Late Recurrence vs. Early Relapse of Breast Cancer

The "late recurrence" or relapse of breast cancer refers to cancers that come back after five years, but may not return for 10 years, 20 years, or even more. For people who have estrogen receptor-positive tumors, the cancer is actually more likely to recur after five years than in the first five years.

In contrast to the common belief that surviving for five years after cancer treatment is equivalent to a cure, with hormone-sensitive (estrogen and/or progesterone receptor-positive) breast tumors there is a steady rate of recurrence risk for at least 20 years after the original diagnosis, even with very small node-negative tumors.

An awareness of the risk of late recurrence is important for a number of reasons. People are often shocked to learn that their breast cancer has come back after say, 15 years, and loved ones who don't understand this risk are often less likely to be supportive as you cope with the fear of recurrence.

While chemotherapy has little effect on the risk of late recurrence hormonal therapy does, and estimating this risk may help determine who should receive extended hormonal therapy (beyond five years). Finally, late recurrences can differ from early relapse (within five years) with regard to sites of metastases and survival.

Factors such as initial tumor size, number of nodes involved, and receptor status play into the risk of late recurrence, but tumor biology appears to have the greatest effect, and research is actively looking for ways to look at gene expression and copy number to predict risk.

Incidence and Statistics

Hormone-sensitive breast cancers (those that are estrogen and/or progesterone receptor-positive) account for roughly 70% of breast cancers. It is these tumors that are more likely (more than 50%) to come back after five years than during the first five years after diagnosis, although some triple-negative tumors pose risk as well.

In the past, less was known about late metastases as many studies followed people for only a short period of time, for example, for a period of five years after diagnosis. To better understand the incidence of late recurrence, a 2017 study published in the New England Journal of Medicine looked at the incidence of recurrence between five years and 20 years post-diagnosis in people up to the age of 75 who had no evidence of cancer (were disease-free) after five years of hormonal therapy (tamoxifen or an aromatase inhibitor).

For those who had hormone receptor-positive tumors, there was a steady rate of recurrence each year from five years to 20 years. A small number of people with triple-negative breast cancer also experienced late recurrences.

Risk of Late Recurrence Is Underestimated

A survey led by the Canadian Breast Cancer Network found that women often underestimate their risk of late recurrence. In the survey, only 10% were aware of the risk of recurrence after five years of tamoxifen therapy, and 40% felt that they were cured after hitting the five-year mark.

Early Recurrence vs. Late Recurrence

A recurrence of breast cancer at any time can be devastating. While 6% to 10% of breast tumors are diagnosed when the disease is already metastatic (stage 4), 90% to 94% of metastatic breast cancers represent a distant recurrence of previous early-stage breast cancer (cancer that was originally stage I, stage II, or stage III).

Since distant metastases are responsible for around 90% of breast cancer deaths, finding ways to reduce the risk of recurrence is critical in improving the survival rate from the disease. Overall, it's estimated that around 30% of breast cancers will recur at distant sites.

Understanding Recurrence

Breast cancer recurrence can be local (within the breast), regional (involving nearby lymph nodes), or distant (with spread to areas such as the bones, lungs, liver, or brain). It is distant recurrences that are discussed here.

Risk Factors for Overall Recurrence

There are several risk factors that raise the risk of recurrence overall (combining both early and late recurrences). These include:

• Tumor size: Larger tumors are more likely to recur than smaller ones both early and late.
• Positive lymph nodes: Tumors that have spread to lymph nodes are more likely to recur at any time than those that have not.
• Age at diagnosis: Breast cancer recurrence is more common in younger people.
• Treatments received and response to treatments: Both chemotherapy and hormonal therapy (tamoxifen or aromatase inhibitors) reduce the risk of recurrence in the first five years.
• Tumor grade: More aggressive tumors (grade 3) are more likely to recur than less aggressive tumors (for example, grade 1), especially in the first five years.

There are also factors that do not appear to affect the risk of recurrence. Recurrence rates are the same for women who have a mastectomy or lumpectomy with radiation and are also the same for women who have a single vs. double mastectomy.

Receptor Status and Recurrence: Early and Late

In discussing receptor status and recurrence rates it's important to note that no two tumors are the same, and breast cancers—even those with the same receptor status—are a heterogeneous group of tumors. That said, receptor status plays a significant role in when recurrences may occur.

With estrogen receptor-negative tumors (HER2 positive or triple-negative), the risk of recurrence peaks at around two years post-diagnosis, and is relatively uncommon after five years.

Estrogen and/or progesterone receptor-positive tumors, in contrast, are more likely to recur more than five years post-diagnosis than in the first five years in people treated with hormonal therapy. That said, some hormone positive tumors are more likely to recur late than others.

