A total of 350 patients were identified, with a median age of 60 years at time of diagnosis, 63% of patients presenting with multiple metastatic sites, primarily in the liver (66.3%). Among patients tested, 7.1% had deficient mismatch repair (d-MMR), and 5.8% harbored BRCA mutations. FOLFIRINOX was the most common first-line treatment (55.1%), followed by gemcitabine plus nab-paclitaxel (15.1%). The median PFS for first-line treatment was 5.3 months, with FOLFIRINOX achieving the longest PFS (6.5 months). The median OS was 10.34 months for the entire cohort, with better survival outcomes observed in patients receiving FOLFIRINOX (12.3 months). Independent prognostic factors for PFS and OS included performance status, type of first-line regimen, and neutrophil-lymphocyte ratio (NLR). Conclusions: This real-world study confirms that clinical outcomes for locally advanced unresectable and metastatic PDAC in Saudi Arabia are consistent with international data, with trend of FOLFIRINOX showing superior outcomes over gemcitabine-based regimens. However, both treatments reflect the persistent poor prognosis of PDAC, underscoring the need for novel therapeutic strategies. Further research is warranted to optimize treatment selection and improve survival outcomes in this population.