Browsing by Subject "Genomic biomarkers"

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    Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS)
    (BMC, 2021-05-24) Grivas, P.; Loriot, Y.; Morales-Barrera, R.; Teo, M. Y.; Zakharia, Y.; Feyerabend, S.; Vogelzang, N.J.; Grande, E.; Adra, N.; Necchi, A.; Rodriguez-Vida, A.; Gupta, S.; Josephs, D.H.; Srinivas, S.; Wride, K.; Thomas, D.; Simmons, A.; Loehr, A.; Dusek, R.L.; Nepert, D.; Chowdhury, S.; Medicine, School of Medicine
    Background: ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). Methods: Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. Results: Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. Conclusions: Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer.
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    Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple negative breast cancer
    (Springer, 2021) Ademuyiwa, Foluso O.; Chen, Ina; Luo, Jingqin; Rimawi, Mothaffar F.; Hagemann, Ian S.; Fisk, Bryan; Jeffers, Gejae; Skidmore, Zachary L.; Basu, Anamika; Richters, Megan; Ma, Cynthia X.; Weilbaecher, Katherine; Davis, Jennifer; Suresh, Rama; Peterson, Lindsay L.; Bose, Ron; Bagegni, Nusayba; Rigden, Caron E.; Frith, Ashley; Rearden, Timothy P.; Hernandez-Aya, Leonel F.; Roshal, Anna; Clifton, Katherine; Opyrchal, Mateusz; Akintola-Ogunremi, Olaronke; Lee, Byung Ha; Ferrando-Martinez, Sara; Church, Sarah E.; Anurag, Meenakshi; Ellis, Matthew J.; Gao, Feng; Gillanders, William; Griffith, Obi L.; Griffith, Malachi; Medicine, School of Medicine
    Purpose: Patients with triple-negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin and to identify molecular alterations and/or immune gene signatures predicting pCR. Experimental design: Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole-exome sequencing (WES) and immune profiling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular profiles. Results: Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-significant trend toward higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80 versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR. Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor inflammation signature, inflammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteasome were upregulated in pre-treatment samples from patients who achieved pCR. Conclusion: Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune profiling differentiated patients with and without pCR.