Sentis HRD Score Test (Genetech) at Chughtai Lab

Sentis HRD Score Test (Genetech) at Chughtai Lab

The Sentis HRD Score test (Genetech) at Chughtai Lab represents a monumental advancement in the field of precision oncology and molecular diagnostics in Pakistan. Homologous Recombination Deficiency (HRD) is a genomic state characterized by a cell’s inability to repair double-stranded DNA breaks using the highly accurate homologous recombination repair (HRR) pathway. When this pathway is impaired, cells are forced to rely on alternative, error-prone DNA repair mechanisms, which leads to a high rate of genomic instability, mutations, and ultimately, oncogenesis. However, this cellular vulnerability also serves as a therapeutic target. Tumors with high HRD scores are exceptionally sensitive to specific targeted therapies, such as Poly (ADP-ribose) polymerase (PARP) inhibitors, and platinum-based chemotherapeutic agents.

The Sentis HRD Score test, developed by Genetech and performed utilizing state-of-the-art Next-Generation Sequencing (NGS) technology, is designed to comprehensively evaluate the genomic scar of a tumor. By analyzing specific patterns of genomic instability across the tumor genome, this test calculates a definitive HRD score. This score, combined with the mutational status of the BRCA1 and BRCA2 genes, provides oncologists with a comprehensive genomic profile of the patient’s tumor. This advanced molecular testing is primarily utilized in patients diagnosed with epithelial ovarian cancer, fallopian tube cancer, primary peritoneal cancer, breast cancer, prostate cancer, and pancreatic cancer. By identifying patients who are HRD-positive, the test enables healthcare providers to transition from generalized treatment protocols to highly personalized, targeted therapeutic strategies, significantly improving clinical outcomes and survival rates.

Chughtai Lab, Pakistan’s premier diagnostic network, offers this highly specialized molecular assay across its extensive network, ensuring that patients in Lahore, Karachi, Islamabad, and other major cities have access to world-class genomic testing. Through this test, Chughtai Lab provides critical diagnostic value, helping clinicians identify therapeutic vulnerabilities in aggressive malignancies, predict treatment responses, and optimize patient care pathways with the highest degree of clinical accuracy.

Clinical Procedure: What to Expect

Patient Preparation

Because the Sentis HRD Score test (Genetech) at Chughtai Lab is a specialized molecular test performed on tumor tissue, the preparation requirements differ significantly from standard blood-based laboratory investigations. Patients and their caregivers should observe the following preparation guidelines:

• Acquisition of Tissue Sample: The primary requirement for this test is a Formalin-Fixed Paraffin-Embedded (FFPE) tumor tissue block along with its corresponding Hematoxylin and Eosin (H&E) stained slide. This tissue is typically obtained from a previous surgical resection or biopsy.
• Pathology Report Submission: A copy of the original histopathology report must be submitted alongside the tissue specimen. This report helps the molecular pathologists at Chughtai Lab correlate clinical findings with genomic data.
• Tumor Cellularity Verification: The tissue specimen must contain an adequate percentage of tumor cells (typically a minimum of 20% to 30% tumor cellularity) to ensure sufficient tumor DNA can be extracted for sequencing. If the initial block has low cellularity, an alternative block from the same procedure may be requested.
• Clinical History and Consent: Patients or their oncologists must complete a detailed clinical history form and sign a molecular testing consent form. This documentation is crucial for accurate clinical interpretation of the genomic variants.
• No Fasting Required: Since the test is performed on pre-existing tissue blocks, there are no dietary restrictions or fasting requirements for the patient.
• Coordination with Chughtai Lab: It is highly recommended to contact Chughtai Lab’s specialized genomic department prior to sample submission to ensure all documentation, tissue block requirements, and transport conditions are met.

