Germline Mutations In BRCA1 Research Articles

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 .

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 .

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 .

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.

Abstract A005: 18F-Fluorthanatrace PARP inhibitor PET tracer: Potential implications for theranostics

Abstract Objective: PARP (poly [ADP-ribose] polymerase) inhibitors are approved for a variety of malignancies including those with a breast, prostate, and ovarian carcinoma, particularly in the setting of a germline or somatic pathogenic BRCA mutation. There is active interest in the development of theranostics including those with a PARP inhibitor backbone. Methods: We evaluate a novel PARP inhibitor (PARPi) PET tracer 18-Fluorine [18F] Fluorthanatrace (FTT). Patients with primary or metastatic solid tumors with measurable disease initiating therapy with a PARP inhibitor monotherapy or in combination with another systemic agent were eligible. Patients underwent 18F-FTT PET/CT prior to initiation of PARPi and a second 18F-FTT PET 2-4 weeks after initiation of a PARP inhibitor. Hematologic toxicity on PARPi monotherapy or combination was assessed using the CTCAEv5.0 criteria. Regions of interest were drawn over the uninvolved bone marrow (usually taken at L3) and normal muscle to obtain the maximum standardized uptake value. Bone marrow to muscle ratio (B/M) was calculated at baseline and on PARPi. Spearman rank correlation coefficient was used. Results: A total of 21 patients were enrolled and underwent 18F-FTT PET. Patients had a median of 0 (range 0-7) prior lines of systemic therapy. The primary disease site included breast (9), ovary (6), primary peritoneal (1), pancreas (1)and other (4). Measurable uptake of 18F-FTT within the tumor and bone marrow was observed in all patients. Median L3 SUVmax at baseline was 4.3 (range 2.1-11.8) vs. 2.33 (range 1.4-2.9) while on PARP inhibitor. Baseline B/M was associated with highest grade hematologic toxicity in patients (n=10) who received talazoparib monotherapy or combination (r=0.65, p=0.042). While B/M was not associated with hematologic toxicity in patients (n=11) who received olaparib monotherapy or combination (r=0.098, p=0.77). Conclusions: 18F-FTT PET can measure target engagement of PARP inhibitors in bone marrow and may have implications for PARP inhibitor-based theranostics and dosing. Results suggest there may be differential impact of different PARPi on bone marrow and should be considered when selecting a backbone for theranostics. Citation Format: Lilie Lin, Mahmoud Hammad, Franklin Wong, Timothy A. Yap. 18F-Fluorthanatrace PARP inhibitor PET tracer: Potential implications for theranostics. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr A005.

A case of de novo neuroendocrine prostate cancer presented with elevated level of serum CEA carrying BRCA2 mutation: case report and literature review

BackgroundDe novo neuroendocrine prostate cancer (NEPC) is a rare subtype of prostate cancer (PCa) and few markers are available for screening and monitoring. Potential circulating or fluid markers might facilitate early diagnosis thus improving prognosis of NEPC, especially for de novo NEPC.Case presentationA man of 71-year was presented with elevated level of serum carcinoembryonic antigen (CEA) (1296.5 ng/ml) and normal PSA (0.47ng/ml). Gastrointestinal endoscopy showed no signs of gastric or colorectal cancer. Fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) and prostate-specific membrane antigen PET-CT (PSMA PET-CT) indicated prostate cancer with metastases including pelvic lymph nodes, bone as well as lung metastases. Biopsy of prostate revealed mixed carcinoma including small cell neuroendocrine carcinoma (SCNEC) and adenocarcinoma (Gleason score of 4 + 5). Immunohistochemistry (IHC) staining and next generation sequencing demonstrated a strong expression of chromogranin A (CgA), synaptophysin (SYN) and CEA, and a germline mutation in BRCA2, respectively. After a prostatic massage, an increased level of CEA (137 ng/ml vs 5 ng/ml) was detected in urine. Olaparib, a Poly ADP-ribose polymerase inhibitor (PARPi), combined with androgen deprivation therapy (ADT) were administrated. FDG PET-CT indicated tumor regression in both quantity and size three months later, and CEA levels of serum and urine decreased to 23 ng/ml and 2.4 ng/ml 4 months later, respectively.ConclusionThis is the first report of a de novo NEPC presented with an elevated level of CEA, in which CEA was also detected in urine specimen post a prostatic massage. After a combination treatment of ADT for 3 months, levels of CEA in both serum and urine decreased sharply when tumor regressed radiologically. CEA might be a marker of screening and monitoring of NEPC.

