Association Between Pathological Response And Tumor Genomic Profiling In Triple Negative Breast Cancer Patients Treated With Neoadjuvant Chemotherapy

Background: Triple negative breast cancer (TNBC) has a marked molecular diversity that promotes clinical heterogeneity. Less than 40% of TNBC patients will achieve a pathological complete response (pCR) to standard neoadjuvant chemotherapy. Patients who do not achieve pCR have a high risk of disease recurrence and subsequent death from breast cancer. Molecular characterization may identify TNBC patients unlikely to achieve pCR and subsequently develop recurrent disease. Methods: We are conducting a multicenter prospective study of clinical stages II and III TNBC patients treated with neoadjuvant docetaxel and carboplatin. We performed tumor whole exome sequencing on 56 patients pre-treatment samples to identify somatic mutation associated with pCR. Thirteen matching samples from cycle 1 day 3 (C1D3) were also analyzed to assess changes in somatic mutation profiles. Results: In this biomarker study, thirty-seven (66.1%) patients are Caucasians, 17 (30.4%) African American. Nineteen (33.9%) achieved pCR following six cycles of neoadjuvant docetaxel and carboplatin. 9063 variants were detected in 5386 unique genes. The overall mutation burden for patients who achieved pCR was not significantly different from non-pCR patients (median of 80 variants, IQR 51-135 in pCR, vs median 72, IQR 44-102 in non-pCR, Wilcoxon rank sum test p=0.78). As expected, TP53 is the most frequently mutated gene observed in 48 of all 56 patients (85.7%). There was a non-significant trend with lower TP53 mutations occurring in 78.9% of patients with pCR, versus 89.2% of non-pCR patients (OR 0.46, 95% CI 0.07 - 2.83; p value 0.42). BRCA2 somatic mutations were observed in 5.4% and 5.3% of pCR and non-pCR samples, respectively. No BRCA1 somatic mutations were identified. EGFR, RAD51AP2, SDK2, L1CAM, KPRP, CACNA1S, CFAP58, COL22A1, and COL4A5 were differentially mutated and almost exclusively found in pCR samples. PCDHA1 and TRMT9B were observed in 18.9% and 16.2%, respectively, of non-pCR samples only. There was a trend of higher variant counts in the thirteen matched samples at C1D3 (median of 82, IQR 49-157) versus corresponding pre-treatment samples (median of 72, IQR 42-92), Wilcoxon rank sum test p=0.29, suggesting clone emergence under treatment pressure. Using the Molecular Signatures Database v7.1, several gene families involved in immune related pathways showed differences between pCR and non-pCR samples. Additionally, borderline differences in hedgehog signaling pathway were identified between pCR and non-pCR samples. There were no differences in apoptosis, DNA repair, EMT, inflammatory response, NOTCH signaling pathways. Conclusion: Across TNBC tumors analyzed, TP53 mutation frequency does not differ in pCR versus non-pCR patients. Somatic mutations in EGFR, RAD51AP2, immune pathways genes, and hedgehog signaling pathway genes may predict pCR to docetaxel and carboplatin chemotherapy. Citation Format: Foluso O Ademuyiwa, Jingqin Luo, Bryan Fisk, Gejae Jeffers, Tracy Summa, Isabella Grigsby, Mothaffar Rimawi, Meenakshi Anurag, Matthew Ellis, Obi Griffith, Malachi Griffith. Association between pathological response and tumor genomic profiling in triple negative breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-07.