Breast cancer study reveals a paradox of mastectomy

Breast cancer surgeons have tended not to push patients towards bilateral mastectomy, since data have long shown that the complete removal of both breasts doesn’t improve survival. New data from a large epidemiological study affirmed that, but an accompanying finding is puzzling. Breast cancer survivors who ended up developing a second breast cancer in the opposite or contralateral breast had a higher risk of death, even though preventing that cancer with surgery didn’t change outcomes.

“That seems like a paradox,” said Steven Narod, a breast cancer researcher and physician at Women’s College Hospital in Toronto and the lead author on the study. “If you get a contralateral breast cancer, your risk of dying goes up. But preventing it doesn’t improve your survival.”

Even so, he and other experts said that the data should not change the decision calculus around opting for a bilateral mastectomy or less intensive procedure. Rather, he said, the study raises key scientific questions about contralateral breast cancers and how breast cancer metastasizes and kills.

To do the study, Narod and his colleagues compared data on 100,000 women who were diagnosed from 2000 to 2019 with breast cancer who received one of three surgical options. All breast cancer patients going in for surgery choose between a lumpectomy, a simpler procedure that only removes the tumor and some surrounding tissues, a single or unilateral mastectomy removing only the affected breast, or a bilateral or double mastectomy. The point of the unilateral mastectomy is that it can prevent the cancer’s return in the same breast, or ipsilateral recurrence. Similarly, bilateral mastectomy prevents cancer from occurring again in either breast. Without it, contralateral breast cancer occurs about 7% of the time.

In the analysis, published on Thursday in JAMA Oncology, there was no significant difference in survival between all three groups. Over 80% of women did not die from breast cancer after 20 years of follow-up, regardless of which surgery they got. At the same time, the paper also showed that women who later got breast cancer in the other breast had a four-fold higher risk of death. Therein lies the conundrum, Narod said. It’s still not entirely clear what is responsible for this result.

One thought is that the situation could be similar to why survival isn’t different between getting a lumpectomy and a single mastectomy, even though recurrence in the same breast is associated with worse outcomes. That’s mainly because mastectomy didn’t lower the risk of metastatic recurrence. In this case, the local recurrence can be a sign that something has gone awry with the initial tumor — like an early indication that the initial treatment failed and microscopic metastases were left behind. “A signal that something is going on systemically,” Narod said. “That the lung, liver, brain, and bones may also be affected.”

That might also suggest the contralateral breast cancer is a metastasis of the first breast cancer, Narod added.

A potential hitch with this explanation, though, is that a significant proportion of women diagnosed with a contralateral breast cancer caught it at an advanced stage when the disease was already incurable. “I don’t think it works in this situation because of the stage shift,” said Seema Khan, a breast surgeon at Northwestern University Feinberg School of Medicine who wrote an accompanying editorial in JAMA oncology but did not work on the study. “Some of the increased hazard is because the stages were worse in the second event.”

Possibly, Khan added, the increased hazard of death among those who got a contralateral breast cancer is an “artifact finding” created by a yet undetermined flaw in the experimental technique or data. Though, she added, this is not the first time a study has pointed out contralateral breast cancer can lead to worse outcomes. A Swedish study in 2007 reported women who got cancer in the second breast within five years of a first breast cancer diagnosis were more likely to die, though women who got the contralateral breast cancer more than 10 years after their first diagnosis were not.

Another idea is that the appearance of a second tumor might trigger more aggressive behavior in malignant cells that scattered across the body from the first tumor, said Julio Aguirre-Ghiso, a cancer researcher at Albert Einstein College of Medicine who did not work on the study. “At stage 0, there can already be dissemination of cells that can cause metastasis,” he said.

What could be happening is after the first cancer is treated, these early, distantly spread cells “are dormant. Sitting there. If nothing happens, they have a low likelihood of converging into a metastasis,” Aguirre-Ghiso said. But it’s possible that if a second tumor occurs, like in the other breast, and that tumor disseminates its own cells across the body, that could accelerate the formation of metastases that were always going to arise from the first cancer anyway.

That could help to explain why it looks like the risk of death is worse among people who develop a contralateral breast cancer, even though those who had a double mastectomy still died at similar rates. Preventing a contralateral breast cancer prevents cancer from arising in the other breast, but not metastases elsewhere in the body.

But that idea, like the others, will still require much study to support. The benefit of that could be finding better ways to prevent metastatic recurrence in breast cancer survivors, Aguirre-Ghiso said.

For breast cancer patients trying to pick which surgery to do, the factors still haven’t changed, said Laura Esserman, a breast surgeon and cancer researcher at the University of California, San Francisco who did not work on the study. Many patients still decide to undergo the more arduous double mastectomy for reasons like anxiety relief, reducing the inconvenience of breast cancer surveillance, or carrying mutations like BRCA 1 that increase cancer risk. Those can be sensible reasons, Esserman said, so long as people are properly informed that the procedure won’t alter their chances of survival.

“I’m a big fan of giving people counseling upfront before surgery,” she said. “I try to give people time to think about it.”