A common germline variant in the proprotein convertase subtilisin/kexin type 9 (PCSK9) (rs562556, V474I) gene rather than a mutation in a breast cancer tumor may be the driving force in significantly increasing the risk of breast cancer metastasis and reducing survival in women with the disease. This finding was from a recent study by Sohail F. Tavazoie, MD, PhD, Leon Hess Professor and Senior Attending Physician at The Rockefeller University in New York City, and his colleagues.1
Dr. Tavazoie and his colleagues found that the PCSK9 gene variant, which is present in the germline of 70% of White women,1 propels breast cancer metastasis by targeting tumoral low-density lipoprotein receptor related protein 1 (LRP1) receptors. These receptors repress the metastasis-promoting genes XAF1 and USP18, leading to the induction of genes the researchers believe may be metastatic colonization promoters.
“Metastasis, we believe, is at least in part a hereditary disorder.”— SOHAIL F. TAVAZOIE, MD, PhD
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To test the impact of the PCSK9 gene on metastatic colonization, the researchers generated a mouse model expressing the human genetic variant and found that those with the variant had an increased risk for breast cancer metastasis. To further understand the implication of PCSK9 on survival outcomes and to identify which patients may be at higher risk for metastatic disease, they then performed a blinded analysis by genotyping a large cohort of women with early-stage breast cancer enrolled in a Swedish study2; they found that those patients with rs562556 homozygotes had a 22% risk of distant metastatic relapse at 15 years, compared with patients without these homozygotes, who had a 2% risk of developing metastatic disease at 15 years. The results of this study may alter how metastatic breast cancer is treated in the future and even potentially prevented.
“Metastasis, we believe, is at least in part a hereditary disorder,” said Dr. Tavazoie. “We have been so focused on the cancer cells—the ‘seeds’—that we’ve ignored the germline—the ‘soil.’ It’s now clear that focusing on the soil is critical.”
In a wide-ranging interview with The ASCO Post, Dr. Tavazoie discussed how inherited genetics are driving cancer metastasis, potential therapeutics available to suppress the PCSK9 gene variant, and what’s next in his research.
Altering Cancer Signals
The findings from your study suggest that the inherited genetic variants of a person’s DNA, rather than mutations in a malignant tumor, are what’s driving metastasis in some patients with breast cancer. Can your findings be applied to other cancer types?
I don’t want to say that the PCSK9 gene variant is the sole driver of breast cancer metastasis. Researchers have been looking for 20 years to find metastasis-driver mutations that are causal and associated with clinical outcomes, but, so far, we haven’t found such somatic mutations.
What is really exciting about our study results is they tell us that inherited genetics are able to drive metastasis. They also tell us that metastasis may occur in the absence of somatic metastasis-driver mutations. It doesn’t mean that somatic mutations don’t exist in this circumstance; I don’t want to completely rule out that possibility. But what our study findings tell us is that contrary to what we have always believed about cancer spread involving somatic mutations and tumor mutations, in breast cancer, there exists a predisposition for metastasis that an individual is born with. And it exists even before the tumor arrives, and that is the individual’s inherited genetics, because the inherited genetics alter the signals the cancer cells will be bombarded with when they arrive at the metastatic site.
“Contrary to what we have always believed about cancer spread involving somatic mutations and tumor mutations, in breast cancer, there exists a predisposition for metastasis that an individual is born with.”— SOHAIL F. TAVAZOIE, MD, PhD
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An individual’s inherited genetics cause all of the protein signals from the organs that constrain the cells from forming metastases or that enable them to form metastases, so that may be bad news for people who have ‘bad-risk’ genetics. But it’s also good news, because if these signals are coming from the host’s own genetics and not the tumor, we may be able to block them with therapeutics.