Olaparib as treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency: Phase 2 LIGHT study final overall survival analysis.

LIGHT (oLaparib In HRD-Grouped Tumor types; NCT02983799) prospectively evaluated olaparib treatment in patients with platinum-sensitive relapsed ovarian cancer (PSROC) assigned to cohorts by known BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive non-BRCAm, and HRD-negative. At the primary analysis, olaparib treatment demonstrated activity across all cohorts, with greatest efficacy in terms of objective response rate and progression-free survival observed in the g/sBRCAm cohorts. The authors report final overall survival (OS). In this phase 2, open-label, noncomparative study, patients with PSROC and one or more prior line of platinum-based chemotherapy were assigned to cohorts by BRCAm and HRD status. OS was a secondary end point. Tumors were analyzed using Myriad BRACAnalysis CDx and MyChoice CDx assays; HRD-positive tumors were defined using a genomic instability score of ≥42. Of 272 enrolled patients, 271 received olaparib and 270 met the inclusion criteria for the efficacy analysis. At data cutoff, 18-month OS rates in the gBRCAm, sBRCAm, HRD-positive non-BRCAm, and HRD-negative cohorts were 86.4%, 88.0%, 78.6%, and 59.6%, respectively. No new safety signals were observed. In a post hoc analysis, patients on treatment for >18 months were most frequently present in g/sBRCAm cohorts (31.0%). Olaparib treatment continued to demonstrate benefit across all cohorts. Consistent with the primary analysis, the highest OS rates were observed in the BRCAm cohorts, regardless of g/sBRCAm. In patients without a BRCAm, a higher OS rate was observed in the HRD-positive non-BRCAm than the HRD-negative cohorts. These results highlight the importance of biomarker testing in this treatment setting.

Morphologic Characteristics Seen in High-grade Serous Ovarian Carcinoma Metastases in Postneoadjuvant Chemotherapy Resections.

The morphologic features of metastatic high-grade serous ovarian carcinoma (HGSOC) after neoadjuvant chemotherapy have not been described. We conducted a 1-year retrospective, single-institution review of pretreatment biopsy and posttreatment metastases in cases of HGSOC treated with neoadjuvant chemotherapy. Two gynecologic pathologists and 1 pathology resident reviewed 11 cases looking for 6 morphologic features. We correlated these features with patient information on HRD abnormalities (HRD score, germline, and/or somatic BRCA mutations). When compared with the pretreatment biopsies of metastases taken at the time of diagnosis, the postneoadjuvant, treated metastases had unique morphologic findings, such as cytoplasmic vacuolization, cellular enlargement with eosinophilic cytoplasm, macro-nucleoli, cellular discohesion, and micropapillary architecture with abundant psammoma bodies. Metastases were also morphologically different from the primary site in the postneoadjuvant resection specimens.

The incidence of pancreatic cancer in women with a BRCA1 or BRCA2 mutation.

The lifetime risk of pancreatic cancer in women with a germline mutation in BRCA1 and BRCA2 is not well established. In an international prospective cohort of female carriers of BRCA1 and BRCA2 mutations, the cumulative incidence of pancreatic cancer from age 40 until 80 years was estimated. A total of 8295 women with a BRCA1 or BRCA2 mutation were followed for new cases of pancreatic cancer. Subjects were followed from the date of baseline questionnaire or age 40 years (whichever came last) until a new diagnosis of pancreatic cancer, death from another cause, or date of last follow-up. Thirty-four incident pancreatic cancer cases were identified in the cohort. The annual risk of pancreatic cancer between age 40 and 80 years was 0.04% for BRCA1 carriers and 0.09% for BRCA2 carriers. Via the Kaplan-Meier method, the cumulative incidence from age 40 to 80 years was 2.2% (95% CI, 1.1%-4.3%) for BRCA1 carriers and 2.7% (95% CI, 1.3%-5.4%) for BRCA2 carriers. Only two of the 34 cases reported a first-degree relative with pancreatic cancer (hazard ratio,4.75; 95% CI, 1.13-19.9; p=.03). Risk factors for pancreatic cancer included alcohol intake and a history of diabetes. The 5-year survival rate for the 34 cases was 8.8%. The lifetime risk of pancreatic cancer is approximately 2% in women with a BRCA1 mutation and 3% for women with a BRCA2 mutation. The poor survival in hereditary pancreatic cancer underscores the need for novel antitumoral strategies.

Bibliometric analysis of olaparib and pancreatic cancer from 2009 to 2022: A global perspective.

