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BACKGROUND.The treatment of myelodysplastic syndromes (MDS) remains a challenge to the clinician despite recent advances. Many patients will either not respond or will have only limited and/or brief responses to single‐agent therapy. Eventually, 30% of patients with MDS will progress and develop acute myeloid leukemia (AML). New strategies are needed for these patients.METHODS.5‐Azacytidine (AZA) and thalidomide were administered to 40 patients with MDS or AML. AZA was given at a dose of 75 mg/m2 subcutaneously for 5 of 28 days together with thalidomide starting at a dose of 50 mg per day and increasing to 100 mg per. Six patients had refractory anemia (RA), 2 patients had RA with ringed sideroblasts, 10 patients had RA with excess blasts (RAEB), 1 patient had RAEB in transformation, 4 patients had chronic myelomonocytic leukemia, 1 patient had chronic idiopathic myelofibrosis, and 16 patients had AML. Thirty‐six patients were evaluable for outcome.RESULTS.A hematologic improvement (HI) was observed in 15 of 36 patients (42%), stable disease was observed in 5 of 36 patients (14%), and 10 of 36 patients (28%) had disease progression. Six patients experienced complete remission (CR), 2 patients experienced an erythroid HI (HI‐E), 1 patient experience an absolute neutrophil count HI (HI‐ANC), 5 patients experienced a platelet HI (HI‐P), and 7 patients had bilineage HI (HI‐P and HI‐ANC or an HI‐E and HI‐ANC). It was noteworthy that 9 of 14 patients with AML had a history of prior MDS, 2 of 9 patients achieved a CR, 4 of 9 patients had HI (HI‐E and bilineage HI), and 1 patient had stable disease and was continuing treatment. DNA microarray analysis of 8 responders and 4 nonresponders revealed that the genes associated with cellular proliferation had higher expression levels in nonresponders.CONCLUSIONS.The current findings indicated that a combination of low‐dose AZA and thalidomide was well tolerated and was effective therapy for the treatment of patients with MDS and AML arising from prior MDS. Cancer 2008. © 2008 American Cancer Society.

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Background: Genomic studies suggest that ∼50% of high-grade serous ovarian cancers (OC) have homologous recombination deficiency (HRD). Germline BRCA1/2 mutations (gBRCAmut) are expected to account for 1/3 of HRD in OC, and identification of non-gBRCAmut HRD tumors likely to respond to PARP inhibitors (PARPi) remains a challenge. Using comprehensive next generation sequencing (NGS)-based tumor genomic profiling, we developed a companion diagnostic HRD assay to predict sensitivity to the PARP inhibitor rucaparib by combining tumor BRCA1/2 status (germline and somatic) and genomic loss of heterozygosity (LOH). The HRD assay is being validated in a Phase 2 study (ARIEL2) and will be prospectively applied to the primary analysis of the ongoing Phase 3 study (ARIEL3) of rucaparib. Methods: The HRD assay uses 50-200ng of DNA from tumor FFPE specimens, which undergoes sequencing library construction and hybrid-capture of all coding exons from 100s of cancer-related genes. Libraries are sequenced to high, uniform depth (>500× unique coverage, Illumina® HiSeq) and data are processed by a customized pipeline that accurately detects all classes of genomic alterations, including BRCA1/2 base substitutions, indels, and homozygous deletions. Genomic LOH is assessed by a CGH-like analysis of sequencing coverage and >3,500 genome-wide SNPs and a tumor is classified as HRD with either BRCA1/2 alteration or high genomic LOH (LOH+). Somatic/germline status of discovered BRCA1/2 alterations is assessed by a previously-presented computational approach (“SGZ”, AACR 2014 abstract #1893), and verified against medical records where available. ARIEL2 is an ongoing single-arm (n = 180), open-label study of rucaparib in recurrent, platinum-sensitive OC patients. The primary objective is to evaluate clinical activity of rucaparib among 3 prospectively defined subgroups: tumor BRCAmut, BRCAwt/LOH+ (“BRCAness”) and BRCAwt/LOH-. Response is determined by RECIST and/or GCIG-CA125 