Treatments and Recurrence: Early and Late

Treatments also play a role in both early and late recurrences. While chemotherapy can significantly reduce the risk of recurrence in the first five years, it has much less influence on the risk of late recurrence.

Hormonal therapy reduces the risk of recurrence in the first five years (it decreases risk by over a third with tamoxifen and even more so with aromatase inhibitors), but can also reduce the risk of late recurrences. It is this reduction in risk that has led to recommendations to extend hormonal therapy for people at high risk beyond five years.

Extending hormonal therapy from five years to 10 years has been shown to reduce the risk of late recurrence, but the risk of recurrence needs to be weighed against the side effects of continued therapy.

A 2019 study found that people with luminal A tumors continued to have significant benefit from tamoxifen therapy for 15 years post-diagnosis.

The addition of bisphosphonates (Zometa or Bonefos) to an aromatase inhibitor in post-menopausal women with early-stage breast cancer may improve survival, but it's too early to determine the effect on late recurrences. Bisphosphonates reduce the risk of bone metastases, but the most common sites of distant late recurrence are the brain, liver, and lungs.

Factors Associated With Late Recurrence

As noted earlier, risk factors for late recurrence can differ from those from recurrences that occur in the first five years.

Tumor Size and Lymph Node Status

The risk of recurrence is linked to the size of the original tumor as well as the number of positive lymph nodes, although these factors alone can't explain all recurrences. In the 2017 study noted earlier, for women who were cancer-free after five years of hormonal therapy, the risk of recurrence was highest for those who had large tumors that had spread to four or more lymph nodes (40% over the next 15 years), and lowest with small, node-negative tumors.

The risk of recurrence of these small, node-negative tumors, however, remains significant at roughly 1% per year until at least 20 years post-diagnosis. Due to the life expectancy of metastatic breast cancer (currently around three years), the risk of death lags somewhat behind recurrence.

Within these ranges, the risk of recurrence was greater in women who had larger tumors (T2) than smaller tumors (T1). Tumor grade and Ki-67 had only moderate predictive value, and progesterone receptor status and HER2 status had no predictive value in this study.

It's noteworthy that women who had one to three positive lymph nodes were twice as likely to have their cancer recur at distant locations between five years and 20 years post-diagnosis than in the first five years, and those who have node-negative tumors were roughly four times more likely to have a late than an early recurrence.

The constant rate of recurrence means that the risk that an estrogen receptor-positive breast cancer will recur between 15 years and 16 years post-diagnosis is the same as the risk that it will recur between five years and six years after diagnosis.

Progesterone Receptor Status

Tumors that are estrogen receptor-positive but progesterone negative appear to have a greater risk of recurrence in the first five years, especially in tumors that are highly proliferative.

The effect of progesterone receptor status on late recurrence is less clear, with conflicting results in different studies. A study published in Oncology looked at risk factors for recurrence after 10 years. In this study of 4774 patients, the 10-year disease-free survival rate was 79.5%, and the incidence of recurrence at 10 years and beyond was 5.8%. It was found that positive lymph nodes at the time of diagnosis as well as progesterone receptor-positive tumors were significantly correlated with very late recurrence.

Estrogen Receptor Positivity

Rather than simply "present or absent" there are different degrees of estrogen sensitivity, with some estrogen receptor-positive tumors being much more sensitive to the effect of estrogen than others. In a 2016 study, almost all people who experienced late relapses had high estrogen receptor titers (greater than or equal to 50%). Cancers with lower tumor grade were also more likely to recur after five years.

Impact of Late Recurrence

The impact of late distant recurrence cannot be stressed enough. Once breast cancer is metastatic, it is no longer curable. While there are some long term survivors with stage 4 breast cancer (metastatic), the average life expectancy is currently only around three years.

Predicting Late Recurrence

Given the importance of late distant relapse of breast cancer, researchers have looked at a number of ways to predict late recurrences.

A calculator (CTS-5 Calculator) is a tool that uses tumor size, number of lymph nodes, age, and tumor grade to predict distant recurrence after five years of endocrine therapy. It divides risk of recurrence over the next five years to 10 years into low risk (less than 5%), intermediate risk (5% to 10%) or high risk (greater than 10%).

Unfortunately, clinical, pathological (under the microscope), and immunohistochemical subtyping (receptor status) findings can give an estimate but are limited in their ability to predict late recurrence for any specific individual.

For this reason, researchers have been evaluating biological factors (molecular subtyping) to further narrow down who is at risk. Molecular subtypes can be divided into:

• Intrinsic subtypes, based on gene expression (PAM50)
• Integrative subtypes, based on copy number and gene expression (IntClust)

Overall, a panel of genomic tests appears to be much more accurate than any single individual test.

