Hani Saghir -Institutionen för kliniska vetenskaper, Lund

Title: Gene Expression Biomarkers in the Neoadjuvant Setting of Breast Cancer

Main supervisor: Niklas Loman (MD, PhD,Associate Professor)

Reviewers: Gottfrid Sjödahl (PhD, Associate Professor); Julia Ellbrant (MD, PhD)

Abstract

Background:

Biomarkers are critical in personalized cancer care for tumor classification and treatment selection. Breast cancer, a molecularly diverse disease, has particularly benefited from subtype-specific therapies. While immunohistochemistry (IHC) is standard for subtyping, genomic biomarkers, enabled by increasingly accessible sequencing technologies, offer deeper insights that can refine treatment decisions.

This doctoral thesis explores gene expression-based (GEX) biomarkers in early breast cancer, focusing on their predictive and prognostic role in the neoadjuvant setting.

Research Questions

1. How reliable are GEX and IHC biomarker statuses from treatment-naïve core-needle biopsies (CNBs) compared to paired untreated surgical specimens?
2. How do pre-treatment clinical and molecular biomarkers correlate with pCR rates, breast-conserving surgery, and survival after neoadjuvant chemotherapy (NACT) in HR+/HER2- breast cancer?
3. How does NACT influence proliferation dynamics in ER+/HER2- tumors as measured by GEX and IHC, and how do these changes relate to relapse-free interval?
4. Can a genomic signature from baseline CNBs predict a favorable molecular response to NACT?

Preliminary Results

1. In 257 untreated cases, ER, PgR, Ki67, and HER2 showed moderate to good concordance between CNBs and surgical specimens using both GEX and IHC. Notably, Ki67 and ER statuses frequently shifted between CNBs and surgical specimens.
2. Among 178 HR+/HER2- patients, biomarkers of reduced endocrine responsiveness and non-luminal biology predicted higher pCR rates but greater relapse risk in residual disease.
3. In 175 ER+/HER2- patients, baseline proliferation was not prognostic. However, a GEX-measured shift from high to low proliferation during NACT was linked to up to 81% relapse risk reduction. GEX outperformed IHC in identifying high-risk patients.

Significance:

These findings emphasize that sampling technique affects biomarker results and that GEX-based proliferation assessment more accurately evaluates treatment response compared to IHC. Relying on GEX instead of IHC may help reduce overtreatment by better identifying high-risk patients. Proliferation response may thus guide therapy decisions more effectively. Additionally, non- luminal biology within HR+/HER2– cancers predicts both response and prognosis, supporting NACT use in this subgroup of HR+/HER2- patients and potential treatment escalation in patients with residual disease.

Published studies:

Saghir H, Veerla S, Malmberg M, Rydén L, Ehinger A, Saal LH, Vallon-Christersson J, Borg Å, Hegardt C, Larsson C, Haidar A, Hedenfalk I, Loman N, Kimbung S. How Reliable Are Gene Expression-Based and Immunohistochemical Biomarkers Assessed on a Core-Needle Biopsy? A Study of Paired Core- Needle Biopsies and Surgical Specimens in Early Breast Cancer. Cancers (Basel). 2022 Aug 18;14(16):4000. doi: 10.3390/cancers14164000. PMID: 36010992; PMCID: PMC9406531.

Summited manuscripts:

Dynamic Assessment of Proliferation to Guide Response-Adapted Therapy in the Setting of Neoadjuvant Chemotherapy in ER+/HER2- Breast Cancer

Hani Saghir,Srinivas Veerla, Niklas Loman, and Siker Kimbung. Journal: NPJ precision oncology

Outcome of neoadjuvant chemotherapy treatment for patients with HR+/HER2- early-stage breast cancer (EBC) by clinical and molecular features in the Swedish SCAN-B population-based cohort

Niklas Loman, Hani Saghir, and Siker Kimbung