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Clinical Utility of Encyclopedic Tumor Analysis to Treat Breast Cancer Patients who have Failed Standard of Care Treatments 1 1 Dadasaheb Akolkar , Darshana Patil , 2 1 Anantbhushan Ranade , Revati Patil , 1 1 1 Sachin Apurwa , Sanket Patil , Pradip Fulmali , 1 1 Pradip Devhare , Navin Srivastava , 1 1 Ajay Srinivasan , Rajan Datar . 1 Datar Cancer Genetics Limited, India. 2 Avinash Cancer Clinic, India. BACKGROUND Advanced refractory breast cancers (Br-Ca) pose formidable management challenges. Post failure of multiple lines of therapy, patients may be considered for palliation or clinical trials. RATIONALE Advanced refractory Br-Ca have latent vulnerabilities which can be identified by deep multi-analyte interrogation of the tumor interactome. We developed an Encyclopedic Tumor Analysis (ETA) which evaluates gene mutations, copy number variations, fusions, gene expression (mRNA and IHC) and in vitro chemoresistance profile of viable tumor cells. ETA findings were used to assign patient-specific label- and organ-agnostic combination treatment regimens. APPROACH We retrospectively evaluated 27 patients with advanced refractory Br-Ca where the cancer had previously progressed following failure of ≥2 prior systemic lines. These patients received ETA-guided treatments. Treatment response was determined from follow-up radiological scans and used to calculate Response Rates, Progression Free Survival. STUDY COHORT Table 1. Subtype ER+/PR+, HER2+ 7 ER+/PR+, HERS- 7 ER-,PR-,HER2- 6 ER-,PR-,HER2+ 7 Table 3. Metastatic Sites Bones 20 Brain 7 Metastatic Sites Minimum 1 Maximum 12 Median 3 Liver 14 Lung 13 Lymph Node 21 Table 4. Prior Treatments Radiation 18 Surgery 17 Median 2 Targeted 8 Minimum 1 Maximum 4 Endocrine 11 Systemic Cytotoxic 27 Systemic Lines Table 2. Grade Grade I 1 Grade II 10 Grade III-IV 13 Grade Unknown 3 Response to ETA-guided treatments was evaluated in 27 female patients with a median age of 47 years (range: 22 – 72 years). ENCYCLOPEDIC TUMOR ANALYSIS • Freshly biopsied tumor tissue and 15 mL blood was obtained from all patients for ETA. • ETA evaluated gene alterations (SNV, CNA, Indels) in DNA, gene expression and fusions in mRNA, expression of signaling and hormone receptors by IHC and in vitro chemoresistance profile of viable tumor cells. • ETA findings were integrated and harmonized to generate patient-specific drug-priority lists with optimum projected efficacy and minimum projected toxicity. Fig 1. Analytes and Analyses in ETA. Fig 2. Actionable Indications. 20 13 12 11 2 ETA identified actionable indications even in those patients where there were no targetable mutations. Indications for Targeted agents were label-agnostic. Fig 4. Targeted and Endocrine Agents. Number of Patients CRP SNV DGE IHC CNA 15 8 6 5 1 1 7 6 mTORi HER2i VEGFi / VEGFRi PDGFRi EGFRi FGFRi ERi ARi Number of Patients Fig 3. Types of Combination Regimens. CNA : Copy Number Alteration; IHC : Immunohistochemistry; DGE : Differential Gene Expression; SNV : Single Nucleotide Variation, CRP : Chemoresistance Profiling; 2 4 9 2 2 7 C T C+T Number of Patients No E With E C: Cytotoxic; T: Targeted; E: Endocrine. Majority of patients received treatment regimens with combination of cytotoxic and targeted agents. Fig 5. Cytotoxic Agents. 13 7 6 3 3 2 Mitotic Inhibitor Anti Metabolite Topo Inhibitor DNA Alkylator Platin agent Anthracycline Number of Patients Diverse profile of cytotoxic agents. TREATMENT RESPONSE Fig 6. Response to ETA Guided Treatments. Fig 7. Kaplan Meier Curve and Progression Free Survival. [email protected] / [email protected] Disclaimer: DCG offers commercial services In the domain of Oncology. Presented at #NCCN2020 United Kingdom | Germany | India FRESH TUMOR TISSUE Tumor Cells BLOOD Tumor DNA Plasma Tumor mRNA Exosomes Mutations gDNA PBMCs germline Gene Expression Chemoresistance Immunohistochemistry SNPs in DME Therapy Recommendation Databases : Safety + Efficacy Drug-Interactions 0.0 0.2 0.4 0.6 0.8 1.0 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Probability PFS (Days) -100 -80 -60 -40 -20 0 20 Change % in SLD 55.56% 100.00% ORR DCR 379 322 275 172 115 80 31 PFS (Days) Day At Risk 0 27 60 24 120 12 180 5 240 4 300 2 Table 5. Therapy related AEs. Edema 7 0 Constipation 2 0 Myalgia 8 3 Anorexia 12 1 Neutropenia 5 2 Pyrexia 4 1 Mucositis Oral 12 4 Thrombocytopenia 4 4 Nausea 3 0 Anemia 5 1 Fatigue 17 0 Adverse Event Any Grade Grade 3 Diarrhoea 5 0 Peripheral neuropathy 2 0 Vomiting 2 0 • Response to ETA-guided treatments assessed radiologically. • Objective Response Rate (ORR) = 55.6%. • Partial Response (PR) was seen in 14 patients. • Changes to tumor dimensions (SLD: Sum of Longest Diameters) calculated as per RECIST v1.1 criteria. • Complete Response (CR) was seen in 1 patient. • 90-day PFS rate was 96.3%. • Kaplan Meier Curve shows robust PFS. • Patients being followed up further for PFS and OS (data not mature). • Stable Disease (SD ≥45 days) was seen in 12 patients. • Disease Control Rate (DCR) = 100%. • Median PFS was ~4 months at the most recent follow-up. • There were no Grade IV Therapy Related Adverse Events. • There we no therapy related deaths. Multi-analyte tumor profiling (ETA) can reveal latent actionable vulnerabilities in refractory cancers. ETA-guided treatments were safe and offered meaningful survival benefits in this heavily pretreated cohort of advanced refractory breast cancers. CONCLUSION • 2018: CT showed progression. • Received #4 Paclitaxel + Radiation • 2017: PET-CT: recurrence + metastases. • 39 year old female patient. • Received #24 Paclitaxel + Trastuzumab. • Received #6 Gemcitabine + Cisplatin. • Received Maintenance Trastuzumab. • TruCut Bx: Grade III IDC ER+, PR-, HER2+. • Presented with lump in breast in 2016. • Received #4 AC, followed by MRM • 2017: PET-CT showed progression. REPRESENTATIVE CASE Analyte Analysis Findings DNA Gene Mutations PIK3CA SNV TP53 SNV RNA Gene Expression VEGF Indication Drug PIK3CA SNV Temsirolimus VEGF Bevacizumab Key ETA Findings Therapy Recommendation Day 0 Day 80 Significant regression of hepatic metastases. PFS: 144 days. OS: 442 days. Fig 8. Treatment Outcome