During the Procedure

The analytical phase of the Sentis HRD Score test is conducted entirely within the highly controlled environment of Chughtai Lab’s advanced molecular biology division. The procedure involves several highly technical steps:

• Specimen Retrieval and Quality Control: Once the FFPE block is received at Chughtai Lab, a consultant pathologist reviews the H&E slide to confirm the diagnosis, assess the percentage of viable tumor cells, and mark areas of high tumor density for microdissection if necessary.
• DNA Extraction: Multiple thin sections (usually 5 to 10 microns thick) are cut from the paraffin block. The paraffin is chemically removed, and the tumor cells are lysed to release genomic DNA. The extracted DNA undergoes rigorous quality control to assess concentration and purity.
• Library Preparation and Next-Generation Sequencing (NGS): The purified DNA is prepared for sequencing by fragmenting the genome and attaching specific molecular adapters. The sample is then loaded onto a high-throughput NGS platform, where millions of DNA fragments are sequenced simultaneously.
• Bioinformatic Analysis: The raw sequencing data is processed using specialized bioinformatics pipelines. The software aligns the sequences to a reference human genome and analyzes three specific markers of genomic instability: Loss of Heterozygosity (LOH), Telomeric Allelic Imbalance (TAI), and Large-scale State Transitions (LST).
• Score Calculation: The computational algorithm combines the measurements of LOH, TAI, and LST to generate a cumulative Genomic Instability Score (GIS). Simultaneously, the sequencing data is analyzed for pathogenic mutations in the BRCA1 and BRCA2 genes.
• Pathologist Interpretation: A multidisciplinary team of molecular pathologists and geneticists reviews the integrated data, correlates it with the patient’s clinical history, and drafts a comprehensive clinical report detailing the HRD status and therapeutic implications.

When is a Sentis HRD Score Test Performed?

Advanced Epithelial Ovarian Cancer

Physicians frequently request the Sentis HRD Score test for patients diagnosed with advanced (Stage III or IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. In these aggressive malignancies, determining the HRD status is critical immediately following primary cytoreductive surgery or first-line platinum-based chemotherapy. Patients whose tumors are identified as HRD-positive (which includes those with BRCA mutations or a high genomic instability score) derive a profound clinical benefit from maintenance therapy with PARP inhibitors. This targeted approach significantly extends progression-free survival compared to standard observation or conventional chemotherapy alone.

Metastatic Triple-Negative Breast Cancer (TNBC)

Triple-negative breast cancer is a highly aggressive subtype characterized by the absence of estrogen receptors, progesterone receptors, and HER2 amplification. Because targeted hormonal therapies are ineffective, chemotherapy has historically been the primary systemic treatment. Oncologists order the Sentis HRD Score test in metastatic TNBC cases to identify tumors that harbor underlying homologous recombination defects. TNBC patients with a high HRD score show exceptional sensitivity to DNA-damaging agents, such as cisplatin or carboplatin, and are prime candidates for clinical trials evaluating PARP inhibitors, offering a more tailored and effective therapeutic pathway.

Metastatic Castration-Resistant Prostate Cancer (mCRPC)

In advanced prostate cancer that has progressed despite androgen deprivation therapy, identifying actionable genomic alterations is essential. The HRD pathway is frequently altered in a subset of these patients. Clinicians order the Sentis HRD Score test to evaluate the presence of BRCA1/2 mutations and overall genomic instability in prostate tumor tissue. Detecting an HRD-positive status in mCRPC patients guides the selection of targeted therapies like olaparib or rucaparib, which have been shown to improve overall survival and delay disease progression in patients with these specific molecular profiles.

Advanced Pancreatic Ductal Adenocarcinoma

Pancreatic cancer is notorious for its rapid progression and limited treatment options. However, a clinically significant subset of pancreatic tumors exhibits homologous recombination deficiency. The Sentis HRD Score test is performed on pancreatic biopsy specimens to detect this molecular phenotype. Identifying HRD-positive pancreatic cancer allows oncologists to select first-line platinum-based chemotherapy regimens (such as FOLFIRINOX) and consider maintenance PARP inhibitor therapy, which can lead to durable tumor responses in a patient population that historically has had a poor prognosis.