In terms of whether we can apply our findings to other cancer types, we do believe there are more such genes to be found in other cancers. For example, in an earlier study, we found that in high-risk melanoma, individuals born with the APOE2 gene variant had worse survival outcomes than those patients carrying the APOE4 gene. We were able to model the APOE2 and APOE4 variants in mice models to learn how the different types of that gene affect melanoma metastasis. We found that the mice expressing the human APOE4 allele exhibited reduced melanoma progression and metastasis compared with the mice expressing APOE2.3
So, we are finding evidence that at least in melanoma and breast cancer, there is a hereditary contribution to cancer metastasis or metastatic relapse. And that opens up the possibility that other germline variants may have similar effects in other cancer types. What’s exciting is that as more and more genomic sequencing is performed in patients, and as we increase the number of patient data sets, they will allow us to identify additional gene variants in cancers and, hopefully, give us biomarkers for therapeutic response and survival outcomes.
Treating High-Risk Patients Prophylactically
I want to ask you about potential therapeutics to suppress genetic predisposition in cancer metastasis. The PCSK9 gene is associated with a role in elevating cholesterol. Your study included preliminary research in mice models suggesting that the PCSK9 gene may be suppressed using the monoclonal antibody evolocumab, which is already approved by the U.S. Food and Drug Administration in the treatment of high cholesterol. Does this indicate that, if efficacy is confirmed in human trials, evolocumab may be suitable to treat high-risk patients for breast cancer metastasis prophylactically?
We are discussing the viability of doing clinical trials with evolocumab in high-risk patients with breast cancer, if we can identify the suitable patient population. If there is a therapeutic that can inhibit the PCSK9 pathway sufficiently and decrease the likelihood of metastatic relapse, and we can confirm that in a clinical trial, then, yes, one can imagine that women who are at high risk for metastatic breast cancer could receive this antibody to block this pathway, which may reduce the risk of metastatic disease. It wouldn’t be a cure; it would be a reduction in risk. We believe this approach would be most effective in recurrence prevention.
Understanding the Influence of PCSK9 on Cancer Metastasis
Based on your research, should women with a family history of breast cancer be tested for the PCSK9 gene?
I don’t want to make that recommendation. We are in early, early days in this research and need to have more science to try to understand how the PCSK9 signaling pathway works and its influence on driving breast cancer metastasis. One concern is we don’t want to raise fears in women, most of whom will never develop breast cancer; and for those who do, we don’t want to increase fear their cancer will metastasize.
We are researching how to block the pathway with combinations of existing therapies. In future studies, hopefully, we will be able to conduct trials of experimental agents or therapeutic agents, such as PCSK9 antibodies, in women who have this pathogenic variance. Once these studies are done, and we know about survival outcomes, then, yes, we can imagine making a recommendation that high-risk women undergo genetic analysis. But we are not at that point yet.
What’s next in your research on how germline variants may be driving cancer metastasis and survival outcomes?
We are still trying to understand the PCSK9 pathway and why it drives cancer metastasis. We also want to understand how LRP1 receptors are regulating the expression of the two metastasis-promoting genes XAF1 and USP18. And we are studying what happens if we combine PCSK9 inhibition therapy with other therapies, such as estrogen-deprivation therapy or a targeted therapy, in patients with breast cancer. They are the main areas of research we have underway, and we hope to report on our findings in the near future.
DISCLOSURE: Dr. Tavazoie reported no conflicts of interest.
REFERENCES
1. Mei W, Tabrizi SF, Godina C, et al: A commonly inherited human PCSK9 germline variant drives breast cancer metastasis via LRP1 receptor. Cell 188:371-389.E28, 2025.
2. Godina C, Tryggvadottir H, Bosch A, et al: Caveolin-1 genotypes as predictor for locoregional recurrence and contralateral disease in breast cancer. Breast Cancer Res Treat 199:335-347, 2023.
3. Ostendorf BN, Bilanovic J, Adaku N, et al: Common germline variants of the human APOE gene modulate melanoma progression and survival. Nat Med 26:1048-1053, 2020.