Intrinsic Subtypes and Late Recurrence

A number of different methods have been evaluated for the ability to predict late recurrence. Some of these include:

Higher expression of estrogen-responsive genes: A 2018 study found that people with ER+/HER2 negative breast cancers who had higher expression of estrogen-responsive genes (using mRNA profiles) and were not treated with extended hormonal therapy had a high risk of recurrence after five years.

Multigene assays: Several multigene assays may help predict late recurrence, but using this information to figure out when to extend hormonal therapy requires more research. A 2018 evaluation of an 18-gene, 10-year signature found that the information regarding prognosis was similar to other tests including Oncotype DX Recurrence Score, Prosigna PAM50 risk of recurrence score, Breast Cancer Index and IHC4.

Integrative Subtypes and Late Recurrence

Researchers recently developed a model to identify 11 integrative subtypes of breast cancer with different risks and timing of recurrence, according to the findings of a 2019 study published online in Nature.

Four integrative subtypes were identified that were associated with a high risk of late recurrence (a recurrence rate of 47% to 62%). Altogether, these four subtypes accounted for roughly 26% of breast cancers that were estrogen receptor-positive and HER2 negative.

These subtypes included tumors that had an enriched copy number alterations in genes that are thought to drive the growth of cancer (driver mutations or alterations), including:

• CCND1
• FGF3
• EMSY
• PAK1
• RSF1
• ZNF703
• FGFR1
• RPS6KB1
• MYC

(It's noteworthy that several of these are targetable, meaning that there are currently targeted therapies available that target the gene mutation or other alteration).

They were also able to identify a subgroup of triple-negative tumors that were unlikely to recur after five years as well as a subgroup in which people continue to be at risk of late recurrence. A Breast Cancer Recurrence Calculator including integrative subtypes has been developed but, at the current time, this is meant for research purposes alone.

Circulating Tumor Cells at 5 Years Post-Diagnosis

In addition, liquid biopsy (blood test samples) for the presence of circulating tumor cells at five years post-diagnosis may also help predict late recurrence.

In a 2018 study published in the Journal of the American Medical Association (JAMA), women who had cancer cells in their blood (circulating tumor cells) five years after diagnosis were roughly 13 times more likely to experience a recurrence as those who did not. The finding was significant only for women who had estrogen receptor-positive tumors, and none of the women who had circulating tumor cells in their blood but estrogen receptor-negative tumors experienced a recurrence.

That said, these findings, along with molecular subtyping offers hopes that doctors will be better able to predict who should receive extended hormonal therapy in the future.

Why Late Recurrence?

The reasons why cancer cells can lie dormant for extended periods of time has eluded researchers to date and is very difficult to study. Dormant cancer cells are difficult to detect, and animal models are lacking. Several hypotheses have been proposed to explain how these cells remain dormant and how they may be reactivated or "wake up." While dormant, these cells are in fact the greatest threat to people diagnosed with early-stage disease.

It's thought that in most cases, breast cancer cells metastasize (in small numbers or micrometastases) before cancer is detected, and roughly 30% of people with early-stage breast cancer have been found to have cancer cells in their bone marrow. Since these cells are not actively dividing, they aren't sensitive to treatments such as chemotherapy that interfere with cell division.

The tumor microenvironment also likely plays a role no matter the mechanism. Cancer cells don't work alone, but actually "recruit" normal cells nearby to assist in their growth and survival. Cross talk between metastatic cancer cells and the tumor microenvironment can affect immune surveillance (whether or not the immune system sees cancer cells), angiogenesis (the growth of new blood vessels that allows a tumor to grow), and more.

In 2019, scientists did discover a set of genes that appears to help keep some cancer cells (myeloma) dormant, offering hope that advances in the understanding of the biology of dormancy are near.

Given the importance of dormant cancer cells, the United Kingdom (U.K.) has set up a challenge (Grand Challenge Award) for scientists to identify and target dormant cancer cells. If treatments can be developed that keep cancer cells in their dormant state or instead can get rid of them even while they are dormant, major progress could be made in survival.

Reducing Risk of Late Recurrence

For people who have estrogen receptor-positive breast cancers (and some triple-negative tumors), reducing the risk of late recurrence is critical in order to reduce deaths from the disease.

Medical Treatment

While chemotherapy primarily reduces early recurrences, hormonal therapy can reduce the risk of late recurrence. Unfortunately, both tamoxifen and aromatase inhibitors have side effects that can reduce a person's quality of life, and the risks and benefits of extending treatment beyond five years must be weighed carefully for each individual. After five years of tamoxifen therapy, extending treatment for another five years of tamoxifen or an aromatase inhibitor reduces the risk of late recurrence by 2% to 5%.