Genetic screening for breast cancer gene 1 (BRCA)1/2 mutations can inform breast/ovarian/pancreatic cancer patients of suitable therapeutic interventions. Four to seven percent of pancreatic cancer patients have germline BRCA mutations. BRCA genes aid in DNA repair, especially homologous recombination, which impacts genomic stability and cancer cell growth. BRCA1 regulates the cell cycle, ubiquitination, and chromatin remodeling, whereas BRCA2 stimulates the immune response. They predict the efficacy of platinum chemotherapy or polymerase (PARP) inhibitors such as olaparib. To determine the trends and future directions in the use of olaparib for pancreatic cancer treatment. To evaluate the trends in how olaparib works in pancreatic cancer, we performed a bibliometric analysis. One hundred and ninety-six related publications were accessed from the Web of Science Core Collection and were published between 2009 and 2022. The analytic parameters included publications, related citations, productive countries and institutes, influential authors, and keyword development. This study visualizes and discusses the current research, including the present global trends and future directions in olaparib and pancreatic cancer. Overall, this study sheds light on optimizing the use of olaparib in pancreatic cancer treatment, offering valuable guidance for researchers in this field. Our findings identified trends in olaparib and pancreatic cancer, with China and the USA leading and with global cooperation tightening. O'Reilly EM's team and Memorial Sloan-Kettering had the highest output. The Journal of Clinical Oncology was the most cited journal. More PARP inhibitors are emerging, and combination therapy is suggested for future therapeutic trends.

EPCO-09. DICER1-MUTANT PRIMARY INTRACRANIAL SARCOMA: ASSESSING THE ONCOGENIC ROLE OF MIRNA DYSREGULATION

Abstract Cross-cancer profiling has shown that mutations in human DICER1 are recurrent in diverse cancers including intracranial sarcoma. Due to the rarity of these tumors, treatment options for these patients remain poorly defined. DICER1 encodes an endoribonuclease that processes the hairpin precursor microRNAs (miRNAs) into functionally mature miRNAs. In particular, hotspot mutations in the RNase IIIb domain of DICER1 are predicted to confer an oncogenic role although the precise mechanism is unknown. In a case of a 28-year-old male who presented with multicentric right frontal dural and parenchymal enhancing masses and underwent partial resection, pathology showed a DICER1-mutant primary intracranial sarcoma with a hotspot E1813G mutation in the RNase IIIb domain. Additionally, due to a family history of an unknown fatal brain tumor in his mother, the patient had additional molecular testing which revealed a germline BRCA2 mutation. After surgery, the patient received intensity-modulated radiation therapy followed by 6 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy with significant radiographic response and clinical improvement. He remains progression-free on radiological surveillance for 13 months since diagnosis. The treatment was well tolerated with clinically manageable myelosuppression (including grade 3 thrombocytopenia). This is the first reported case of an adult DICER1-mutant primary intracranial sarcoma patient with a germline BRCA2 mutation although the interaction between these oncogenic mechanisms is unclear. Based on the role of DICER1 in miRNA processing and to test the hypothesize that DICER1 mutations drive primary intracranial sarcoma through dysregulation of miRNA function, we have established a multi-institutional collaboration that is collecting and profiling DICER 1 mutant primary intracranial sarcoma cases from across the United States preliminary results of which will be presented. Identification of a miRNA-driven oncogenic mechanism in these tumors may yield novel targeted approaches beyond intensive chemotherapy for these patients.

CTIM-32. PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES (SOLARA)

Abstract BACKGROUND Despite progress in the treatment of brain metastasis for HER2+ breast cancer, outcomes for patients with HER2-negative breast cancer brain metastases remain poor. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective in combination with radiation therapy as a DNA damage response inhibitor. Triple-negative breast cancer (TNBC) has higher rates of homologous recombination deficiency compared to other subtypes, and together with HER2-negative, BRCA-mutated breast cancer would be particularly sensitive to PARP inhibition. PARP inhibition has also demonstrated promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials. In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with brain metastases. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated brain metastases through synergy with PARP inhibition, while controlling micrometastatic disease via potentiation of the immune response. METHODS We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) breast cancer brain metastases [NCT04711824]. A total of 41 patients are planned for enrollment at 8 sites. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II). Secondary objectives include assessing intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. As of May 2024, phase I has been completed without dose-limiting toxicity, and phase II is currently enrolling. Funding/drug provision from AstraZeneca.

