Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer.

Abstract

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.

TRIAL REGISTRATION:

Clinical trial information: NCT02124902, Registered 24 April 2014 & NCT02547987, Registered 10 September 2015.

• Authors: Foluso O Ademuyiwa, Ina Chen, Jingqin Luo, Mothaffar F Rimawi, Ian S Hagemann, Bryan Fisk, Gejae Jeffers, Zachary L Skidmore, Anamika Basu, Megan Richters, Cynthia X Ma, Katherine Weilbaecher, Jennifer Davis, Rama Suresh, Lindsay L Peterson, Ron Bose, Nusayba Bagegni, Caron E Rigden, Ashley Frith, Timothy P Rearden, Leonel F Hernandez-Aya, Anna Roshal, Katherine Clifton, Mateusz Opyrchal, Olaronke Akintola-Ogunremi, Byung Ha Lee, Sara Ferrando-Martinez, Sarah E Church, Meenakshi Anurag, Matthew J Ellis, Feng Gao, William Gillanders, Obi L Griffith, Malachi Griffith
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 189 Issue 1 Pg. 187-202 (Aug 2021) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 34173924 (Publication Type: Clinical Trial, Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Chemical References

• Docetaxel
• Carboplatin

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Breast Neoplasms
• Carboplatin (therapeutic use)
• Docetaxel (therapeutic use)
• Female
• Humans
• Neoadjuvant Therapy
• Neoplasm Recurrence, Local
• Treatment Outcome
• Triple Negative Breast Neoplasms (drug therapy, genetics)