BACKGROUND: The PARP inhibitor (PARPi) olaparib is approved for homologous recombination repair (HRR) gene-altered metastatic castration-resistant prostate cancer (mCRPC). However, there is significant heterogeneity in response to PARPi in patients with mCRPC. Better clinical biomarkers are needed to identify patients likely to benefit from PARPi.
METHODS: Patients with prostate adenocarcinoma and panel sequencing at Dana-Farber Cancer Institute were identified. Mutational signature analysis was performed using SigMA to characterize tumors as HRR deficient (HRD). The validity of SigMA to identify patients likely to benefit from olaparib was compared to the current FDA label (presence of a deleterious alteration in one of 14 HRR genes).
RESULTS: 546 patients were identified, of which 34% were HRD. Among patients with HRR gene alterations, only patients with BRCA2 two-copy loss (2CL) were more likely to be HRD compared to patients without HRR gene alterations (74% vs 31%; P = 9.1 × 10-7). 28 patients with mCRPC received olaparib, of which 13 were HRD and 9 had BRCA2 2CL. SigMA improved upon the current FDA label for predicting PSA50 (sensitivity: 100% vs 90%; specificity: 83% vs 44%; PPV: 77% vs 47%; NPV: 100% vs 89%) and rPFS > 6 months (sensitivity: both 92%; specificity: 93% vs 53%; PPV: 92% vs 63%; NPV: 93% vs 89%). On multivariate analysis, incorporating prognostic clinical factors and HR gene alterations, SigMA-predicted HRD independently associated with improved PSA-PFS (HR = 0.086, p = 0.00082) and rPFS (HR = 0.078, p = 0.0070).
CONCLUSIONS: SigMA-predicted HRD may better identify patients likely to benefit from olaparib as compared to the current FDA label. Larger studies are needed for further validation.

Ovarian carcinoma (OC) still represents an insidious and fatal malignancy, and few significant results have been obtained in the last two decades to improve patient survival. Novel targeted therapies such as poly (ADP-ribose) polymerase inhibitors (PARPi) have been successfully introduced in the clinical management of OC, but not all patients will benefit, and drug resistance almost inevitably occurs. The identification of patients who are likely to respond to PARPi-based therapies relies on homologous recombination deficiency (HRD) tests, as this condition is associated with response to these treatments. This review summarizes the genomic and functional HRD assays currently used in clinical practice and those under evaluation, the clinical implications of HRD testing in OC, and their current pitfalls and limitations. Special emphasis will be placed on the functional HRD assays under development and the use of machine learning and artificial intelligence technologies as novel strategies to overcome the current limitations of HRD tests for a better-personalized treatment to improve patient outcomes.

BACKGROUND: Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance.
METHODS: Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi.
RESULTS: AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively.
CONCLUSIONS: Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option.

The emergence of targeted therapies has transformed ovarian cancer treatment. However, biomarker profiling for precision medicine is limited by access to quality, tumour-enriched tissue samples. The use of cell-free DNA (cfDNA) in ascites presents a potential solution to this challenge. In this study, next-generation sequencing was performed on ascites-derived cfDNA samples (26 samples from 15 human participants with ovarian cancer), with matched DNA from ascites-derived tumour cells (n = 5) and archived formalin-fixed paraffin-embedded (FFPE) tissue (n = 5). Similar tumour purity and variant detection were achieved with cfDNA compared to FFPE and ascites cell DNA. Analysis of large-scale genomic alterations, loss of heterozygosity and tumour mutation burden identified six cases of high genomic instability (including four with pathogenic BRCA1 and BRCA2 mutations). Copy number profiles and subclone prevalence changed between sequential ascites samples, particularly in a case where deletions and chromothripsis in Chr17p13.1 and Chr8q resulted in changes in clinically relevant TP53 and MYC variants over time. Ascites cfDNA identified clinically actionable information, concordant to tissue biopsies, enabling opportunistic molecular profiling. This advocates for analysis of ascites cfDNA in lieu of accessing tumour tissue via biopsy.