Unlocking the Potential of Multigene Parallel Sequencing: A Concomitant Germline RET and BRCA1 Mutation in a Hereditary Medullary Thyroid Carcinoma

We report a rare case of a 33-year-old South Asian woman who visited the Molecular Pathology and Genomics Department referred for hereditary germline cancer genetic testing after being diagnosed with high-grade, multifocal medullary carcinoma of the thyroid. Genetic counselling showed an elaborate family history of cancer. Germline cancer testing on 113 genes for pancancer panel by next-generation sequencing showed a pathogenic heterozygous single nucleotide variant in RET gene c.1901G>C p.Cys634Ser (codon10) and an incidental finding of the presence of a pathogenic splice variant in BRCA1 gene c.213-1G>C at the intron 4 of the gene. The patient was further managed with a paradigm of Precision Medicine (PM) based on the 5Ps like participation, psychological support, and prediction of risk assessment, prevention, and personalisation.

Brca1 haploinsufficiency promotes early tumor onset and epigenetic alterations in a mouse model of hereditary breast cancer.

Germline BRCA1 mutation carriers face a high breast cancer risk; however, the underlying mechanisms for this risk are not completely understood. Using a new genetically engineered mouse model of germline Brca1 heterozygosity, we demonstrate that early tumor onset in a Brca1 heterozygous background cannot be fully explained by the conventional 'two-hit' hypothesis, suggesting the existence of inherent tumor-promoting alterations in the Brca1 heterozygous state. Single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses uncover a unique set of differentially accessible chromatin regions in ostensibly normal Brca1 heterozygous mammary epithelial cells, distinct from wild-type cells and partially mimicking the chromatin and RNA-level changes in tumor cells. Transcription factor analyses identify loss of ELF5 and gain of AP-1 sites in these epigenetically primed regions; in vivo experiments further implicate AP-1 and Wnt10a as strong promoters of Brca1-related breast cancer. These findings reveal a previously unappreciated epigenetic effect of Brca1 haploinsufficiency in accelerating tumorigenesis, advancing our mechanistic understanding and informing potential therapeutic strategies.

Factors influencing gynecologic risk reduction surgeries for BRCA1 or BRCA2 germline mutation carriers

Factors influencing gynecologic risk reduction surgeries for BRCA1 or BRCA2 germline mutation carriers

Breast cancer outcomes in women with ovarian cancer and a pathogenic germline BRCA mutation

BackgroundWomen with ovarian cancer (OC) and a pathogenic variant in the BRCA1 or BRCA2 genes are at increased risk of developing breast cancer (BC). Evidence for long term outcomes in these patients who undergo bilateral risk reduction mastectomy (RRM) after ovarian cancer is sparse. The aim of this study was to analyse the long-term breast cancer-related outcomes of patients who have been diagnosed with ovarian cancer and found to have BRCA1 or 2 pathogenic variants. MethodsLocal approval was granted. The hospital clinical genetics database was interrogated to identify women who have been diagnosed with OC and a germline BRCA1/2 pathogenic variant between January 2010-March 2020. Patient demographics, OC treatment as well as any BC related information was analysed. Results148 women were diagnosed with OC and a pathogenic variant in BRCA1/2 in the study period. 47 patients were excluded as they did not have treatment at our institution. 101 patients were included. The median age at diagnosis of OC was 52 years (IQR 46–61). Eighty-four (82%) were FIGO stage 3 or 4 OC. At a median follow-up of 63 months (IQR 39–94), 55 (54.4%) women had been diagnosed with a recurrence of ovarian cancer and 38 (37%) women have died. Twenty-one (21%) women were diagnosed with BC. 13 (12.9%) had BC before OC, 4 after and 4 synchronous with OC. Of the remaining patients who did not have BC, 6 underwent bilateral risk reduction mastectomy (RRM) after treatment for OC. DiscussionRisk of disease recurrence and death due to stage 3 and 4 ovarian cancer remained high in this time period. RRM can be undertaken in carefully selected patients, however we would recommend reserving this for women who have favourable OC disease prognosis.

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.

Real-World Clinical Outcomes of Treatment With Olaparib for BRCA1/2 Mutation-Positive Metastatic Breast Cancer in Japanese Patients.

