Can viral infections lead on to cancer recurrence?

A study suggests that a viral infection such as influenza and SARS/CoV-2 can set off an inflammatory cascade that “wakes up” the sleeping cancer cells located in distant organs such as lungs and bone marrow, leading them to proliferate

A new study published in the journal Nature has caught the attention of cancer researchers worldwide. In this work, scientists showed that infection with the influenza virus can apparently reactivate dormant cancer cells in the lungs of mice with breast cancer.

Breast cancer is well-known for its ability to sometimes return many years after a person has been declared cancer-free. Over the years, researchers have examined a variety of possible triggers for such late recurrences. This new study suggests that a viral infection such as influenza can set off an inflammatory cascade that “wakes up” these sleeping cells that might be located in distant organs such as lungs and bone marrow, leading them toproliferate. In the mouse experiments, a key player was interleukin-6 (IL-6), an inflammatory molecule released in the respiratory tract after influenza infection and not the virus itself. The authors also described other immune mechanisms that could contribute to this awakening, such as the suppression of CD8⁺ T cells by CD4⁺ T cells in the early post-infection period, the role of neutrophil extracellular traps (NETs), and the activation of inflammatory pathways like type I interferon signalling. 

Rekindling the flames

Together, these changes create a lung environment that supports the activation of previously dormant cancer cells. The researchers likened dormant cancer cells to glowing embers left behind after a campfire, with a viral infection acting like a sudden breeze that rekindles the flames. This reawakening of dormant cells is not the same as the initial spread of cancer to distant sites during tumour growth — a process known as metastasis. Instead, it refers to cancer cells that had already spread earlier but remained silent, inactive and undetected for years before becoming active again.

While this may sound alarming, it is important to remember that these findings come from a mouse model, and what happens in mice does not always happen in humans. Nonetheless, this is a landmark study in the search for answers to why cancers recur after a gap, and it points to potential pathways for further research.

This is not the first time scientists have searched for such risk factors. Previous studies have looked at the possible role of surgery, chemotherapy, radiotherapy, hormonal changes, and other influences. None of these, however, have been conclusively proven to have a definitive impact in triggering recurrence. In scientific research, identifying a possible link does not necessarily mean that everyone exposed to that factor will experience the described outcome. Besides, many of these initial theories have been proven wrong over time.

Twofold increase in cancer-related deaths

To explore whether a similar link might exist in humans exposed to respiratory viral infections such as the SARS-CoV2, the researchers analysed two large cancer patient databases. The first was the UK Biobank, where they identified individuals who had been diagnosed with cancer before 2015 and had no known metastatic disease up to the start of the COVID-19 pandemic — in other words, people who had been doing well for at least five years prior. They compared cancer outcomes between those who tested positive for COVID-19 during the first year of the pandemic (before vaccines were available) and those who tested negative. They found that cancer-related mortality — not just deaths from COVID itself — was nearly twofold higher among those who had tested positive, with the excess risk appearing most prominently within the first year after infection.

Because vaccines introduced in the second year of the pandemic made infections milder, the study focused only on infections that occurred in 2020 – when the severity and death rate of COVID was relatively high. The other reason for choosing this timeframe was the clear demarcation between people who had the infection versus those who did not. The question they asked was whether COVID-19 could act as a trigger for cancer recurrence after a long gap. In this retrospective analysis, they found a correlation that echoed their findings in mice. The UK Biobank analysis however was not limited to breast cancer.

The second analysis, using data from Flatiron Health — a U.S.-based oncology database that included breast cancer patients — also found a similar correlation, with a less striking odds ratio of 1.44. In plain terms, this suggests that people with a prior history of breast cancer who developed COVID-19 were about 40% more likely to experience a recurrence than those who were not infected.

Important caveats

While this may sound concerning, there are two important caveats. First, the absolute risk — which applies to the individual — is not mentioned in the paper and by extrapolating, it appears small. For example, if the baseline five-year recurrence risk for breast cancer is assumed to be 10%, an odds ratio of 1.44 would mean that about 14 out of every 100 people who had a prior breast cancer diagnosis and later got COVID-19 might experience a recurrence — compared to 10 out of 100 who did not get COVID-19. This means around four additional cases per 100 infected individuals over a five-year period — if this link is real.

Second, it is difficult to separate deaths caused by cancer from those caused by COVID-related lung complications when relying on medical records. Many so-called “cancer deaths” could actually be due to the after-effects of COVID-19, and vice versa. These determinations were not based on autopsies or detailed imaging in most cases, so the line between the two causes of death is often blurred.

Invaluable insights

The value of this research is threefold. First, it adds to our understanding of possible triggers for cancer recurrence, particularly in breast cancer, where patients can remain disease-free for many years before relapse.

Second, it opens the door to exploring new preventive strategies that might block the immune pathways involved in awakening dormant cells. Third, if the hypothesis holds true, it reinforces the importance for cancer survivors of avoiding viral infections such as COVID-19 and influenza.

However, until these findings are confirmed by other independent studies, there is no reason for anxiety. Initial hypotheses are often modified or disproved when larger, more rigorous research is conducted in diverse settings.

Featured image credit: Michelle Leman