BACKGROUND: Homologous recombination deficiency (HRD) is one of the crucial hallmarks of cancer. It is associated with a favorable response to platinum-based chemotherapy. We explored the distinctive clinicopathological features of gastric cancer (GC) with HRD and the clinical significance of HRD in platinum-based first-line chemotherapy for unresectable metastatic GC.
METHODS: We enrolled 160 patients with GC in this study. Their tumor samples were subjected to genomic profiling utilizing targeted tumor sequencing. HRD was defined as the presence of alterations in any of 16 HR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, WRN, and XRCC2). The clinicopathological features and treatment outcomes of first-line chemotherapy for unresectable metastatic GC were compared between HRD and non-HRD groups.
RESULTS: Forty-seven patients (29.4%) were classified into the HRD group. This group had a significantly lower proportion of macroscopic type 3 or 4 tumors and higher TMB than the non-HRD group. Among patients who underwent platinum-based first-line chemotherapy, the HRD group had a greater response rate and longer progression-free survival after treatment (median 8.0 months vs. 3.0 months, P = 0.010), with an adjusted hazard ratio of 0.337 (95% confidence interval 0.151-0.753). HRD status was not associated with treatment outcomes in patients who did not undergo platinum-based chemotherapy.
CONCLUSIONS: Low proportion of macroscopic type 3 or 4 tumors and a high TMB are distinctive features of GC with HRD. HRD status is a potential predictive marker in platinum-based first-line chemotherapy for unresectable metastatic GC.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved as first-line therapies for breast cancer gene (BRCA)-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. They are also effective for new and recurrent ovarian cancers that are BRCA- or homologous recombination deficiency (HRD)-positive. However, data on these mutations and PARPi use in the Middle East are limited.
OBJECTIVE: To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer.
METHODS: This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations, and 25 of 65 ovarian cancer patients tested for HRD. These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023. Data were summarized using descriptive statistics and compared using counts and percentages. Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria.
RESULTS: Among the 472 breast cancer patients, 12.1% underwent BRCA testing, and 38.5% of 65 ovarian cancer patients received HRD testing. Pathogenic mutations were found in 25.6% of the tested patients: 26.3% breast cancers had germline BRCA (gBRCA) mutations and 24.0% ovarian cancers showed HRD. Notably, 40.0% of gBRCA-positive breast cancers and 66.0% of HRD-positive ovarian cancers were Middle Eastern and Asian patients, respectively. PARPi treatment was used in 5 (33.3%) gBRCA-positive breast cancer patients as first-line therapy (n = 1; 7-months progression-free), for maintenance (n = 2; > 15-months progression-free), or at later stages due to compliance issues (n = 2). Four patients (66.6%) with HRD-positive ovarian cancer received PARPi and all remained progression-free.
CONCLUSIONS: Lower testing rates but higher BRCA mutations in breast cancer were found. Ethnicity reflected United Arab Emirates demographics, with breast cancer in Middle Eastern and ovarian cancer in Asian patients.

BACKGROUND: The aim of this study was to assess homologous recombination deficiency (HRD) status and its correlation with carboplatin treatment response in early triple-negative breast cancer (TNBC) patients.
METHODS: Tumor tissues from 225 consecutive TNBC patients were evaluated with an HRD panel and homologous recombination-related (HRR) gene expression data. HRD positivity was defined as a high HRD score and/or BRCA1/2 pathogenic or likely pathogenic mutation. Clinicopathological factors, neoadjuvant treatment response, and prognosis were analyzed with respect to HRD status in these TNBC patients.
RESULTS: HRD positivity was found in 53.3% of patients and was significantly related to high Ki67 levels (P = 0.001). In patients who received neoadjuvant chemotherapy, HRD positivity (P = 0.005) or a high HRD score (P = 0.003) was significantly associated with a greater pathological complete response (pCR) rate, especially in those treated with carboplatin-containing neoadjuvant regimens (HRD positivity vs. negativity: 50.00% vs. 17.65%, P = 0.040). HRD positivity was associated with favorable distant metastasis-free survival (hazard ratio HR 0.49, 95% confidence interval CI 0.26-0.90, P = 0.022) and overall survival (HR 0.45, 95% CI 0.20-0.99, P = 0.049), irrespective of carboplatin treatment.
CONCLUSIONS: TNBC patients with high HRDs had high Ki67 levels and BRCA mutations. HRD-positive TNBC patients treated with carboplatin had a higher pCR rate. Patients with HRD positivity had a better prognosis, irrespective of carboplatin treatment, warranting further evaluation.