Background Olaparib is effective in the treatment of metastatic breast cancer (MBC) patients, mainly confirmed by deleterious germline BRCA mutations. However, real-world data are scarce. Methodology A total of 10 cases from our institute and 17 cases from the relevant Japanese literature were reviewed. All 27 patients had MBC with confirmed deleterious germline BRCA mutations. Tumor reduction, response duration, disease-free interval (DFI), overall survival (OS), and safety were assessed. Additionally, exploratory research was conducted on the characteristics of a subgroup of patients who had a long-term response to olaparib. Results In the 10 cases from two Juntendo hospitals who received olaparib from July 2018 to December 2021, the median age was 48 years (range = 37-63 years). The same numbers of BRCA1 and BRCA2 mutations and the same ratios of luminal and triple negative (TN) breast cancer cases were observed. The metastatic sites, mainly visceral, included the lungs (n = 4), liver (n = 5), and bone (n = 6). The median duration of drug use was four months (range = 1-36 months). The median number of treatment regimens from metastasis to olaparib administration was 2.0 (range = 1-9 regimens). The median DFI was 21 months (range = 0-106 months). The median OS was not reached (range = 16-191 months). In the subgroup analysis of six cases in which olaparib was effective for four months or more, there was a case where DFI was longer than 100 months. Treatment-related toxicities (TRTs) included neutropenia (n = 5; 50%), anemia (n = 4; 40%), thrombocytopenia (n = 2; 20%), nausea (n = 1; 10%), and fatigue (n = 1; 10%). CTCAE (version 5.0) grade ≥3 TRTs included anemia (n = 1; 10%) and neutropenia (n = 5; 50%). On the other hand, neutropenia was previously said to be as low as 27.3%, lower than anemia (40.0%), in a population including various races. We additionally examined another 17 cases from the Japanese literature. Conclusions To our knowledge, this study reports the first real-world data of Japanese patients with MBC and confirmed deleterious germline BRCA mutations. Our data showed that olaparib is effective in the real world. The incidence of neutropenia seemed higher in Japanese patients.

BRCA promoter methylation in triple-negative breast cancer is preserved in xenograft models and represents a potential therapeutic marker for PARP inhibitors.

Most triple-negative breast cancers (TNBC) are sporadic in nature and often associated with dysfunction of the BRCA1 or BRCA2 genes. Since somatic BRCA mutations are rare in breast cancer (BC), this dysfunction frequently is the result of BRCA promoter methylation. Despite the phenotypic similarities of these tumors to those with germline or somatic BRCA mutation, the evidence of response to PARP inhibitors is unclear. We analyzed the prevalence of BRCA promoter methylation in 29 BC metastases through the well-established Illumina Infinium EPIC Human Methylation Bead Chip. In cases with BRCA methylation, the xenograft of the same tumor was tested. Additionally, we compared BC xenografts with an identified BRCA methylation to their matched primary tumors and subsequently investigated the efficacy of PARP inhibitors on tumor organoids from a BRCA2 promoter-methylated BC. BRCA2 promotor hypermethylation was identified in one pleural metastasis of a young patient as well as in the xenograft tissue. We also identified five more xenograft models with BRCA2 promotor hypermethylation. Analysis of one matched primary tumor confirmed the same BRCA2 methylation. PARP inhibitor treatment of tumor organoids derived from the BRCA2 methylated xenograft tumor tissue of the young patient showed a significant decline in cell viability, similar to organoids with somatic BRCA1 mutation, while having no effect on organoids with BRCA1 wildtype. BRCA promotor hypermethylation seems to be a rare event in metastatic BC but is preserved in subsequent xenograft models and might represent an attractive therapeutic marker for PARP inhibitors.

Functional Analysis of BARD1 Missense Variants on Homology-Directed Repair in Ovarian and Breast Cancers.

Women with germline BRCA1 mutations face an increased risk of developing breast and ovarian cancers. BARD1 (BRCA1 associated RING domain 1) is an essential heterodimeric partner of BRCA1, and mutations in BARD1 are also associated with these cancers. While BARD1 mutations are recognized for their cancer susceptibility, the exact roles of numerous BARD1 missense mutations remain unclear. In this study, we conducted functional assays to assess the homology-directed DNA repair (HDR) activity of all BARD1 missense substitutions identified in 55 breast and ovarian cancer samples, using the real-world data from the COSMIC and cBioPortal databases. Seven BARD1 variants (V85M, P187A, G491R, R565C, P669L, T719R, and Q730L) were confirmed to impair DNA damage repair. Furthermore, cells harboring these BARD1 variants exhibited increased sensitivity to the chemotherapeutic drugs, cisplatin, and olaparib, compared to cells expressing wild-type BARD1. These findings collectively suggest that these seven missense BARD1 variants are likely pathogenic and may respond well to cisplatin-olaparib combination therapy. This study not only enhances our understanding of BARD1's role in DNA damage repair but also offers valuable insights into predicting therapy responses in patients with specific BARD1 missense mutations.