There have been some studies (but not all) that suggest regular aspirin use is associated with a lower risk of recurrence, but aspirin is associated with side effects as well. A clinical trial is currently in progress that will hopefully better define the role of aspirin in this setting. Until then, people can talk to their oncologists about the benefits and risks, especially if there are other reasons why aspirin may be beneficial, such as to reduce the risk of heart disease.

What Women Can Do Themselves

There are some things women can do themselves to lower their risk of late recurrence:

• Regular exercise (30 minutes daily) is associated with a lower risk of death from breast cancer as well as death from all causes.
• It's important for everyone to have their vitamin D level tested, although the role of vitamin D is still uncertain. Vitamin D deficiency is associated with bone loss, a concern for most people who have coped with breast cancer.
• Losing weight if you are overweight, or maintaining a healthy weight is important as well.

Future Directions

Research is in progress not only to better understand who may have a late recurrence but to evaluate potential methods to reduce these recurrences. Studies are in progress looking at aspirin, omega-3-fatty acids, and adjuvant therapy—the "CLEVER" study with Afinitor (everolimus) and Plaquenil (hydroxycloroquine)—with the hope of targeting dormant cancer cells, and more.

Researchers are also wondering whether using CDK4/6 inhibitors, such as Ibrance (palbociclib) or Kisqali (ribocicib), in early-stage breast cancer might reduce recurrences, but there is no evidence at this time.

Keeping Dormant Cancer Cells From "Waking Up"

Despite the importance, research on what triggers dormant cancer cells to wake up is in its infancy.

Screening for Recurrence

Though there are some tests that may detect (see biomarker) breast cancer recurrence before symptoms are present, diagnosing a recurrence early has not been shown to improve survival rates at the current time.

Coping With the Fear of Recurrence

Coping with the fear of recurrence can be challenging, especially when the risk of recurrence persists as with estrogen receptor-positive breast cancers. In the past, many people sensed that if they hit the five-year mark, the chances they were home free were high. Longer-term research has, unfortunately, dispelled this belief.

Some degree of fear can be a good thing. An awareness that breast cancer can come back often prompts people to be careful with follow-up appointments and to pursue healthy lifestyle changes to reduce risk. Yet, too much fear can be paralyzing.

The Myth and Stigma of the "5-Year" Cure

Many people still believe that breast cancer, even hormone-positive disease, is essentially cured after five years; this can lead to misunderstandings in families. Loved ones who don't understand late recurrence may downplay your feelings, or criticize you when you think "brain tumor" each time you get a headache.

Until information on late recurrence becomes more widely known, and even though it's frustrating, you may need to educate loved ones about the risk, and why you should be concerned when you develop new or unexplained symptoms.

When Cancer Recurs After 5 Years

When cancer recurs at a distant site it is no longer early-stage breast cancer. The characteristics of cancer may change as well. Tumors that are initially estrogen receptor-positive may now be negative and vice versa (something referred to as "discordance"). HER2 status can also change.

For this reason, and because there are now a number of alterations that can be targeted (drugs that can treat specific genetic changes), it's important for people to have a biopsy and genetic testing of their tumor (such as next-generation sequencing).

Prognosis of Late vs. Early Cancer Recurrence

Late recurrence is associated with a better prognosis than early recurrence in estrogen receptor-positive breast cancer. A 2018 study in Clinical Breast Cancer found that survival after recurrence was significantly longer in people with a late versus early recurrence (52 months versus 40 months). In this study, the lungs were the most common site of late distant recurrence.

A Word From Verywell

Learning that late recurrences are common with hormone receptor-positive breast cancer can be disconcerting. The constant rate of recurrence after five years goes against popular opinion that surviving five years equates with a cure or, at least, each year you survive means a lower risk of recurrence.

While most often we hear of triple-negative or HER2 positive breast cancer being "worse," there are challenges regardless of the type of breast cancer you have. In some ways, hormone receptor-positive tumors are more treatable but may be less curable.

Every breast cancer is different, and even cancers of the same stage and receptor status are a heterogeneous group of tumors. For this reason, it's important to talk to your oncologist about your particular cancer. Some people clearly benefit from extended hormonal therapy (more than five years) but for others, the risks outweigh benefits.

As with all aspects of cancer care, addressing the risk of late recurrence requires you to be your own advocate in your care. Taking an active part in the breast cancer community can not only give you an opportunity to talk with others who are coping with the prolonged risk of recurrence, but to learn about the latest research into recurrence risk and possible options to lower the risk.