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Sarcomas rarely develop in bones previously compromised by infarcts. These infarct-associated sarcomas often present as undifferentiated pleomorphic sarcomas (UPS), and their genetic characteristics are poorly understood. High-grade UPS of bone are typically treated with a combination of surgery and chemotherapy, similar to osteosarcoma. We conducted a detailed clinicopathologic and genomic analysis of 6 cases of intraosseous sarcomas arising from histologically and radiographically confirmed bone infarcts. We analyzed 523 genes for sequence-level mutations using next-generation sequencing with the TruSight Oncology 500 panel and utilized whole-genome single nucleotide polymorphism Microarray (OncoScan CNV) to detect copy number alterations and loss of heterozygosity (LOH). Genomic instability was assessed through homologous recombination deficiency (HRD) metrics, incorporating LOH, telomeric allelic imbalance, and large-scale state transitions. Fluorescence in situ hybridization and immunohistochemistry validated the findings. The cohort included 3 men and 3 women, with a median age of 70 years, and tumors located in the femur and tibia. Five of the 6 patients developed distant metastases. Treatment involved surgery and chemotherapy or immune checkpoint inhibitors. Genomic analysis revealed significant complexity and high HRD scores, ranging from 32 to 57 (with a cutoff of 32). Chromosome 12 alterations, including segmental amplification or chromothripsis, were observed in 4 cases. Notably, MDM2 amplification, confirmed by fluorescence in situ hybridization, was detected in 2 cases. Homozygous deletion of CDKN2A/B was observed in all six cases. Tumor mutational burden levels ranged from 2.4 to 7.9 mutations per megabase. Notable pathogenic mutations included H3-3A mutations (p.G35R and p.G35W), and mutations in HRAS, DNMT3A, NF2, PIK3CA, POLE, and TP53, each in one case. These results suggest that high-grade infarct-associated sarcomas of bone, whereas sharing high levels of structural variations with osteosarcoma, may exhibit potentially less frequent TP53 mutations and more common CDKN2A/B deletions. This points to the possibility that the mutation spectrum and disrupted pathways could be distinct from conventional osteosarcoma.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, notably resistant to existing therapies. Current research indicates that PDAC patients deficient in homologous recombination (HR) benefit from platinum-based treatments and poly-ADP-ribose polymerase inhibitors (PARPi). However, the effectiveness of PARPi in HR-deficient (HRD) PDAC is suboptimal, and significant challenges remain in fully understanding the distinct characteristics and implications of HRD-associated PDAC. We analyzed 16 PDAC patient-derived tissues, categorized by their homologous recombination deficiency (HRD) scores, and performed high-plex immunofluorescence analysis to define 20 cell phenotypes, thereby generating an in-situ PDAC tumor-immune landscape. Spatial phenotypic-transcriptomic profiling guided by regions-of-interest (ROIs) identified a crucial regulatory mechanism through localized tumor-adjacent macrophages, potentially in an HRD-dependent manner. Cellular neighborhood (CN) analysis further demonstrated the existence of macrophage-associated high-ordered cellular functional units in spatial contexts. Using our multi-omics spatial profiling strategy, we uncovered a dynamic macrophage-mediated regulatory axis linking HRD status with SIGLEC10 and CD52. These findings demonstrate the potential of targeting CD52 in combination with PARPi as a therapeutic intervention for PDAC.