Breast cancer biomarkers : dynamics during treatment and metastatic progression

<p dir="ltr">Breast cancer is a major global health challenge as incidence is increasing, and risk of recurrence remains a significant concern for long-term survivors. In an era of expanding therapeutic options, identifying biomarkers that can inform on prognosis and guide individualized treatment is of critical importance. This thesis explores both established and emerging biomarkers in breast cancer, examining their expression, dynamics over time and across different disease stages. In addition, it investigates key prognostic factors that influence long-term outcomes and factors associated with poor prognosis in the metastatic setting.</p><p dir="ltr">In Paper I, a systematic review and meta-analysis was conducted to examine PD- L1 expression rates in primary breast tumors and metastatic lesions, including differences in expression according to cell type, metastasis site and the degree of discordance between primary tumors and their recurrences. The meta-analysis included 20 studies and revealed a significant discordance in PD-L1 expression between primary tumors and metastatic lesions, with overall expression rates being higher among primary tumors. Expression rates varied across metastatic sites, with the highest rates observed in lymph nodes and lungs, and the lowest in bone and liver. A substantial bidirectional discordance in PD-L1 status was observed in matched samples. Nearly half of the patients with PD-L1 positive primary tumors exhibited PD-L1 negative metastasis, while approximately one third of those with PD-L1 negative primary tumors converted to PD-L1 positive status in their metastatic lesions. The findings of the study highlight the critical importance of obtaining metastatic biopsies to accurately determine patients eligible for immune checkpoint blockade.</p><p dir="ltr">Paper II investigated prognostic factors beyond pathologic complete response (pCR) that influence long-term outcomes in patients treated with neoadjuvant chemotherapy (NACT). A retrospective cohort of 2 487 individuals who received NACT for primary breast cancer between 2007 and 2020 in the Stockholm- Gotland region was analyzed using the National Quality Register for Breast Cancer and medical records. While pCR was confirmed as a favorable prognostic marker, it also demonstrated that patients achieving pCR are a heterogenous group with varying long-term risks. Factors independently associated with distant recurrence-free survival (DRFS) included lymph node involvement, tumor stage, estrogen receptor status, age and HER2 status. Furthermore, the study revealed a temporal dynamic of recurrence risk, with the highest risk occurring within the first two years post-surgery, though never entirely disappearing over time. Patients with residual disease consistently exhibited higher recurrence risk. These findings emphasize the importance of considering additional clinical and pathological factors beyond pCR when evaluating long-term risk, guiding treatment decisions, and designing future clinical trials.</p><p dir="ltr">Paper III explored the distribution, temporal dynamics, and prognostic significance of HER2 status, including HER2-low, in a population-based cohort of patients with breast cancer treated with NACT. The study revealed a discordance rate of approximately 30% between untreated tumors, residual disease and metastatic lesions. HER2-low status was observed to be associated with ER expression. Notably, survival analysis revealed temporal differences in the risk curve between HER2-low and HER2 0 breast cancer. Patients with HER2 0 tumors had a higher initial peak in recurrence risk, which gradually declined over time, eventually falling below the risk observed in patients with HER2-low tumors. The likelihood of detecting a HER2-low status increased with the number of biopsies performed. The findings in paper III highlight the prognostic significance of HER2 status as well as the importance of obtaining repeated biopsies throughout the disease trajectory.</p><p dir="ltr">In Paper IV women with very poor prognosis following a metastatic breast cancer (MBC) diagnosis were examined. The study showed that almost one in six women diagnosed with MBC died within 90 days. These patients were typically older, had more aggressive primary tumor biology, a higher clinical stage at initial diagnosis, more frequent visceral metastases, and received less chemotherapy in the primary setting. Notably, nearly half of the patients with poor prognosis never received systemic antitumoral treatment. Multivariable analysis identified age, metastasis site, adjuvant chemotherapy, primary tumor grade and period of diagnosis as independent factors of short survival. The study identified a subgroup of MBC patients with extremely poor prognosis and highlights the need for improved understanding and targeted research to enhance long-term outcomes.</p><p dir="ltr">In conclusion, this thesis underscores the critical importance of performing repeated biopsies throughout the disease trajectory to enable more accurate and individualized treatment. It further highlights the heterogeneity of breast cancer both across time and anatomical sites. Collectively, these findings deepen our understanding of biomarkers in breast cancer and hold the potential to ultimately improve outcomes for patients with breast cancer.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Caroline Boman</b>, Ioannis Zerdes, Kira Mårtensson, Jonas Bergh, Theodoros Foukakis, Antonios Valachis and Alexios Matikas. Discordance of PD-L1 status between primary and metastatic breast cancer: A systematic review and meta-analysis. Cancer Treat Rev. 2021 Sep;99:102257. doi:10.1016/j.ctrv.2021.102257. PMID: 34237488<br><a href="https://doi.org/10.1016/j.ctrv.2021.102257">https://doi.org/10.1016/j.ctrv.2021.102257<br></a><br></p><p dir="ltr">II. <b>Caroline Boman</b>, Christian Tranchell, Xingrong Liu, Louise Eriksson Bergman, Maria Angeliki Toli, Jonas Bergh, Theodoros Foukakis and Alexios Matikas. Prognosis After Pathologic Complete Response to Neoadjuvant Therapy in Early-Stage Breast Cancer: A Population-Based Study. J Natl Compr Canc Netw. 2025 Mar 12:1- 7. doi:10.6004/jnccn.2024.7093. PMID: 40073831<br><a href="https://doi.org/10.6004/jnccn.2024.7093">https://doi.org/10.6004/jnccn.2024.7093<br></a><br></p><p dir="ltr">III. <b>Caroline Boman</b>, Xingrong Liu, Louise Eriksson Bergman, Wenwen Sun, Christian Tranchell, Maria Angeliki Toli, Balazs Acs, Jonas Bergh, Theodoros Foukakis and Alexios Matikas. A population-based study on trajectories of HER2 status during neoadjuvant chemotherapy for early breast cancer and metastatic progression. Br J Cancer. 2024 Sep;131(4):718-728. doi:<a href="https://doi.org/10.1038/s41416-024-02777-6" rel="noreferrer" target="_blank">https://doi.org/10.1038/s41416-024-02777-6</a>. PMID: 38942987</p><p dir="ltr">IV. <b>Caroline Boman</b>, Luisa Edman Kessler, Jonas Bergh, Alexios Matikas and Theodoros Foukakis. Women with short survival after diagnosis of metastatic breast cancer: a population-based registry study. Breast Cancer Res Treat. 2022 Jul;194(1):49-56. doi:<a href="https://doi.org/10.1007/s10549-022-06591-7" rel="noreferrer" target="_blank">https://doi.org/10.1007/s10549-022-06591-7</a>. PMID: 35461374</p>