For decades, biomedical research has focused largely on acquired genetic changes—so-called somatic mutations—as the main drivers of cancer progression. These mutations accumulate over time within cells, altering their normal behavior and turning them malignant. However, recent studies are beginning to reveal a missing piece of the puzzle: inherited genetics, meaning the DNA we are born with, may influence not only our risk of developing cancer but also how the disease behaves, grows, and spreads. A study published in The ASCO Post on June 25, 2025, led by Swedish researchers, exemplifies this paradigm shift. The research identifies a common germline variant in the PCSK9 gene that is strongly associated with metastasis in early-stage breast cancer patients.
The findings are remarkable in both magnitude and clinical relevance. The study analyzed data from over 1,500 Swedish women diagnosed with early-stage breast cancer. The researchers found that women who were homozygous for a specific single nucleotide polymorphism (SNP), known as rs562556, had a significantly higher 15-year risk of developing metastasis (22%) compared to non-carriers (2%). This difference is not only statistically significant—it’s clinically alarming. It means that inherited genetics, beyond rare mutations like BRCA1 or BRCA2, may play a more decisive role in how breast cancer evolves than previously thought.
The PCSK9 gene, traditionally studied in the context of cardiovascular disease, is known to regulate LDL receptor degradation in liver cells, thereby influencing blood cholesterol levels. In recent years, however, researchers have begun to uncover its role in inflammatory, immunological, and cellular survival pathways, all of which are critical in metastasis. Tumor cells, to invade distant organs, must resist apoptosis, alter their adhesion properties, degrade the extracellular matrix, and often evade immune detection. Although prior studies hinted at a potential link between PCSK9 and these processes, this new research offers the clearest evidence yet of its role in metastatic behavior.
But the study didn’t stop at epidemiological correlations. To test whether this association had a biological basis, the researchers used mouse models of breast cancer and treated them with evolocumab, a monoclonal antibody approved by the FDA to inhibit PCSK9 in patients with hypercholesterolemia. The result was striking: evolocumab significantly reduced metastasis in these models. This suggests that rs562556 is not just a genetic risk marker, but also a potential therapeutic target.
This raises a powerful question: could evolocumab be repurposed to prevent metastasis in breast cancer? The idea is compelling. If we could identify women at high genetic risk and treat them proactively, we might reduce recurrences and improve long-term survival. However, translating this strategy from mice to humans comes with challenges. First, clinical trials would need to confirm that the anti-metastatic effect of evolocumab holds true in people. Second, we’d have to determine the optimal timing: Should the drug be administered before surgery? As adjuvant therapy? Or during long-term surveillance? Finally, its long-term safety profile in patients without cholesterol disorders must be thoroughly evaluated.
The significance of this study goes beyond PCSK9 itself. It represents a major step forward for predictive genomics, a field that seeks to identify genetic variants—common or rare—that can predict not only disease risk but also disease progression, recurrence, or treatment response. In breast cancer, tests like Oncotype DX and MammaPrint already assess tumor gene expression to estimate recurrence risk and guide chemotherapy decisions. But these tests are tumor-based. The PCSK9 study introduces a new concept: using the host’s inherited genome as a predictor of cancer behavior. This could complement—or even precede—tumor-based decision-making in clinical practice.
That said, the findings also raise important ethical considerations. Should a woman know she carries a gene that predisposes her to metastasis, even if she hasn’t been diagnosed with cancer? How should this information be communicated to young women or those with a family history of breast cancer? Should insurers take such genomic data into account when offering coverage? These questions must be addressed with sensitivity and care. Precision medicine must not only be technologically advanced—it must be emotionally intelligent and ethically sound.
Figure 1. A common germline variant in the PCSK9 gene increases the risk of breast cancer metastasis. This SNP is inherited at birth and promotes tumor spread through elevated PCSK9 activity. In preclinical models, the PCSK9 inhibitor evolocumab reduces metastasis, highlighting its potential as a preventive strategy in genetically predisposed patients.
Finally, the study opens new avenues of research. Could PCSK9 play a similar role in other cancers, such as prostate, lung, or colon cancer? Could its inhibition reduce metastatic risk in other tumor types? These questions are already being explored in laboratories worldwide and may lead to a new class of preventive anti-metastatic therapies, especially in patients who have undergone curative treatment but remain at latent risk.
Identifying a common, inherited genetic variant that predicts breast cancer metastasis and opens the door to repurposing an FDA-approved drug is one of the most promising breakthroughs in precision oncology in recent years. It reinforces the idea that cancer is not just a random event nor solely a tumor-centric process—it is a complex interplay between tumor genetics and host biology. Understanding this interaction brings us closer, step by step, to a future of cancer care that is more preventive, more personalized, and—above all—more humane.
Main Reference:
Cavallo, J. (s/f). How a commonly inherited genetic alteration is driving breast cancer metastasis and predicting survival. Ascopost.com. Recuperado el 25 de junio de 2025, de https://ascopost.com/issues/june-25-2025/how-a-commonly-inherited-genetic-alteration-is-driving-breast-cancer-metastasis-and-predicting-survival/?utm_source=TAP-EN-062025&utm_medium=email&utm_term=2d920833f4061328684845d8fde3b955
Other References:
Mei W, Faraj Tabrizi S, Godina C, Lovisa AF, Isaksson K, Jernström H, Tavazoie SF. A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor. Cell. 2025 Jan 23;188(2):371-389.e28. doi: 10.1016/j.cell.2024.11.009. Epub 2024 Dec 9. PMID: 39657676; PMCID: PMC11770377.
Godina, C., Tryggvadottir, H., Bosch, A., Borgquist, S., Belting, M., Isaksson, K., & Jernström, H. (2023). Caveolin-1 genotypes as predictor for locoregional recurrence and contralateral disease in breast cancer. Breast cancer research and treatment, 199(2), 335–347. https://doi.org/10.1007/s10549-023-06919-x
Ostendorf, B. N., Bilanovic, J., Adaku, N., Tafreshian, K. N., Tavora, B., Vaughan, R. D., & Tavazoie, S. F. (2020). Common germline variants of the human APOE gene modulate melanoma progression and survival. Nature medicine, 26(7), 1048–1053. https://doi.org/10.1038/s41591-020-0879-3
