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Browsing by Author "Ademuyiwa, Foluso O."
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Item Circulating tumour DNA characterisation of invasive lobular carcinoma in patients with metastatic breast cancer(Elsevier, 2022) Davis, Andrew A.; Gerratana, Lorenzo; Clifton, Katherine; Medford, Arielle J.; Velimirovic, Marko; Hensing, Whitney L.; Bucheit, Leslie; Shah, Ami N.; D’Amico, Paolo; Reduzzi, Carolina; Zhang, Qiang; Dai, Charles S.; Denault, Elyssa N.; Bagegni, Nusayba A.; Opyrchal, Mateusz; Ademuyiwa, Foluso O.; Bose, Ron; Gradishar, William J.; Behdad, Amir; Ma, Cynthia X.; Bardia, Aditya; Cristofanilli, Massimo; Medicine, School of MedicineBackground: Limited data exist to characterise molecular differences in circulating tumour DNA (ctDNA) for patients with invasive lobular carcinoma (ILC). We analysed metastatic breast cancer patients with ctDNA testing to assess genomic differences among patients with ILC, invasive ductal carcinoma (IDC), and mixed histology. Methods: We retrospectively analysed 980 clinically annotated patients (121 ILC, 792 IDC, and 67 mixed histology) from three academic centers with ctDNA evaluation by Guardant360™. Single nucleotide variations (SNVs), copy number variations (CNVs), and oncogenic pathways were compared across histologies. Findings: ILC was significantly associated with HR+ HER2 negative and HER2 low. SNVs were higher in patients with ILC compared to IDC or mixed histology (Mann Whitney U test, P < 0.05). In multivariable analysis, HR+ HER2 negative ILC was significantly associated with mutations in CDH1 (odds ratio (OR) 9.4, [95% CI 3.3-27.2]), ERBB2 (OR 3.6, [95% confidence interval (CI) 1.6-8.2]), and PTEN (OR 2.5, [95% CI 1.05-5.8]) genes. CDH1 mutations were not present in the mixed histology cohort. Mutations in the PI3K pathway genes (OR 1.76 95% CI [1.18-2.64]) were more common in patients with ILC. In an independent cohort of nearly 7000 metastatic breast cancer patients, CDH1 was significantly co-mutated with targetable alterations (PIK3CA, ERBB2) and mutations associated with endocrine resistance (ARID1A, NF1, RB1, ESR1, FGFR2) (Benjamini-Hochberg Procedure, all q < 0.05). Interpretation: Evaluation of ctDNA revealed differences in pathogenic alterations and oncogenic pathways across breast cancer histologies with implications for histologic classification and precision medicine treatment.Item 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 MedicinePurpose: 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.