Selection of Targeted PARP Inhibitor Maintenance Therapy

The overarching clinical indication for performing the Sentis HRD Score test is to establish eligibility for targeted maintenance therapies. PARP inhibitors work through the principle of synthetic lethality; by blocking the PARP enzyme, they prevent the repair of single-strand DNA breaks. In HRD-positive cells, which already lack the ability to repair double-strand breaks, this leads to catastrophic DNA damage and selective cell death. The test is performed to identify this specific therapeutic window, ensuring that expensive and highly potent targeted therapies are prescribed only to patients who are biologically predisposed to respond to them.

What Does a Sentis HRD Score Detect?

The Sentis HRD Score test (Genetech) at Chughtai Lab is designed to detect a wide array of genomic alterations and instability markers. Specifically, the test evaluates and reports on the following parameters:

• BRCA1 Pathogenic Mutations: Detects germline and somatic insertions, deletions, and single-nucleotide variants within the BRCA1 gene.
• BRCA2 Pathogenic Mutations: Identifies deleterious mutations within the BRCA2 gene that impair homologous recombination.
• Loss of Heterozygosity (LOH): Measures the percentage of genomic regions that have lost one parental allele, a key indicator of permanent DNA repair scars.
• Telomeric Allelic Imbalance (TAI): Evaluates DNA copy number imbalances extending to the telomeric regions of chromosomes.
• Large-scale State Transitions (LST): Detects chromosomal breaks and translocations of at least 10 megabases between adjacent genomic segments.
• Genomic Instability Score (GIS): Calculates a cumulative numerical score based on LOH, TAI, and LST to quantify overall genomic damage.
• Homologous Recombination Deficiency (HRD) Status: Classifies the tumor as HRD-Positive (high GIS or BRCA-mutated) or HRD-Negative (low GIS and BRCA-wildtype).
• Somatic Variants of Uncertain Significance (VUS): Identifies genetic variations in BRCA1/2 whose clinical significance is currently unclassified but clinically relevant for monitoring.
• ATM Gene Alterations: Detects mutations in the ATM serine/threonine kinase, a key upstream regulator of the DNA damage response.
• PALB2 Gene Mutations: Identifies alterations in the partner and localizer of BRCA2, which can contribute to homologous recombination deficiency.
• CHEK2 Gene Variants: Evaluates mutations in the checkpoint kinase 2 gene, involved in cell cycle arrest following DNA damage.
• RAD51C and RAD51D Mutations: Identifies defects in essential proteins of the homologous recombination repair complex.
• BRIP1 Gene Alterations: Detects mutations in the BRCA1-interacting protein C-terminal helicase 1.
• BARD1 Gene Mutations: Evaluates alterations in the BRCA1-associated RING domain protein 1.
• FANCA Gene Variants: Detects mutations associated with the Fanconi anemia pathway, closely linked to HRR.
• CDK12 Gene Alterations: Identifies mutations in cyclin-dependent kinase 12, which regulates transcription of DNA repair genes.
• Tumor Cellularity Percentage: Reports the proportion of tumor cells relative to normal stromal cells in the analyzed sample.
• DNA Quality and Degradation Index: Assesses the integrity of the extracted DNA to ensure the validity of the sequencing run.
• Copy Number Variations (CNVs): Identifies amplifications or deletions of large chromosomal segments containing cancer-related genes.
• Single Nucleotide Variants (SNVs): Detects point mutations across the targeted genomic regions.
• Small Insertions and Deletions (Indels): Identifies micro-insertions or deletions that disrupt the reading frame of DNA repair genes.
• Platinum Chemotherapy Sensitivity: Infers the likelihood of tumor response to platinum-based agents based on the genomic scar profile.
• PARP Inhibitor Susceptibility: Provides a molecular rationale for the clinical efficacy of PARP inhibitor therapies.

