What makes breast cancer come back?

By Maria Cohut, Ph.D. on October 26, 2022 — Fact checked by Hannah Flynn

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Millions of people live with breast cancer, the most common form of cancer worldwide — and also, in most cases, one of the most treatable. However, even after successful treatment, breast cancer can recur. How does breast cancer spread, why does it sometimes come back, and can lifestyle changes help improve the prognosis for people with a breast cancer diagnosis? We discuss these and other questions in our monthly podcast.

According to data from the World Health Organization (WHO), in 2020 alone there were 2.3 million womenTrusted Source globally who received a diagnosis of breast cancer. Men can also develop breast cancer.

In the United States, approximately 264,000 womenTrusted Source and 2,400 men receive a breast cancer diagnosis each year, according to the Centers for Disease Control and Prevention (CDC). In the United Kingdom, there are about 55,500 new cases of breast cancer in women, and approximately 370 in men, as per Cancer Research UK data.

Breast cancer is thus easily the most commonly occurringTrusted Source form of cancer, but it is also one of the most treatable. “The average 5-year survival rate for women in the [US] with non-metastatic invasive breast cancer is 90%. The average 10-year survival rate for women with non-metastatic invasive breast cancer is 84%,” states the American Society of Clinical Oncology (ASCO) Foundation.

However, there are many different types of breast cancer, some more aggressive than others, which spread more easily and can be more difficult to treat. But why and how does cancer spread from the initial tumor to other parts of the body?

And why does breast cancer sometimes come back, or recur, in people whose initial breast cancer treatment was successful?

The current installment of our In Conversation podcast discusses these and other questions about breast cancer and recurrence risk. Our guests are Dr. Rachael Natrajan and Dr. Liz O’Riordan.

Dr. Natrajan is head of the functional genomics team in the Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research (ICR) in London. She specializes in the study of different breast cancer subtypes through the genetic analysis of cancer tumors, with a view to developing new treatments specific to each of these subtypes.

Dr. O’Riordan was a consultant breast cancer surgeon and is a breast cancer patient and advocate. She is the co-author of The Complete Guide to Breast Cancer: How to Feel Empowered and Take Control, a book that explains the different types of breast cancer treatment, and offers advice on how to cope emotionally, sexually, and physically with a breast cancer diagnosis. Her memoir, Under the Knife: The Rise and Fall of a Female Surgeon, is upcoming.

This feature is based on an edited and shortened record of the discussion featured in our podcast. You can listen to this episode of our podcast in full below or on your preferred platform.

Breast cancer: ‘A collection of diseases’

Breast cancer, like many chronic diseases, can take many forms, and while some types of breast cancer are easy to pick up, even in the early stages, others can be a lot more difficult to diagnose.

Dr. O’Riordan received her initial diagnosis of breast cancer in 2015, when it had already progressed to grade 3 breast cancer. “Basically, the higher the stage, the higher the cancer, the higher risk of it coming back,” she explained in the podcast.

“I had a sneaky cancer. Mine was not seen on a mammogram. It was 2 and a half centimeters on an ultrasound, and I just thought it was a cyst — and I have expert hands. An MRI showed it was actually 6 centimeters of mixed ductal and lobular cancer, ER-positive, HER2-negative.”

– Dr. Liz O’Riordan

Dr. O’Riordan then went through neoadjuvant chemotherapy, and she also underwent a mastectomy — and this was only the beginning of the lengthy combination of treatments she ultimately underwent.

“Lobular breast cancer is one of the rarer types [of breast cancer] and I think it’s important at this point to emphasize that breast cancer isn’t just one disease. It’s a collection of multiple diseases,” Dr. Natrajan noted.

She also went on to explain what it means to have ER-positive, HER2-negative breast cancer: “[I]t’s positive for the estrogen receptor, which means that the cells and the cancer express estrogen, which means in general, you’d be then eligible for estrogen deprivation therapy. People may have heard of drugs like tamoxifen or aromatase inhibitorsTrusted Source — they’ll work to suppress [the] signaling of estrogen, which […] drives the cells to keep dividing, keep proliferating.”