criteria. Results: The HRD assay was performed on tumors from 121 patients, of whom 25% were found to be BRCA mutant (17 germline/12 somatic), 42% had the BRCAness signature (BRCAwt/LOH+), and 33% were biomarker negative (BRCAwt/LOH-). Efficacy data available for 61 patients revealed objective response rates (combined RECIST/CA125 criteria) at 70%, 40% and 8%, respectively. Responses were observed for all classes of genomic alterations, and in gBRCAmut and non-gBRCAmut tumors. Conclusions: Preliminary clinical data indicates that the HRD assay identifies OC patients likely to respond to rucaparib and highlights the potential for innovative companion diagnostics enabled by comprehensive genomic profiling based on NGS. Citation Format: James Sun, Iain McNeish, Robert L. Coleman, Amit Oza, Clare Scott, David M. O'Malley, Kevin K. Lin, Christine Burns, Christine Vietz, Philip J. Stephens, Murtaza Mehdi, Matthew Hawryluk, Heidi Giordano, Mitch Raponi, Lindsey Rolfe, Jeff Isaacson, Vincent A. Miller, Andrew Allen, Elizabeth Swisher, Roman Yelensky. A novel companion diagnostic predicts response to the PARP inhibitor rucaparib in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4670. doi:10.1158/1538-7445.AM2015-4670

Introduction: In patients with advanced-stage ovarian cancer, FDA has recently granted approval of treatment with PARP inhibitors (PARPi) in patients harboring deleterious BRCA mutations (~25% of population). However, there is clear evidence of “BRCA-like” patients who respond to PARPi without BRCA mutations. To identify such patients, it has been shown that deficiency in homologous recombination repair leads to a common phenotype of genome-wide loss of heterozygosity (LOH). Depending on the cutoff employed, genomic LOH could identify more than twice the number of ovarian cancer patients who could benefit from PARPi than measuring BRCA alone. We present here an NGS-based platform developed and performed in compliance with FDA 21 CFR part 820. The assay provides a tumor measurement of BRCA1/2 (FDA-approved as FoundationFocus CDx BRCA) as well as genomic LOH, and is on the same platform as the comprehensive FoundationOne CDx, which interrogates 324 genes. Methods: DNA extracted from FFPE tumor tissue underwent whole-genome shotgun library construction and hybridization-based capture, followed by sequencing using Illumina HiSeq 4000. Sequence data were processed using a proprietary analysis pipeline designed to detect base substitutions, indels, copy number alterations (CNA), genomic rearrangements, microsatellite instability (MSI), and tumor mutational burden (TMB). A genome-wide LOH profile based on SNPs is measured as part of the CNA pipeline, and is summarized as the percentage of the tumor genome displaying LOH (scored from 0-100%), with ≥16% being considered LOH high based on clinical data derived from ARIEL2 Part 1, a phase II study of the PARPi rucaparib for the treatment of platinum-sensitive ovarian cancer (ARIEL2; NCT01891344) Results: For analytical validity, BRCA limit of detection (LoD) was at allele frequency 5.9% for substitutions and non-repetitive indels, and 30% tumor content for LOH. Overall percent agreement with comparator NGS assay was 97.3% for BRCA. No orthogonal platform concordance was established for LOH as no validated test exists. Within-assay reproducibility was measured with overall concordance of 100% for BRCA, and 98% for LOH. Conclusion: We developed a novel diagnostic assay (in compliance with FDA 21 CFR part 820) that can measure BRCA and genomic LOH simultaneously, and established robust analytical validation data. Citation Format: James X. Sun, Kevin Lin, Yali Li, Kyle Gowen, Yuting He, Coren Milbury, Christine Burns, Jun Luo, Steve Roels, Murtaza Mehdi, John Truesdell, Pei Ma, Lakshman Ramamurthy, Christine Vietz, Jeri Beltman, Thomas Harding, Doron Lipson, Jeffrey Ross, Vincent Miller, Philip Stephens, Michael Doherty, Julia Elvin. A validated diagnostic assay for identifying ovarian cancer patients with deleterious BRCA mutations and high genomic loss of heterozygosity (LOH) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4544.