Turnaround Time and Report Access at Chughtai Lab

Due to the highly complex nature of Next-Generation Sequencing, bioinformatics processing, and clinical interpretation, the Sentis HRD Score test (Genetech) at Chughtai Lab has a specialized reporting timeline. Typically, the comprehensive molecular report is completed within 14 to 21 working days from the date of sample receipt and verification of adequate tumor cellularity.

Chughtai Lab utilizes a highly advanced, integrated laboratory information management system (LIMS) to ensure seamless report delivery. Once the report is finalized and signed off by the consultant molecular pathologist, patients and their referring oncologists receive an automated SMS notification. Reports can be accessed instantly and downloaded in PDF format via the official Chughtai Lab website or through the “Chughtai Active” mobile application. Additionally, physical copies of the reports can be collected from any of Chughtai Lab’s numerous diagnostic centers located across Pakistan, or delivered directly to the patient’s home through their dedicated report delivery service.

Sentis HRD Score Findings Overview

The following table outlines the key parameters evaluated during the Sentis HRD Score test, along with their clinical interpretation:

Structure / Parameter Evaluated	Normal Findings	Possible Abnormal Findings
BRCA1 Gene Status	Wild-type (No pathogenic mutations detected)	Pathogenic or likely pathogenic somatic or germline mutations
BRCA2 Gene Status	Wild-type (No pathogenic mutations detected)	Pathogenic or likely pathogenic somatic or germline mutations
Genomic Instability Score (GIS)	Low Score (Below established clinical threshold)	High Score (Equal to or above established clinical threshold, indicating high genomic scarring)
Loss of Heterozygosity (LOH)	Minimal areas of single-allele loss across the genome	Extensive regions of LOH, indicating widespread chromosomal deletion and repair failure
Telomeric Allelic Imbalance (TAI)	Normal chromosomal copy numbers at telomeric regions	Significant copy number variations and imbalances at chromosome ends
Large-scale State Transitions (LST)	Intact chromosomal structures with minimal large-scale breaks	High frequency of chromosomal breaks and translocations of 10Mb or larger
HRR Pathway Genes (non-BRCA)	No deleterious alterations in ATM, PALB2, RAD51, etc.	Pathogenic mutations in ATM, PALB2, RAD51C/D, CHEK2, or other HRR genes
Overall HRD Status	HRD-Negative (Homologous Recombination Proficient)	HRD-Positive (Homologous Recombination Deficient)

Note: Diagnostic findings should always be interpreted by a qualified healthcare professional together with the patient’s symptoms, medical history, physical examination, laboratory investigations, previous imaging studies, and other relevant clinical information. Additional investigations or specialist consultation may be recommended depending on the findings.

Why Choose Chughtai Lab for Sentis HRD Score Test?

• State-of-the-Art Molecular Pathology: Chughtai Lab houses a highly advanced genomics and molecular diagnostics division equipped with cutting-edge Next-Generation Sequencing (NGS) platforms.
• Experienced Medical Specialists: The genomic assays are interpreted by a dedicated team of consultant pathologists, molecular biologists, and clinical geneticists with extensive training in oncology diagnostics.
• Strategic Partnership with Genetech: By offering the official Sentis HRD Score test in collaboration with Genetech, Chughtai Lab ensures adherence to international testing standards and validated clinical algorithms.
• Rigorous Quality Assurance: Chughtai Lab maintains strict internal quality control protocols and participates in international external quality assessment programs to guarantee the highest accuracy of molecular reports.
• Convenient Sample Submission: With a vast network of collection centers across Pakistan, patients can easily submit their tissue blocks and clinical documents at a location convenient to them.
• Comprehensive Clinical Reporting: The final report provides clear, actionable therapeutic insights, detailing the genomic instability score, BRCA status, and potential sensitivity to PARP inhibitors and platinum chemotherapies.
• Secure and Digital Report Access: Patients and oncologists can access reports online through the Chughtai Lab portal or the “Chughtai Active” mobile app, ensuring rapid clinical decision-making.
• Patient-Centric Support Services: Chughtai Lab offers dedicated customer support and genetic counseling guidance to help patients and families navigate complex genomic test results.