HER2 is [a] gene that in some breast cancers is highly expressed,” Dr. Natrajan added. “So the cells have lots of this protein circulating around and that drives how they grow, makes them more aggressive. But now there are therapies that suppress that growth, anti-HER2 therapies, so things like Herceptin.”

But why are some types of breast cancer easier to diagnose than others? We are taught to do thorough breast self-examinations to check for unusual lumps, which can be a sign of cancer. However, lumps do not always appear in breast cancer, explained Dr. Natrajan.

This can make it easier for the signs to slip by unnoticed during self-examinations, and even on mammograms.

“In the vast majority of women and men diagnosed with breast cancer, their cells stick together, as they’re called ductal cancers, whereas like Liz was saying […] she has a lobular breast cancer — that’s where there’s a defect in a protein called E-cadherin. It makes the cells not stick together, they grow in what we call single files — that means they’re less likely to be picked up on normal mammograms because they don’t follow the form of a solid mass.”

– Dr. Rachel Natrajan

All breast cancers respond differently

The specific form of breast cancer that a person has will also influence the form of therapy they receive to treat it. Dr. Natrajan and her collaborators are working to take that knowledge further by looking at the genetic makeup of cancer tumors, hoping that, ultimately, a better understanding of individual tumors may also lead to more targeted and effective treatments.

“In terms of the genetics, what’s going on at the DNA level, [cancers] look different as well,” said Dr. Natrajan. “Some lobular cancers have higher frequencies and mutations, and different genes. And we think some of this causes those cancers not to respond so well to certain therapies, particularly long-term.”

When asked how, exactly, some breast cancer cells manage to escape intense and aggressive forms of treatments, the researcher explained that “the selective pressure of the therapy itself can drive resistance,” meaning, in part, that some fast-dividing cells are able to evolve in such a way as to become resistant to the therapies they had initially responded to.

However, those that divide more slowly could also play a part in this equation:

“[O]ften chemotherapy and radiotherapy target cells that are growing and dividing quickly. But there may be slower cancer cells that haven’t found a ‘friend.’ And because their competition has gone, the fast cells have died, those slower-growing cells may mutate and start to grow again.”

Why does breast cancer recur?
The mechanism outlined by Dr. Natrajan can also be part of the reason why breast cancer sometimes comes back despite an initially successful treatment that has resulted in the removal of the original tumor.

Some cancer cells — that have left the original tumor site and reached other parts of the body, a process known as metastasis — enter a state of so-called dormancyTrusted Source, meaning that they are able to grow and divide, but for the moment remain stagnant.

Sometimes, many years after the initial cancer treatment, dormant cells can reawaken and give rise to new tumors in different parts of the body. These tumors may also be of a different kind compared to the original one — for example, they may have different receptors that make them more aggressive.

“I think [doctors] assume [that] any cancer that is invasive has the ability to spread and move around the body and any woman with an invasive cancer may have a couple of cells that have left that cancer and have gone into the lymph or the blood,” explained Dr. O’Riordan.

“The surgery is removing all the physical cancer the we can see. And the aim of chemo and radiotherapy and hormone treatments is to mop up any of those little cells floating around the body. So they’ve come from the original breast cancer, but they’re often dormant, they may start to wake up for whatever reason. And as they wake up, they can further mutate and change. So you may have very different receptors to the original breast cancer, but they have come from that original tumor.”

– Dr. Liz O’Riordan

“[T]here are so many different types of breast cancers. So you’ve got ER-positive, negative HER2-positive, negative lobular, ductal, triple negative, the different complications… And when they mutate and come back, a triple negative [breast cancer] can suddenly develop ER-positive cancers and the positive [metastases] can develop resistance,” she later added.

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