Abstract 4320: Genomic change in residual triple-negative breast cancers after neoadjuvant chemotherapy
Bibliographic record
Abstract
Abstract Background: Triple negative breast cancer (TNBC) is characterized by its aggressive phenotype and its genomic instability. TNBC patients who do not respond to neoadjuvant chemotherapy have a very poor prognosis. Currently, little is known about the mechanisms of drug resistance and how to overcome it in TNBC. Our study aims at identifying molecular factors enriched for in residual TNBC tumors after standard neoadjuvant chemotherapy. Methods: We obtained specimens from 60 TNBC patients participating in a clinical trial (Q-CROC-03). Biopsies were collected prior to and after standard neoadjuvant chemotherapy and residual cancer was collected at the time of surgery. Matched tumor specimens (pre and post) from 9 patients were analyzed by array comparative genomic hybridization (CGH), gene expression microarrays and whole exome sequencing. All samples contained >50% tumor cellularity. Results: Gene expression data was used to identify the different TNBC subtypes (TNBCtype). Six of the 7 subtypes were represented in at least one sample from our cohort. In the post-chemo samples, we observed a change in TNBC subtype compared to the pre-chemo samples in 6 pairs. The most common switch was to the Immuno Modulatory subtype (IM). aCGH analysis showed relatively few differences in copy number variants (CNV) following chemotherapy in 3 out of 8 patients. Whole exome sequencing revealed increased allele frequency or appearance of de novo mutations in TP53 gene in the residual cancers of 2 of the 3 patients presenting differences in CNVs post treatment. Interestingly, pathway analyses revealed that genes involved in DNA binding, chromosomal organization and nucleosome organization were differentially expressed (>2fold) in 2 of the patients with CNV changes. Our results suggest that increased levels of TP53 mutations and altered transcriptional expression of genes involved in chromosomal functions could be associated with the presence of CNV changes in drug resistant tumors. Conclusion: In summary, the genome of TNBCs does not undergo major changes during neoadjuvant chemotherapy; however, enrichment for or de novo TP53 mutations is associated with the appearance of novel CNVs in drug resistant residual tumors. Citation Format: Adriana Aguilar-Mahecha, Ewa Przybytkowski, Josiane Lafleur, Cathy Lan, Stephanie Légaré, Najmeh Alirezaie, Carole Séguin, Federico Discepola, Bojan Kovacina, Catalin Mihalcioiu, André Robidoux, Elizabeth Marcus, Josée Anne Roy, Manuela Pelmus, Olga Aleynikova, Sheida Nabavi, Jacek Majewski, Mark Basik. Genomic change in residual triple-negative breast cancers after neoadjuvant chemotherapy. [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 4320. doi:10.1158/1538-7445.AM2015-4320
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".